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1.	Singh, K. P., et al. (författare) Clinical standards for the management of adverse effects during treatment for TB 2023 Ingår i: The International Journal of Tuberculosis and Lung Disease. - : International Union Against Tuberculosis and Lung Disease. - 1027-3719 .- 1815-7920. ; 27:7, s. 506-519 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitiv-ity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person -centred, consensus-based approach to minimise the impact of AE TB treatment.
2.	Ayoun Alsoud, Rami, et al. (författare) Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development 2023 Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 14 Tidskriftsartikel (refereegranskat)abstract Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10-40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.
3.	Svensson, Elin M., 1985-, et al. (författare) The Potential for Treatment Shortening With Higher Rifampicin Doses : Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis 2018 Ingår i: Clinical Infectious Diseases. - : OXFORD UNIV PRESS INC. - 1058-4838 .- 1537-6591. ; 67:1, s. 34-41 Tidskriftsartikel (refereegranskat)abstract Background. Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin. Methods. Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed. Results. Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%-41%) to 55% (49%-61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L.h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109. Conclusions. Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority.
4.	Clewe, Oskar, 1986- (författare) Novel Pharmacometric Methods for Informed Tuberculosis Drug Development 2016 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract With approximately nine million new cases and the attributable cause of death of an estimated two millions people every year there is an urgent need for new and effective drugs and treatment regimens targeting tuberculosis. The tuberculosis drug development pathway is however not ideal, containing non-predictive model systems and unanswered questions that may increase the risk of failure during late-phase drug development. The aim of this thesis was hence to develop pharmacometric tools in order to optimize the development of new anti-tuberculosis drugs and treatment regimens.The General Pulmonary Distribution model was developed allowing for prediction of both rate and extent of distribution from plasma to pulmonary tissue. A distribution characterization that is of high importance as most current used anti-tuberculosis drugs were introduced into clinical use without considering the pharmacokinetic properties influencing drug distribution to the site of action. The developed optimized bronchoalveolar lavage sampling design provides a simplistic but informative approach to gathering of the data needed to allow for a model based characterization of both rate and extent of pulmonary distribution using as little as one sample per subject. The developed Multistate Tuberculosis Pharmacometric model provides predictions over time for a fast-, slow- and non-multiplying bacterial state with and without drug effect. The Multistate Tuberculosis Pharmacometric model was further used to quantify the in vitro growth of different strains of Mycobacterium tuberculosis and the exposure-response relationships of three first line anti-tuberculosis drugs. The General Pharmacodynamic Interaction model was successfully used to characterize the pharmacodynamic interactions of three first line anti-tuberculosis drugs, showing the possibility of distinguishing drug A’s interaction with drug B from drug B’s interaction with drug A. The successful separation of all three drugs effect on each other is a necessity for future work focusing on optimizing the selection of anti-tuberculosis combination regimens.With a focus on pharmacokinetics and pharmacodynamics, the work included in this thesis provides multiple new methods and approaches that individually, but maybe more important the combination of, has the potential to inform development of new but also to provide additional information of the existing anti-tuberculosis drugs and drug regimen.
5.	Janssen, Saskia, et al. (författare) Cough as Noninvasive Biomarker for Monitoring Tuberculosis Treatment : A Proof-of-Concept Study 2023 Ingår i: Annals of the American Thoracic Society. - : AMERICAN THORACIC SOCIETY. - 2329-6933 .- 2325-6621. ; 20:12, s. 1822-1825 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
6.	Svensson, Elin M, 1985- (författare) Pharmacometric Models to Improve Treatment of Tuberculosis 2016 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Tuberculosis (TB) is the world’s most deadly infectious disease and causes enormous public health problems. The comorbidity with HIV and the rise of multidrug-resistant TB strains impede successful therapy through drug-drug interactions and the lack of efficient second-line treatments. The aim of this thesis was to support the improvement of anti-TB therapy through development of pharmacometric models, specifically focusing on the novel drug bedaquiline, pharmacokinetic interactions and methods for pooled population analyses.A population pharmacokinetic model of bedaquiline and its metabolite M2, linked to semi-mechanistic models of body weight and albumin concentrations, was developed and used for exposure-response analysis. Treatment response was quantified by measurements of mycobacterial load and early bedaquiline exposure was found to significantly impact the half-life of bacterial clearance. The analysis represents the first successful characterization of a concentration-effect relationship for bedaquiline.Single-dose Phase I studies investigating potential interactions between bedaquiline and efavirenz, nevirapine, ritonavir-boosted lopinavir, rifampicin and rifapentine were analyzed with a model-based approach. Substantial effects were detected in several cases and dose-adjustments mitigating the impact were suggested after simulations. The interaction effects of nevirapine and ritonavir-boosted lopinavir were also confirmed in patients with multidrug-resistant TB on long-term treatment combining the antiretrovirals and bedaquiline. Furthermore, the outcomes from model-based analysis were compared to results from conventional non-compartmental analysis in a simulation study. Non-compartmental analysis was found to consistently underpredict the interaction effect when most of the concentration-time profile was not observed, as commonly is the case for compounds with very long terminal half-life such as bedaquiline.To facilitate pooled analyses of individual patient data from multiple sources a structured development procedure was outlined and a fast diagnostic tool for extensions of the stochastic model components was developed. Pooled analyses of nevirapine and rifabutin pharmacokinetics were performed; the latter generating comprehensive dosing recommendations for combined administration of rifabutin and antiretroviral protease inhibitors.The work presented in this thesis demonstrates the usefulness of pharmacometric techniques to improve treatment of TB and especially contributes evidence to inform optimized dosing regimens of new and old anti-TB drugs in various clinical contexts.
7.	Svensson, Robin J., et al. (författare) A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses 2018 Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 103:4, s. 674-683 Tidskriftsartikel (refereegranskat)abstract Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling. The final population pharmacokinetic model included an enzyme turnover model accounting for time-dependent elimination due to autoinduction, concentration-dependent clearance, and dose-dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis–Menten relationship. The relationship between bioavailability and dose was described using an Emax relationship. The model will be key in determining exposure–response relationships for rifampicin and should be considered when designing future trials and when treating future patients with high-dose rifampicin.
8.	Svensson, Robin J., et al. (författare) Greater Early Bactericidal Activity at Higher Rifampicin Doses Revealed by Modeling and Clinical Trial Simulations 2018 Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 218:6, s. 991-999 Tidskriftsartikel (refereegranskat)abstract Background. The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure-response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin.Methods. Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates.Results. The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25-10.3 days.Conclusions. A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin.
9.	Svensson, Robin J., et al. (författare) Model-Based Relationship between the Molecular Bacterial Load Assay and Time to Positivity in Liquid Culture 2019 Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 63:10 Tidskriftsartikel (refereegranskat)abstract The molecular bacterial load (MBL) assay is a new tuberculosis biomarker which provides results in ∼4 hours. The relationship between MBL and time-to-positivity (TTP) has not been thoroughly studied, and predictive models do not exist. We aimed to develop a model for MBL and identify the MBL-TTP relationship in patients. The model was developed on data from 105 tuberculosis patients from Malawi, Mozambique, and Tanzania with joint MBL and TTP observations quantified from patient sputum collected for 12 weeks. MBL was quantified using PCR of mycobacterial RNA and TTP using the mycobacterial growth indicator tube (MGIT) 960 system. Treatment consisted of isoniazid, pyrazinamide, and ethambutol in standard doses together with rifampin 10 or 35 mg/kg of body weight. The developed MBL-TTP model included several linked submodels, a component describing decline of bacterial load in sputum, another component describing growth in liquid culture, and a hazard model translating bacterial growth into a TTP signal. Additional components for contaminated and negative TTP samples were included. Visual predictive checks performed using the developed model gave good description of the observed data. The model predicted greater total sample loss for TTP than MBL due to contamination and negative samples. The model detected an increase in bacterial killing for 35 versus 10 mg/kg rifampin (P = 0.002). In conclusion, a combined model for MBL and TTP was developed that described the MBL-TTP relationship. The full MBL-TTP model or each submodel was used separately. Second, the model can be used to predict biomarker response for MBL given TTP data or vice versa in historical or future trials.
10.	Van Wijk, Rob C., 1991-, et al. (författare) Anti‐tuberculosis effect of isoniazid scales accurately from zebrafish to humans 2020 Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 177:24, s. 5518-5533 Tidskriftsartikel (refereegranskat)abstract Background and purposeThere is a strong need for innovation in anti-tuberculosis drug development. The zebrafish larva is an attractive disease model in tuberculosis research. To translate pharmacological findings to higher vertebrates, including humans, the internal exposure of drugs needs to be quantified and linked to observed response.Experimental approachIn zebrafish studies, drugs are commonly dissolved in the external water, posing a challenge to quantify internal exposure. We developed experimental methods to quantify internal exposure, including nano-scale blood sampling, and to quantify the bacterial burden, using automated fluorescence imaging analysis, with isoniazid as paradigm compound. We used pharmacokinetic-pharmacodynamic modelling to quantify the exposure-response relationship responsible for the antibiotic response. To translate isoniazid response to humans, the quantitative exposure-response relationship in zebrafish was linked to simulated concentration-time profiles in humans, and two quantitative translational factors on sensitivity to isoniazid and stage of infection were included.Key resultsBlood concentration was only 20% of the external drug concentration. The bacterial burden increased exponentially and an isoniazid dose corresponding to 15 mg·L-1internal concentration (minimum inhibitory concentration) lead to bacteriostasis of the mycobacterial infection in the zebrafish. The concentration-effect relationship was quantified, and based on that relationship and the translational factors, the isoniazid response was translated to humans, which correlated well with observed data.Conclusions and implicationsThis proof-of-concept confirms the potential of the zebrafish larvae as tuberculosis disease model in translational pharmacology, and contributes to innovative anti-tuberculosis drug development which is strongly needed.
11.	Van Wijk, Rob C., 1991-, et al. (författare) Quantification of Natural Growth of Two Strains of Mycobacterium Marinum for Translational Antituberculosis Drug Development 2020 Ingår i: Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 13:6, s. 1060-1064 Tidskriftsartikel (refereegranskat)abstract The zebrafish infected with Mycobacterium marinum (M. marinum) is an attractive tuberculosis disease model, showing similar pathogenesis to Mycobacterium tuberculosis (M. tuberculosis) infections in humans. To translate pharmacological findings from this disease model to higher vertebrates, a quantitative understanding of the natural growth of M. marinum in comparison to the natural growth of M. tuberculosis is essential. Here, the natural growth of two strains of M. marinum, E11 and MUSA, is studied over an extended period using an established model‐based approach, the multistate tuberculosis pharmacometric (MTP) model, for comparison to that of M. tuberculosis. Poikilotherm‐derived strain E11 and human‐derived strain MUSA were grown undisturbed up to 221 days and viability of cultures (colony forming unit (CFU)/mL) was determined by plating at different time points. Nonlinear mixed effects modeling using the MTP model quantified the bacterial growth, the transfer among fast, slow, and non‐multiplying states, and the inoculi. Both strains showed initial logistic growth, reaching a maximum after 20–25 days for E11 and MUSA, respectively, followed by a decrease to a new plateau. Natural growth of both E11 and MUSA was best described with Gompertz growth functions. For E11, the inoculum was best described in the slow‐multiplying state, for MUSA in the fast‐multiplying state. Natural growth of E11 was most similar to that of M. tuberculosis, whereas MUSA showed more aggressive growth behavior. Characterization of natural growth of M. marinum and quantitative comparison with M. tuberculosis brings the zebrafish tuberculosis disease model closer to the quantitative translational pipeline of antituberculosis drug development.
12.	Van Wijk, Rob C, 1991-, et al. (författare) Seasonal influence on respiratory tract infection severity including COVID-19 quantified through Markov Chain modeling 2023 Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 12:9, s. 1250-1261 Tidskriftsartikel (refereegranskat)abstract Respiratory tract infections (RTIs) are a burden to global health, but their characterization is complicated by the influence of seasonality on incidence and severity. The Re-BCG-CoV-19 trial (NCT04379336) assessed BCG (re)vaccination for protection from coronavirus disease 2019 (COVID-19) and recorded 958 RTIs in 574 individuals followed over 1 year. We characterized the probability of RTI occurrence and severity using a Markov model with health scores (HSs) for four states of symptom severity. Covariate analysis on the transition probability between HSs explored the influence of demographics, medical history, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), or influenza vaccinations, which became available during the trial, SARS-CoV-2 serology, and epidemiology-informed seasonal influence of infection pressure represented as regional COVID-19 pandemic waves, as well as BCG (re)vaccination. The infection pressure reflecting the pandemic waves increased the risk of RTI symptom development, whereas the presence of SARS-CoV-2 antibodies protected against RTI symptom development and increased the probability of symptom relief. Higher probability of symptom relief was also found in participants with African ethnicity and with male biological gender. SARS-CoV-2 or influenza vaccination reduced the probability of transitioning from mild to healthy symptoms. Model diagnostics over calendar-time indicated that COVID-19 cases were under-reported during the first wave by an estimated 2.76-fold. This trial was performed during the initial phase of the COVID-19 pandemic in South Africa and the results reflect that situation. Using this unique clinical dataset of prospectively studied RTIs over the course of 1 year, our Markov Chain model was able to capture risk factors for RTI development and severity, including epidemiology-informed infection pressure.
13.	Alffenaar, Jan-Willem C., et al. (författare) Pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs : An evaluation of in vitro, in vivo methodologies and human studies 2022 Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13 Forskningsöversikt (refereegranskat)abstract There has been an increased interest in pharmacokinetics and pharmacodynamics (PKPD) of anti-tuberculosis drugs. A better understanding of the relationship between drug exposure, antimicrobial kill and acquired drug resistance is essential not only to optimize current treatment regimens but also to design appropriately dosed regimens with new anti-tuberculosis drugs. Although the interest in PKPD has resulted in an increased number of studies, the actual bench-to-bedside translation is somewhat limited. One of the reasons could be differences in methodologies and outcome assessments that makes it difficult to compare the studies. In this paper we summarize most relevant in vitro, in vivo, in silico and human PKPD studies performed to optimize the drug dose and regimens for treatment of tuberculosis. The in vitro assessment focuses on MIC determination, static time-kill kinetics, and dynamic hollow fibre infection models to investigate acquisition of resistance and killing of Mycobacterium tuberculosis populations in various metabolic states. The in vivo assessment focuses on the various animal models, routes of infection, PK at the site of infection, PD read-outs, biomarkers and differences in treatment outcome evaluation (relapse and death). For human PKPD we focus on early bactericidal activity studies and inclusion of PK and therapeutic drug monitoring in clinical trials. Modelling and simulation approaches that are used to evaluate and link the different data types will be discussed. We also describe the concept of different studies, study design, importance of uniform reporting including microbiological and clinical outcome assessments, and modelling approaches. We aim to encourage researchers to consider methods of assessing and reporting PKPD of anti-tuberculosis drugs when designing studies. This will improve appropriate comparison between studies and accelerate the progress in the field.
14.	Ayoun Alsoud, Rami, 1992- (författare) Pharmacometric tools to support translational drug development 2024 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The use of model-informed drug development has been shown to save significant costs and improve decision making early in the drug development process. The work in this PhD thesis aimed to employ pharmacometric tools to support translational drug development from the preclinical to the late clinical stages.Pharmacometric modeling was used to characterize the treatment-shortening potential of different anti tuberculosis regimens. The results provided additional evidence in favor of the treatment-shortening capacity of the BPaMZ regimen over BPaL and standard of care, HRZE.Pharmacokinetic-pharmacodynamic (PKPD) modeling was used to enable the evaluation of the exposure-response of a new anti-tubercular drug, MPL-447, in C3HeB/FeJ mice, thought to be of a translational value in tuberculosis drug development. Model-based evaluation revealed a significant impact of necrotic lesion development in mice on both bacterial growth and sensitivity to treatment with MPL-447, highlighting the significance of accounting for the heterogenous lesion profile in the C3HeB/FeJ mouse model when evaluating drug efficacy.Pharmacokinetic (PK) modeling was employed to perform interspecies PK scaling of the CB 4332 protein using information from three preclinical species. This approach accounted for the impact of immunogenicity and species-related differences in elimination. Simulations predicted the protein plasma concentrations in humans after different dosing regimens and suggested that a 7 mg/kg dose would be required to reach the target at steady-state.Using combined biomarker data, PKPD modeling was employed to simultaneously analyze two tuberculosis efficacy biomarkers. The final biomarker model facilitated the prediction of the relationship between the two biomarkers over time. With this modeling framework, missing biomarker data can be predicted using information from the other biomarker.Several model-based approaches were also explored to evaluate pediatric study power in rare diseases. These approaches were performed analyzing pediatric data alone or combined with the adult data. While Bayesian priors performed well when analyzing pediatric data alone, less technical modeling approaches proved sufficient when pediatric and adult data were combined.In conclusion, the research presented in this thesis has addressed various challenges encountered in translational drug development. The work has contributed to the evaluation of new anti-tubercular drugs and regimens, the assessment of newly proposed animal models, and optimizing the utilization of biomarker information. Furthermore, this thesis has provided insights into the selection of First-in-Human dose for a protein, showcasing the applicability of model-based approaches in this critical decision-making process. The research has contributed to improving analysis approaches for pediatrics in rare diseases.
15.	De Jager, Veronique, et al. (författare) Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis : The COMRADE Randomized, Phase 2A Clinical Trial 2022 Ingår i: American Journal of Respiratory and Critical Care Medicine. - : American Thoracic Society. - 1073-449X .- 1535-4970. ; 205:10, s. 1228-1235 Tidskriftsartikel (refereegranskat)abstract Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain.Objectives: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin.Methods: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBA(CFU0-14)) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13.Measurements and Main Results: Sixty participants enrolled. Median EBA(CFU0-14) counts (2.5th-97.5th percentiles) were 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-037), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log(10) h), for arms C-F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events.Conclusions: Bactericidal activity was greater with the World Health Organization-recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens.
16.	Faraj, Alan, et al. (författare) Drug effect of clofazimine on persisters explain an unexpected increase in bacterial load from patients Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Tuberculosis (TB) drug development is dependent on informative trials to secure development of new antibiotics and combination regimens. Clofazimine (CFZ) and pyrazinamid (PZA) are important components of recommended standard multi-drug treatments of TB. Paradoxically, in a Phase IIa trial aiming to define the early bactericidal activity (EBA) of CFZ and PZA monotherapy over the first 14 days of treatment, no significant drug effect was demonstrated for the two drugs using traditional statistical analysis. Using a model-based analysis we characterized statistically significant exposure-response relationships for both drugs that could explain the original findings of increase in colony forming units (CFU) with CFZ treatment and no effect with PZA. Sensitive analyses are crucial for exploring drug effects in early clinical trials to make right decisions for advancement to further development. We propose that this quantitative semi-mechanistic approach provides a rational framework for analysing Phase IIa EBA studies, and can accelerate anti-TB drug development.
17.	Faraj, Alan, et al. (författare) Drug Effect of Clofazimine on Persisters Explains an Unexpected Increase in Bacterial Load in Patients 2020 Ingår i: Antimicrobial Agents and Chemotherapy. - : AMER SOC MICROBIOLOGY. - 0066-4804 .- 1098-6596. ; 64:5 Tidskriftsartikel (refereegranskat)abstract Antituberculosis (anti-TB) drug development is dependent on informative trials to secure the development of new antibiotics and combination regimens. Clofazimine (CLO) and pyrazinamide (PZA) are important components of recommended standard multidrug treatments of TB. Paradoxically, in a phase IIa trial aiming to define the early bactericidal activity (EBA) of CLO and PZA monotherapy over the first 14 days of treatment, no significant drug effect was demonstrated for the two drugs using traditional statistical analysis. Using a model-based analysis, we characterized the statistically significant exposure-response relationships for both drugs that could explain the original findings of an increase in the numbers of CFU with CLO treatment and no effect with PZA. Sensitive analyses are crucial for exploring drug effects in early clinical trials to make the right decisions for advancement to further development. We propose that this quantitative semimechanistic approach provides a rational framework for analyzing phase IIa EBA studies and can accelerate anti-TB drug development.
18.	Faraj, Alan (författare) Pharmacometric models to inform dose selection and study design : Applied in hemophilia and tuberculosis 2024 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract While tuberculosis is a global pandemic, hemophilia is a rare disease which many have not heard of. Due to tuberculosis mainly being a problem in developing countries and hemophilia being a rare disease, they are not as heard of as other diseases such as cancer or metabolic diseases which are on the rise in Western societies. The quality of life for patients suffering from these diseases is notably impaired and novel drugs are warranted to further improve the treatment and management of both diseases. As market incentives are a limiting factor, it is important that the efforts that are taken to develop novel drugs are carried out in an informative manner. One strategy to incorporate as much information as possible to inform decision making in drug development is to use pharmacometric methods. Such strategies enable simultaneous analysis of different types of data that are generated during drug development programs. In this thesis, the aim was to develop and apply pharmacometric models to facilitate dose selection and study designs in clinical programs that aim at developing new drugs for tuberculosis and hemophilia. A standardized analysis approach of early clinical trials studying drugs against tuberculosis was presented including power calculations that showed the number of patients needed to detect drug effects. Such efforts are important as showing drug effect in early trials will aid decision making into significantly longer and costlier late trials. The approach was used to analyze a clinical trial studying if the current dose of meropenem can be lowered without negatively impacting drug effects and improving the already poor tolerability of the drug. The study found that lowering the dose may lower activity without any improvement of the tolerability properties. Furthermore, population pharmacokinetic models were developed for two novel hemostatic drugs in development for prophylactic and on-demand treatment of hemophilia. Based on the models, clinical trials in adult and pediatric subjects were supported. One of the trials were performed and it was showed with a model-based analysis that the new drug which is given subcutanously has similar efficacy as current intravenously given standard of care alternatives. Using the developed models, different strategies for designing pharmacokinetic trials in children was also presented. In conclusion, the work performed within this thesis has contributed to the development of new drugs against tuberculosis and hemophilia.
19.	Forsman, LD, et al. (författare) Suboptimal moxifloxacin and levofloxacin drug exposure during treatment of patients with multidrug-resistant tuberculosis: results from a prospective study in China 2021 Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 57:3 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
20.	Keutzer, Lina, et al. (författare) Derivation and Clinical Utility of Safety Targets for Linezolid-Related Adverse Events in Drug-Resistant Tuberculosis Treatment 2023 Ingår i: Pharmaceuticals. - : MDPI. - 1424-8247. ; 16:11 Tidskriftsartikel (refereegranskat)abstract Long-term usage of linezolid can result in adverse events such as peripheral neuropathy, anemia and thrombocytopenia. Therapeutic drug monitoring data from 75 drug-resistant tuberculosis patients treated with linezolid were analyzed using a time-to-event (TTE) approach for peripheral neuropathy and anemia and indirect response modelling for thrombocytopenia. Different time-varying linezolid pharmacokinetic exposure indices (AUC0-24h,ss, Cav, Cmax and Cmin) and patient characteristics were investigated as risk factors. A treatment duration shorter than 3 months was considered dropout and was modelled using a TTE approach. An exposure-response relationship between linezolid Cmin and both peripheral neuropathy and anemia was found. The exposure index which best described the development of thrombocytopenia was AUC0-24h. The final TTE dropout model indicated an association between linezolid Cmin and dropout. New safety targets for each adverse event were proposed which can be used for individualized linezolid dosing. According to the model predictions at 6 months of treatment, a Cmin of 0.11 mg/L and 1.4 mg/L should not be exceeded to keep the cumulative probability to develop anemia and peripheral neuropathy below 20%. The AUC0-24h should be below 111 h center dot mg/L or 270 h center dot mg/L to prevent thrombocytopenia and severe thrombocytopenia, respectively. A clinical utility assessment showed that the currently recommended dose of 600 mg once daily is safer compared to a 300 mg BID dosing strategy considering all four safety endpoints.
21.	Koele, Simon E., et al. (författare) Early bactericidal activity studies for pulmonary tuberculosis : A systematic review of methodological aspects 2023 Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 61:5 Forskningsöversikt (refereegranskat)abstract A milestone in the development of novel antituberculosis drugs is the demonstration of early bactericidal activity (EBA) in a phase IIa clinical trial. The significant variability in measurements of bacterial load complicates data analysis in these trials.A systematic review and evaluation of methods for determination of EBA in pulmonary tuberculosis studies was undertaken. Bacterial load quantification biomarkers, reporting intervals, calculation methods, statistical testing, and handling of negative culture results were extracted. In total, 79 studies were identi-fied in which EBA was determined. Colony-forming units on solid culture media and/or time-to-positivity in liquid media were the biomarkers used most often, reported in 72 (91%) and 34 (43%) studies, respec-tively. Twenty-two different reporting intervals were presented, and 12 different calculation methods for EBA were identified. Statistical testing for a significant EBA compared with no change was performed in 54 (68%) studies, and between-group testing was performed in 32 (41%) studies. Negative culture result handling was discussed in 34 (43%) studies.Notable variation was found in the analysis methods and reporting of EBA studies. A standardized and clearly reported analysis method, accounting for different levels of variability in the data, could aid the generalization of study results and facilitate comparison between drugs/regimens.
22.	Mockeliunas, Laurynas, et al. (författare) Model-Informed Precision Dosing of Linezolid in Patients with Drug-Resistant Tuberculosis 2022 Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:4 Tidskriftsartikel (refereegranskat)abstract Linezolid is an efficacious medication for the treatment of drug-resistant tuberculosis but has been associated with serious safety issues that can result in treatment interruption. The objectives of this study were thus to build a population pharmacokinetic model and to use the developed model to establish a model-informed precision dosing (MIPD) algorithm enabling safe and efficacious dosing in patients with multidrug- and extensively drug-resistant tuberculosis. Routine hospital therapeutic drug monitoring data, collected from 70 tuberculosis patients receiving linezolid, was used for model development. Efficacy and safety targets for MIPD were the ratio of unbound area under the concentration versus time curve between 0 and 24 h over minimal inhibitory concentration (fAUC(0-24h)/MIC) above 119 and unbound plasma trough concentration (fC(min)) below 1.38 mg/L, respectively. Model building was performed in NONMEM 7.4.3. The final population pharmacokinetic model consisted of a one-compartment model with transit absorption and concentration- and time-dependent auto-inhibition of elimination. A flat dose of 600 mg once daily was appropriate in 67.2% of the simulated patients from an efficacy and safety perspective. Using the here developed MIPD algorithm, the proportion of patients reaching the efficacy and safety target increased to 81.5% and 88.2% using information from two and three pharmacokinetic sampling occasions, respectively. This work proposes an MIPD approach for linezolid and suggests using three sampling occasions to derive an individualized dose that results in adequate efficacy and fewer safety concerns compared to flat dosing.
23.	Mockeliunas, Laurynas, et al. (författare) Risk Factors for COVID-19 and Respiratory Tract Infections during the Coronavirus Pandemic 2024 Ingår i: Vaccines. - : MDPI. - 2076-393X. ; 12:3 Tidskriftsartikel (refereegranskat)abstract (1) Background: Some individuals are more susceptible to developing respiratory tract infections (RTIs) or coronavirus disease (COVID-19) than others. The aim of this work was to identify risk factors for symptomatic RTIs including COVID-19 and symptomatic COVID-19 during the coronavirus pandemic by using infection incidence, participant baseline, and regional COVID-19 burden data. (2) Methods: Data from a prospective study of 1000 frontline healthcare workers randomized to Bacillus Calmette-Gu & eacute;rin vaccination or placebo, and followed for one year, was analyzed. Parametric time-to-event analysis was performed to identify the risk factors associated with (a) non-specific symptomatic respiratory tract infections including COVID-19 (RTIs+COVID-19) and (b) symptomatic RTIs confirmed as COVID-19 using a polymerase chain reaction or antigen test (COVID-19). (3) Results: Job description of doctor or nurse (median hazard ratio [HR] 1.541 and 95% confidence interval [CI] 1.299-1.822), the reported COVID-19 burden (median HR 1.361 and 95% CI 1.260-1.469 for 1.4 COVID-19 cases per 10,000 capita), or a BMI > 30 kg/m(2) (median HR 1.238 and 95% CI 1.132-1.336 for BMI of 35.4 kg/m(2)) increased the probability of RTIs+COVID-19, while positive SARS-CoV-2 serology at enrollment (median HR 0.583 and 95% CI 0.449-0.764) had the opposite effect. The reported COVID-19 burden (median HR 2.372 and 95% CI 2.116-2.662 for 1.4 COVID-19 cases per 10,000 capita) and a job description of doctor or nurse (median HR 1.679 and 95% CI 1.253-2.256) increased the probability of developing COVID-19, while smoking (median HR 0.428 and 95% CI 0.284-0.648) and positive SARS-CoV-2 serology at enrollment (median HR 0.076 and 95% CI 0.026-0.212) decreased it. (4) Conclusions: Nurses and doctors with obesity had the highest probability of developing RTIs including COVID-19. Non-smoking nurses and doctors had the highest probability of developing COVID-19 specifically. The reported COVID-19 burden increased the event probability, while positive SARS-CoV-2 IgG serology at enrollment decreased the probability of RTIs including COVID-19, and COVID-19 specifically.
24.	Mockeliunas, Laurynas, et al. (författare) Standards for model-based early bactericidal activity analysis and sample size determination in tuberculosis drug development 2023 Ingår i: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 14 Tidskriftsartikel (refereegranskat)abstract Background: A critical step in tuberculosis (TB) drug development is the Phase 2a early bactericidal activity (EBA) study which informs if a new drug or treatment has short-term activity in humans. The aim of this work was to present a standardized pharmacometric model-based early bactericidal activity analysis workflow and determine sample sizes needed to detect early bactericidal activity or a difference between treatment arms.Methods: Seven different steps were identified and developed for a standardized pharmacometric model-based early bactericidal activity analysis approach. Non-linear mixed effects modeling was applied and different scenarios were explored for the sample size calculations. The sample sizes needed to detect early bactericidal activity given different TTP slopes and associated variability was assessed. In addition, the sample sizes needed to detect effect differences between two treatments given the impact of different TTP slopes, variability in TTP slope and effect differences were evaluated.Results: The presented early bactericidal activity analysis approach incorporates estimate of early bactericidal activity with uncertainty through the model-based estimate of TTP slope, variability in TTP slope, impact of covariates and pharmacokinetics on drug efficacy. Further it allows for treatment comparison or dose optimization in Phase 2a. To detect early bactericidal activity with 80% power and at a 5% significance level, 13 and 8 participants/arm were required for a treatment with a TTP-EBA(0-14) as low as 11 h when accounting for variability in pharmacokinetics and when variability in TTP slope was 104% [coefficient of variation (CV)] and 22%, respectively. Higher sample sizes are required for smaller early bactericidal activity and when pharmacokinetics is not accounted for. Based on sample size determinations to detect a difference between two groups, TTP slope, variability in TTP slope and effect difference between two treatment arms needs to be considered.Conclusion: In conclusion, a robust standardized pharmacometric model-based EBA analysis approach was established in close collaboration between microbiologists, clinicians and pharmacometricians. The work illustrates the importance of accounting for covariates and drug exposure in EBA analysis in order to increase the power of detecting early bactericidal activity for a single treatment arm as well as differences in EBA between treatments arms in Phase 2a trials of TB drug development.
25.	Svensson, Robin J., et al. (författare) Improved power for TB Phase IIa trials using a model-based pharmacokinetic-pharmacodynamic approach compared with commonly used analysis methods 2017 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 72:8, s. 2311-2319 Tidskriftsartikel (refereegranskat)abstract Background: The demand for new anti-TB drugs is high, but development programmes are long and costly. Consequently there is a need for new strategies capable of accelerating this process.Objectives: To explore the power to find statistically significant drug effects using a model-based pharmacokinetic-pharmacodynamic approach in comparison with the methods commonly used for analysing TB Phase IIa trials.Methods: Phase IIa studies of four hypothetical anti-TB drugs (labelled A, B, C and D), each with a different mechanism of action, were simulated using the multistate TB pharmacometric (MTP) model. cfu data were simulated over 14 days for patients taking once-dailymonotherapy at four different doses per drug and a reference (10mg/kg rifampicin). The simulated data were analysed using t-test, ANOVA, mono-and bi-exponential models and a pharmacokinetic-pharmacodynamic model approach (MTP model) to establish their respective power to find a drug effect at the 5% significance level.Results: For the pharmacokinetic-pharmacodynamic model approach, t-test, ANOVA, mono-exponential model and bi-exponential model, the sample sizes needed to achieve 90% power were: 10, 30, 75, 20 and 30 (drug A); 30, 75, 245, 75 and 105 (drug B); 70, > 1250, 315, > 1250 and >1250 (drug C); and 30, 110, 710, 170 and 185 (drug D), respectively.Conclusions: A model-based design and analysis using a pharmacokinetic-pharmacodynamic approach can reduce the number of patients required to determine a drug effect at least 2-fold compared with current methodologies. This could significantly accelerate early-phase TB drug development.
26.	Svensson, Robin J., 1989- (författare) Pharmacometric Models to Improve the Treatment and Development of Drugs against Tuberculosis 2019 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract With 10 million new infections yearly, tuberculosis has a major impact on the human well-being of the world. Most patients have infections susceptible to a first-line treatment with a treatment success rate of 80%, a number that can potentially be improved by optimising the first-line treatment. Besides susceptible disease, each year half a million patients are infected by tuberculosis with resistance to first-line treatment where only 50% of patients get cured. Thus, new drugs against resistant tuberculosis are desperately needed but given the inefficiency of developing new anti-tuberculosis drugs, enough new drugs will not reach patients in time. The aim of this thesis was to develop pharmacometric models to optimise the development and use of current and future drugs for treating tuberculosis.A population pharmacokinetic model for rifampicin, the most prominent first-line drug, was developed and later used for developing exposure-response models followed by clinical trial simulations. The developed exposure-response models were based on liquid culture data and were expanded to describe the relationship between liquid culture results and a new biomarker, the molecular bacterial load assay which is a quicker alternative to liquid culture and is also contamination-free.The in vitro-derived semi-mechanistic Multistate Tuberculosis Pharmacometric (MTP) model was applied to clinical rifampicin and clofazimine colony forming unit datasets. This novel application of the MTP model allowed detection of statistically significant exposure-response relationships between rifampicin and clofazimine for the specific killing of non-multiplying, persister bacteria. Furthermore, the MTP model was compared to conventional statistical analyses for detecting drug effects in Phase IIa. If designing and analysing Phase IIa using the MTP model, the required sample size for detecting drug effects can be lowered. An improved design and analysis of pre-clinical treatment outcome assessments was developed which increased the information gain compared to a conventional design yet kept the animal use at a minimum. Lastly, a therapeutic drug monitoring approach was suggested based on updated targets for rifampicin, a framework easily expandable to second-line drugs.In conclusion this thesis presents the development of pharmacometric models which will streamline both the development and use of drugs against tuberculosis.
27.	Upton, Caryn M., et al. (författare) Safety and efficacy of BCG re-vaccination in relation to COVID-19 morbidity in healthcare workers : A double- blind, randomised, controlled, phase 3 trial 2022 Ingår i: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 48 Tidskriftsartikel (refereegranskat)abstract Background BCG vaccination prevents severe childhood tuberculosis (TB) and was introduced in South Africa in the 1950s. It is hypothesised that BCG trains the innate immune system by inducing epigenetic and functional reprogramming, thus providing non-specific protection from respiratory tract infections. We evaluated BCG for reduction of morbidity and mortality due to COVID-19 in healthcare workers in South Africa. Methods This randomised, double-blind, placebo-controlled trial recruited healthcare workers at three facilities in the Western Cape, South Africa, unless unwell, pregnant, breastfeeding, immunocompromised, hypersensitivity to BCG, or undergoing experimental COVID-19 treatment. Participants received BCG or saline intradermally (1:1) and were contacted once every 4 weeks for 1 year. COVID-19 testing was guided by symptoms. Hospitalisation, COVID-19, and respiratory tract infections were assessed with Cox proportional hazard modelling and time-to-event analyses, and event severity with post hoc Markovian analysis. This study is registered with ClinicalTrials.gov, NCT04379336. Findings Between May 4 and Oct 23, 2020, we enrolled 1000 healthcare workers with a median age of 39 years (IQR 30-49), 70.4% were female, 16.5% nurses, 14.4% medical doctors, 48.5% had latent TB, and 15.3% had evidence of prior SARS-CoV-2 exposure. Hospitalisation due to COVID-19 occurred in 15 participants (1.5%); ten (66.7%) in the BCG group and five (33.3%) in the placebo group, hazard ratio (HR) 2.0 (95% CI 0.69-5.9, p= 0.20), indicating no statistically significant protection. Similarly, BCG had no statistically significant effect on COVID-19 (p= 0.63, HR = 1.08, 95% CI 0.82-1.42). Two participants (0.2%) died from COVID-19 and two (0.2%) from other reasons, all in the placebo group. Interpretation BCG did not protect healthcare workers from SARS-CoV-2 infection or related severe COVID-19 disease and hospitalisation.
28.	Van Wijk, Rob C, 1991-, et al. (författare) Reproducibility in pharmacometrics applied in a phase III trial of BCG-vaccination for COVID-19 2023 Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13 Tidskriftsartikel (refereegranskat)abstract Large clinical trials often generate complex and large datasets which need to be presented frequently throughout the trial for interim analysis or to inform a data safety monitory board (DSMB). In addition, reliable and traceability are required to ensure reproducibility in pharmacometric data analysis. A reproducible pharmacometric analysis workflow was developed during a large clinical trial involving 1000 participants over one year testing Bacillus Calmette-Guerin (BCG) (re)vaccination in coronavirus disease 2019 (COVID-19) morbidity and mortality in frontline health care workers. The workflow was designed to review data iteratively during the trial, compile frequent reports to the DSMB, and prepare for rapid pharmacometric analysis. Clinical trial datasets (n = 41) were transferred iteratively throughout the trial for review. An RMarkdown based pharmacometric processing script was written to automatically generate reports for evaluation by the DSMB. Reports were compiled, reviewed, and sent to the DSMB on average three days after the data cut-off, reflecting the trial progress in real-time. The script was also utilized to prepare for the trial pharmacometric analyses. The same source data was used to create analysis datasets in NONMEM format and to support model script development. The primary endpoint analysis was completed three days after data lock and unblinding, and the secondary endpoint analyses two weeks later. The constructive collaboration between clinical, data management, and pharmacometric teams enabled this efficient, timely, and reproducible pharmacometrics workflow.
29.	Wicha, Sebastian G., et al. (författare) Forecasting Clinical Dose-Response From Preclinical Studies in Tuberculosis Research : Translational Predictions With Rifampicin 2018 Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 104:6, s. 1208-1218 Tidskriftsartikel (refereegranskat)abstract A crucial step for accelerating tuberculosis drug development is bridging the gap between preclinical and clinical trials. In this study, we developed a preclinical model-informed translational approach to predict drug effects across preclinical systems and early clinical trials using the in vitro-based Multistate Tuberculosis Pharmacometric (MTP) model using rifampicin as an example. The MTP model predicted rifampicin biomarker response observed in 1) a hollow-fiber infection model, 2) a murine study to determine pharmacokinetic/pharmacodynamic indices, and 3) several clinical phase IIa early bactericidal activity (EBA) studies. In addition, we predicted rifampicin biomarker response at high doses of up to 50 mg/kg, leading to an increased median EBA(0-2 days) (90% prediction interval) of 0.513 log CFU/mL/day (0.310; 0.701) compared to the standard dose of 10 mg/kg of 0.181 log/CFU/mL/day (0.076; 0.483). These results suggest that the translational approach could assist in the selection of drugs and doses in early-phase clinical tuberculosis trials.
30.	Ayoun Alsoud, Rami, et al. (författare) Model-based effect evaluation of a novel Mmpl3 inhibitor in C3HeB/FeJ compared to BALB/c mouse models and translation to humans Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Background and Purpose: During tuberculosis drug development, the design of early clinical studies is informed by preclinical animal models. The aim of this work was to describe the exposure-response relationship of a novel inhibitor of mycobacterial MmpL3, prodrug MPL-447, in C3HeB/FeJ mice with non-necrotic or necrotic lesions, and to compare to chronic BALB/c mice information.Experimental Approach: C3HeB/FeJ mice were randomised to placebo and three treatment groups (25, 50 or 100 mg/kg MPL-447). Colony forming unit (CFU) were obtained until week 8 post-treatment. Semi-mechanistic modelling was used to describe growth and killing in relation to exposure. Early bactericidal activity after 14 days (EBA0-14) in humans was predicted using the final model, translational factors and allometric scaling of pharmacokinetics to humans and compared to chronic BALB/c.Key Results: The final model showed 1100% growth and 42% killing of the fast-multiplying bacteria in C3HeB/FeJ mice with necrotic lesions compared to those with non-necrotic lesions. Simulations revealed similar log10CFU reduction on day 14 in C3HeB/FeJ mice with non-necrotic lesions as in chronic BALB/c mice in response to treatment, but 1.7-fold lower reduction in C3HeB/FeJ mice with necrotic lesions. Similar human EBA0-14 was predicted irrespective of the mouse model used. Conclusion and Implications: The difference in killing of fast-multiplying bacteria in C3HeB/FeJ mice with necrotic lesions compared to C3HeB/FeJ mice without or chronic BALB/C mice was not translated to human early clinical predictions, most likely due to low abundance of these bacteria in humans.
31.	Ayoun Alsoud, Rami, et al. (författare) Model-based interspecies scaling for predicting human pharmacokinetics of CB 4332, a complement factor I protein Annan publikation (övrigt vetenskapligt/konstnärligt)abstract The extrapolation of a protein pharmacokinetics (PK) from preclinical to clinical studies can be less reliable than for small molecules. CB 4332 is a 150 kDa recombinant complement factor I (CFI) protein. In order to support clinical development, interspecies scaling of CB 4332 using traditional and model-based approaches was performed to inform first-in-human (FIH) dose selection. Plasma concentration versus time data from four preclinical PK studies of single intravenous (i.v.) and subcutaneous (s.c.) CB 4332 dosing in mice, rats and nonhuman primates (NHPs) were modeled simultaneously using naive pooling including allometric scaling. The human-equivalent dose was calculated using the preclinical no observed adverse effect level (NOAEL) as part of the dose-by-factor approach. Pharmacokinetic modelling of CB 4332 revealed species-specific differences in the elimination, which was accounted for by including an additional rat-specific clearance. Signs of anti-drug antibodies (ADA) formation in all rats and some NHPs were observed. Consequently, an additional ADA-induced clearance parameter was estimated including the time of onset. Using the traditional dose-by-factor approach, a maximum recommended starting s.c. dose of 0.9 mg/kg once weekly was calculated using the NOAEL observed in NHPs. The model-based clinical trial simulations predicted it to result in a trough concentration at steady state 12.8% of the determined efficacy target for CB 4332 in humans. Interspecies scaling was performed for CB 4332 using traditional and model-based scaling, where PK modeling allowed the inclusion of preclinical PK information from three species, accounted for potential effects of ADA and species differences in elimination, and allowed the prediction of human PK for FIH dose selection.
32.	Björnsson, Marcus A., et al. (författare) Modelling of pain intensity and informative dropout in a dental pain model after naproxcinod, naproxen and placebo administration 2011 Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 71:6, s. 899-906 Tidskriftsartikel (refereegranskat)abstract AIMS To describe pain intensity (PI) measured on a visual analogue scale (VAS) and dropout due to request for rescue medication after administration of naproxcinod, naproxen or placebo in 242 patients after wisdom tooth removal. METHODS Non-linear mixed effects modelling was used to describe the plasma concentrations of naproxen, either formed from naproxcinod or from naproxen itself, and their relationship to PI and dropout. Goodness of fit was assessed by simultaneous simulations of PI and dropout. RESULTS Baseline PI for the typical patient was 52.7 mm. The PI was influenced by placebo effects, using an exponential model, and by naproxen concentrations using a sigmoid E-max model. Typical maximal placebo effect was a decrease in PI by 20.2%, with an onset rate constant of 0.237 h-1. EC50 was 0.135 mu mol l-1. A Weibull time-to-event model was used for the dropout, where the hazard was dependent on the predicted PI and by the PI at baseline. Since the dropout was not at random, it was necessary to include the simulated dropout in visual predictive checks (VPC) of PI. CONCLUSIONS This model describes the relationship between drug effects, PI and the likelihood of dropout after naproxcinod, naproxen and placebo administration. The model provides an opportunity to describe the effects of other doses or formulations, after dental extraction. VPC created by simultaneous simulations of PI and dropout provides a good way of assessing the goodness of fit when there is informative dropout.
33.	Chen, Chunli, et al. (författare) Assessing Pharmacodynamic Interactions in Mice using the Multistate Tuberculosis Pharmacometric and General Pharmacodynamic Interaction Models 2017 Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 6:11, s. 787-797 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract The aim of this study was to investigate pharmacodynamic (PD) interactions in mice infected with Mycobacterium tuberculosis using population pharmacokinetics (PKs), the Multistate Tuberculosis Pharmacometric (MTP) model, and the General Pharmacodynamic Interaction (GPDI) model. Rifampicin, isoniazid, ethambutol, or pyrazinamide were administered in monotherapy for 4 weeks. Rifampicin and isoniazid showed effects in monotherapy, whereas the animals became moribund after 7 days with ethambutol or pyrazinamide alone. No PD interactions were observed against fast-multiplying bacteria. Interactions between rifampicin and isoniazid on killing slow and non-multiplying bacteria were identified, which led to an increase of 0.86 log(10) colony-forming unit (CFU)/lungs at 28 days after treatment compared to expected additivity (i.e., antagonism). An interaction between rifampicin and ethambutol on killing non-multiplying bacteria was quantified, which led to a decrease of 2.84 log(10) CFU/lungs at 28 days after treatment (i.e., synergism). These results show the value of pharmacometrics to quantitatively assess PD interactions in preclinical tuberculosis drug development.
34.	Chen, Chunli, et al. (författare) Comparisons of analysis methods for assessment of pharmacodynamic interactions including design recommendations 2018 Ingår i: AAPS Journal. - : Springer Science and Business Media LLC. - 1550-7416. ; 20 Tidskriftsartikel (refereegranskat)abstract Quantitative evaluation of potential pharmacodynamic (PD) interactions is important in tuberculosis drug development in order to optimize Phase 2b drug selection and ultimately to define clinical combination regimens. In this work, we used simulations to (1) evaluate different analysis methods for detecting PD interactions between two hypothetical anti-tubercular drugs in in vitro time-kill experiments, and (2) provide design recommendations for evaluation of PD interactions. The model used for all simulations was the Multistate Tuberculosis Pharmacometric (MTP) model linked to the General Pharmacodynamic Interaction (GPDI) model. Simulated data were re-estimated using the MTP–GPDI model implemented in Bliss Independence or Loewe Additivity, or using a conventional model such as an Empirical Bliss Independence-based model or the Greco model based on Loewe Additivity. The GPDI model correctly characterized different PD interactions (antagonism, synergism, or asymmetric interaction), regardless of the underlying additivity criterion. The commonly used conventional models were not able to characterize asymmetric PD interactions, i.e., concentration-dependent synergism and antagonism. An optimized experimental design was developed that correctly identified interactions in ≥ 94% of the evaluated scenarios using the MTP–GPDI model approach. The MTP–GPDI model approach was proved to provide advantages to other conventional models for assessing PD interactions of anti-tubercular drugs and provides key information for selection of drug combinations for Phase 2b evaluation.
35.	Clewe, Oskar, et al. (författare) A model-based analysis identifies differences in phenotypic resistance between in vitro and in vivo : implications for translational medicine within tuberculosis. 2020 Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 47:5, s. 421-430 Tidskriftsartikel (refereegranskat)abstract Proper characterization of drug effects on Mycobacterium tuberculosis relies on the characterization of phenotypically resistant bacteria to correctly establish exposure-response relationships. The aim of this work was to evaluate the potential difference in phenotypic resistance in in vitro compared to murine in vivo models using CFU data alone or CFU together with most probable number (MPN) data following resuscitation with culture supernatant. Predictions of in vitro and in vivo phenotypic resistance i.e. persisters, using the Multistate Tuberculosis Pharmacometric (MTP) model framework was evaluated based on bacterial cultures grown with and without drug exposure using CFU alone or CFU plus MPN data. Phenotypic resistance and total bacterial number in in vitro natural growth observations, i.e. without drug, was well predicted by the MTP model using only CFU data. Capturing the murine in vivo total bacterial number and persisters during natural growth did however require re-estimation of model parameter using both the CFU and MPN observations implying that the ratio of persisters to total bacterial burden is different in vitro compared to murine in vivo. The evaluation of the in vitro rifampicin drug effect revealed that higher resolution in the persister drug effect was seen using CFU and MPN compared to CFU alone although drug effects on the other bacterial populations were well predicted using only CFU data. The ratio of persistent bacteria to total bacteria was predicted to be different between in vitro and murine in vivo. This difference could have implications for subsequent translational efforts in tuberculosis drug development.
36.	Clewe, Oskar, et al. (författare) A model-informed preclinical approach for prediction of clinical pharmacodynamic interactions of anti-TB drug combinations 2018 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 73:2, s. 437-447 Tidskriftsartikel (refereegranskat)abstract Background: Identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting for many reasons. The aim of this work was to develop a model-informed preclinical approach for prediction of clinical pharmacodynamic drug interactions in order to inform early anti-TB drug development.Methods: In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The multistate TB pharmacometric (MTP) model was used to characterize the natural growth and exposure-response relationships of each drug after mono exposure. Pharmacodynamic interactions during combination exposure were characterized by linking the MTP model to the general pharmacodynamic interaction (GPDI) model with successful separation of the potential effect on each drug's potency (EC50) by the combining drug(s).Results: All combinations showed pharmacodynamic interactions at cfu level, where all combinations, except isoniazid plus ethambutol, showed more effect (synergy) than any of the drugs alone. Using preclinical information, the MTP-GPDI modelling approach was shown to correctly predict clinically observed pharmacodynamic interactions, as deviations from expected additivity.Conclusions: With the ability to predict clinical pharmacodynamic interactions, using preclinical information, the MTP-GPDI model approach outlined in this study constitutes groundwork for model-informed input to the development of new and enhancement of existing anti-TB combination regimens.
37.	Clewe, Oskar, et al. (författare) A multistate tuberculosis pharmacometric model : a framework for studying anti-tubercular drug effects in vitro 2016 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 71:4, s. 964-974 Tidskriftsartikel (refereegranskat)abstract ObjectivesMycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states.MethodsThe natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time–kill curves from log-phase (0.25–16 mg/L) and stationary-phase (0.5–64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure–response relationships.ResultsThe final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R2 = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively.ConclusionsThe model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro.
38.	Ekqvist, David, et al. (författare) Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin : a study protocol of a phase II clinical trial (HighShort-RP) 2022 Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:3 Tidskriftsartikel (refereegranskat)abstract Introduction: Increased dosing of rifampicin and pyrazinamide seems a viable strategy to shorten treatment and prevent relapse of drug-susceptible tuberculosis (TB), but safety and efficacy remains to be confirmed. This clinical trial aims to explore safety and pharmacokinetics-pharmacodynamics of a high-dose pyrazinamide-rifampicin regimen.Methods and analysis: Adult patients with pulmonary TB admitted to six hospitals in Sweden and subjected to receive first-line treatment are included. Patients are randomised (1:3) to either 6-month standardised TB treatment or a 4-month regimen based on high-dose pyrazinamide (40 mg/kg) and rifampicin (35 mg/kg) along with standard doses of isoniazid and ethambutol. Plasma samples for measurement of drug exposure determined by liquid chromatography tandem-mass spectrometry are obtained at 0, 1, 2, 4, 6, 8, 12 and 24 hours, at day 1 and 14. Maximal drug concentration (C-max) and area under the concentration-time curve (AUC(0-24h)) are estimated by non-compartmental analysis. Conditions for early model-informed precision dosing of high-dose pyrazinamide-rifampicin are pharmacometrically explored. Adverse drug effects are monitored throughout the study and graded according to Common Terminology Criteria for Adverse Events V.5.0. Early bactericidal activity is assessed by time to positivity in BACTEC MGIT 960 of induced sputum collected at day 0, 5, 8, 15 and week 8. Minimum inhibitory concentrations of first-line drugs are determined using broth microdilution. Disease severity is assessed with X-ray grading and a validated clinical scoring tool (TBscore II). Clinical outcome is registered according to WHO definitions (2020) in addition to occurrence of relapse after end of treatment. Primary endpoint is pyrazinamide AUC(0-24h) and main secondary endpoint is safety.Ethics and dissemination: The study is approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. Informed written consent is collected before study enrolment. The study results will be submitted to a peer-reviewed journal.
39.	Faraj, Alan, et al. (författare) Difference in persistent tuberculosis bacteria between in vitro and sputum from patients : implications for translational predictions 2020 Ingår i: Scientific Reports. - : NATURE RESEARCH. - 2045-2322. ; 10:1 Tidskriftsartikel (refereegranskat)abstract This study aimed to investigate the number of persistent bacteria in sputum from tuberculosis patients compared to in vitro and to suggest a model-based approach for accounting for the potential difference. Sputum smear positive patients (n=25) provided sputum samples prior to onset of chemotherapy. The number of cells detected by conventional agar colony forming unit (CFU) and most probable number (MPN) with Rpf supplementation were quantified. Persistent bacteria was assumed to be the difference between MPNrpf and CFU. The difference in persistent bacteria between in vitro and human sputum prior to chemotherapy was quantified using different model-based approaches. The persistent bacteria in sputum was 17% of the in vitro levels, suggesting a difference in phenotypic resistance, whereas no difference was found for multiplying bacterial subpopulations. Clinical trial simulations showed that the predicted time to 2 log fall in MPNrpf in a Phase 2a setting using in vitro pre-clinical efficacy information, would be almost 3 days longer if drug response was predicted ignoring the difference in phenotypic resistance. The discovered phenotypic differences between in vitro and humans prior to chemotherapy could have implications on translational efforts but can be accounted for using a model-based approach for translating in vitro to human drug response.
40.	Faraj, Alan, et al. (författare) Model-based approaches to prospectively power pediatric pharmacokinetic trials with limited sample size Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Rare disease studies in pediatric subjects are challenging due to small sample sizes. Pharmacokinetic (PK) information in pediatric subjects is important and often used for matching strategy towards adults informing pediatric development program. Prior to studying PK in children, it is important to optimize the sparse sampling schedule and show that the study is designed to estimate key PK parameters with sufficient certainty. In this work, the sampling schedule in children was optimized for marzeptacog alfa activated (MarzAA) and dalcinonacog alfa (DalcA), two drugs in development for treatment of hemophilia. Subsequently, evaluation of different model-based approaches to calculate the power to estimate clearance (CL) and volume of distribution (V) using a fixed sample size (n=24) was performed. Usage of Bayesian priors (up to 2x inflation of the adult priors) performed well (power 80 %), but with lower power with decreasing informativeness (5x and 10x inflation of the adult priors), in particular for DalcA. Reusing the full adult model or a simplified model for standalone analysis of the pediatric data did not perform well (<80% power). Fixing the adult PK parameters except for CL and V performed well when pooling adult and pediatric data (power 100 %). In general, the power to estimate V alone or CL together with V was lower than for CL, indicating that the sampling schedules were more informative for CL. Although Bayesian prior approaches were shown to perform well without need of pooling data, other approaches that require less technical expertise and no need for simplification of the adult model were found to be good alternatives when pooling of data is possible.
41.	Faraj, Alan, et al. (författare) Model-informed pediatric dose selection of marzeptacog alfa (activated) : An exposure matching strategy 2023 Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 12:7, s. 977-987 Tidskriftsartikel (refereegranskat)abstract Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human rFVII variant intended for subcutaneous (s.c.) administration to treat or prevent bleeding in individuals with hemophilia A (HA) or B (HB) with inhibitors, and other rare bleeding disorders. The s.c. administration provides benefits over i.v. injections. The objective of the study was to support the first-in-pediatric dose selection for s.c. MarzAA to treat episodic bleeding episodes in children up through 11 years in a registrational phase III trial. Assuming the same exposure-response relationship as in adults, an exposure matching strategy was used with a population pharmacokinetics model. A sensitivity analysis evaluating the impact of doubling in absorption rate and age-dependent allometric exponents on dose selection was performed. Subsequently, the probability of trial success, defined as the number of successful trials for a given pediatric dose divided by the number of simulated trials (n = 1000) was studied. A successful trial was defined as outcome where four, three, or two out of 24 pediatric subjects per trial were allowed to fall outside the adult exposures after s.c. administration of 60 mu g/kg. A dose of 60 mu g/ kg in children with HA/HB was supported by the clinical trial simulations to match exposures in adults. The sensitivity analyses further supported selection of the 60 mu g/kg dose level in all age groups. Moreover, the probability of trial success evaluations given a plausible design confirmed the potential of a 60 mu g/kg dose level. Taken together, this work demonstrates the utility of model-informed drug development and could be helpful for other pediatric development programs for rare diseases.
42.	Faraj, Alan, et al. (författare) Model-Informed Support of Dose Selection for Prophylactic Treatment with Dalcinonacog Alfa in Adult and Paediatric Hemophilia B Patients 2023 Ingår i: Advances in Therapy. - : Springer Nature. - 0741-238X .- 1865-8652. ; 40:9, s. 3739-3750 Tidskriftsartikel (refereegranskat)abstract IntroductionDalcinonacog alfa (DalcA), a novel subcutaneously administered recombinant human factor IX (FIX) variant is being developed for adult and paediatric patients with hemophilia B (HB). DalcA has been shown to raise FIX to clinically meaningful levels in adults with HB. This work aimed to support dosing regimen selection in adults and perform first-in-paediatric dose extrapolations using a model-based pharmacokinetic (PK) approach.MethodsA population PK model was built using adult data from two clinical trials (NCT03186677, NCT03995784). With allometry in the model, clinical trial simulations were performed to study alternative dosing regimens in adults and children. Steady-state trough levels and the time-to-reach target were derived to inform dose selection.ResultsAlmost 90% of the adults were predicted to achieve desirable FIX levels, i.e. 10% FIX activity, following daily 100 IU/kg dosing, with 90% of the subjects reaching target within 1.6-7.1 days. No every-other-day regimen met the target. A dose of 125 IU/kg resulted in adequate FIX levels down to 6 years, whereas a 150 IU/kg dose was needed below 6 down to 2 years of age. For subjects down to 6 years that did not reach target with 125 IU/kg, a dose escalation to 150 IU/kg was appropriate. The children below 6 to 2 years were shown to need a dose escalation to 200 IU/kg if 150 IU/kg given daily was insufficient.ConclusionThis study supported the adult dose selection for DalcA in the presence of sparse data and enabled first-in-paediatric dose selection to achieve FIX levels that reduce risk of spontaneous bleeds.
43.	Faraj, Alan, et al. (författare) Phase III dose selection of marzeptacog alfa (activated) informed by population pharmacokinetic modeling : A novel hemostatic drug 2022 Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 11:12, s. 1628-1637 Tidskriftsartikel (refereegranskat)abstract Marzeptacog alfa (activated) (MarzAA) is an activated recombinant human FVII (rFVIIa) variant developed as subcutaneous (s.c.) administration for the treatment or prevention of bleeding episodes in patients with hemophilia A (HA) or hemophilia B (HB) with inhibitors and other rare bleeding disorders. Population pharmacokinetic (PK) modeling was applied for dose selection for a pivotal phase III clinical trial evaluating s.c. MarzAA for episodic treatment of spontaneous or traumatic bleeding episodes. The population PK model used MarzAA intravenous and s.c. data from previously completed clinical trials in patients with HA/HB with or without inhibitors. Based on the model, clinical trial simulations were performed to predict MarzAA exposure after different dosing regimens. The exposure target was identified using an exposure-matching strategy with a wild-type rFVIIa but adjusting for the difference in potency between the two compounds. Simulations demonstrated a sufficient absorption rate and prolonged exposure following a single 60 μg/kg dose leading to 51% and 70% of the population reaching levels above the target after 3 and 6 h, respectively. According to the phase III protocol, if a second dose was required after 3 h because of a lack of efficacy, 90% of the population was observed to be above target 6 h after the initial dose. The model-informed drug development approach integrated information from several trials and guided dose selection in the pivotal phase III clinical trial for episodic treatment of an acute bleeding event in individuals with HA or HB with inhibitors without the execution of a phase II trial for that indication.
44.	Faraj, Alan, et al. (författare) Subcutaneous Marzeptacog Alfa (Activated) for On‐Demand Treatment of Bleeding Events in Subjects With Hemophilia A or B With Inhibitors 2024 Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 115:3, s. 498-505 Tidskriftsartikel (refereegranskat)abstract Marzeptacog alfa (MarzAA) is under development for subcutaneous treatment of episodic bleeds in patients with hemophilia A/B and was studied in a phase III trial evaluating MarzAA compared with standard-of-care (SoC) for on-demand use. The work presented here aimed to evaluate MarzAA and SoC treatment of bleeding events on a standardized four-point efficacy scale (poor, fair, good, and excellent). Two continuous-time Markov modeling approaches were explored; a four-state model analyzing all four categories of bleeding improvement and a two-state model analyzing a binarized outcome (treatment failure (poor/fair), and treatment success (good/excellent)). Different covariates impacting improvement of bleeding episodes as well as a putative relationship between MarzAA exposure and improvement of bleeding episodes were evaluated. In the final four-state model, higher baseline diastolic blood pressure and higher age (> 33 years of age) were found to negatively and positively impact improvement of bleeding condition, respectively. Bleeding events occurring in knees and ankles were found to improve faster than bleeding events at other locations. The covariate effects had most impact on early treatment success (≤ 3 hours) whereas at later timepoints (> 12 hours), treatment success was similar for all patients indicating that these covariates might be clinically relevant for early treatment response. A statistically significant relationship between MarzAA zero-order absorption and improvement of bleedings (P < 0.05) were identified albeit with low precision. No statistically significant difference in treatment response between MarzAA and intravenous SoC was identified, indicating the potential of MarzAA for treatment of episodic bleeding events with a favorable subcutaneous administration route.
45.	Forsman, Lina Davies, et al. (författare) Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China : a study protocol of a prospective observational cohort study 2018 Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 8:9 Tidskriftsartikel (refereegranskat)abstract Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in multidrug-resistant TB (MDR-TB) are scarce. This translational study aims to characterise the area under the concentration-time curve of individual MDR-TB drugs, divided by the MIC for Mycobacterium tuberculosis isolates, to explore associations with markers of treatment progress and to develop useful strategies for clinical implementation of TDM in MDR-TB.Methods and analysis: Adult patients with pulmonary MDR-TB treated in Xiamen, China, are included. Plasma samples for measure of drug exposure are obtained at 0, 1, 2, 4, 6, 8 and 10 hours after drug intake at week 2 and at 0, 4 and 6 hours during weeks 4 and 8. Sputum samples for evaluating time to culture positivity and MIC determination are collected at days 0, 2 and 7 and at weeks 2, 4, 8 and 12 after treatment initiation. Disease severity are assessed with a clinical scoring tool (TBscore II) and quality of life evaluated using EQ-5D-5L. Drug concentrations of pyrazinamide, ethambutol, levofloxacin, moxifloxacin, cycloserine, prothionamide and para-aminosalicylate are measured by liquid chromatography tandem-mass spectrometry and the levels of amikacin measured by immunoassay. Dried blood spot on filter paper, to facilitate blood sampling for analysis of drug concentrations, is also evaluated. The MICs of the drugs listed above are determined using custom-made broth microdilution plates and MYCOTB plates with Middlebrook 7H9 media. MIC determination of pyrazinamide is performed in BACTEC MGIT 960.Ethics and dissemination: This study has been approved by the ethical review boards of Karolinska Institutet, Sweden and Fudan University, China. Informed written consent is given by participants. The study results will be submitted to a peer-reviewed journal. Trial registration number NCT02816931; Pre-results.
46.	Gupta, Neeraj, et al. (författare) Transforming Translation Through Quantitative Pharmacology for High-Impact Decision Making in Drug Discovery and Development 2020 Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 107:6, s. 1285-1289 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
47.	Jönsson, Siv, et al. (författare) Population Pharmacokinetics of Ethambutol in South African Tuberculosis Patients 2011 Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 55:9, s. 4230-4237 Tidskriftsartikel (refereegranskat)abstract Ethambutol, one of four drugs in the first-line antitubercular regimen, is used to protect against rifampin resistance in the event of preexisting resistance to isoniazid. The population pharmacokinetics of ethambutol in South African patients with pulmonary tuberculosis were characterized using nonlinear mixed-effects modeling. Patients from 2 centers were treated with ethambutol (800 to 1,500 mg daily) combined with standard antitubercular medication. Plasma concentrations of ethambutol were measured following multiple doses at steady state and were determined using a validated high-pressure liquid chromatography-tandem mass spectrometric method. The data comprised 189 patients (54% male, 12% HIV positive) weighing 47 kg, on average (range, 29 to 86 kg), and having a mean age of 36 years (range, 16 to 72 years). The estimated creatinine clearance was 79 ml/min (range, 23 to 150 ml/min). A two-compartment model with one transit compartment prior to first-order absorption and allometric scaling by body weight on clearance and volume terms was selected. HIV infection was associated with a 15% reduction in bioavailability. Renal function was not related to ethambutol clearance in this cohort. Interoccasion variability exceeded interindividual variability for oral clearance (coefficient of variation, 36 versus 20%). Typical oral clearance in this analysis (39.9 liters/h for a 50-kg individual) was lower than that previously reported, a finding partly explained by the differences in body weight between the studied populations. In summary, a population model describing the pharmacokinetics of ethambutol in South African tuberculosis patients was developed, but additional studies are needed to characterize the effects of renal function.
48.	Keutzer, Lina, et al. (författare) A modeling-based proposal for safe and efficacious reintroduction of bedaquiline after dose interruption : A population pharmacokinetics study 2022 Ingår i: CPT. - : John Wiley & Sons. - 2163-8306. ; 11:5, s. 628-639 Tidskriftsartikel (refereegranskat)abstract Bedaquiline (BDQ) is recommended for treatment of multidrug-resistant tuberculosis (MDR-TB) for the majority of patients. Given its long terminal half-life and safety concerns, such as QTc-prolongation, re-introducing BDQ after multiple dose interruption is not intuitive and there are currently no existing guidelines. In this simulation-based study, we investigated different loading dose strategies for BDQ re-introduction, taking safety and efficacy into account. Multiple scenarios of time and length of interruption as well as BDQ re-introduction, including no loading dose, 1- and 2-week loading doses (200 mg and 400 mg once daily), were simulated from a previously published population pharmacokinetic (PK) model describing BDQ and its main metabolite M2 PK in patients with MDR-TB. The efficacy target was defined as 95.0% of the average BDQ concentration without dose interruption during standard treatment. Because M2 is the main driver for QTc-prolongation, the safety limit was set to be below the maximal average M2 metabolite concentration in a standard treatment. Simulations suggest that dose interruptions between treatment weeks 3 and 72 (interruption length: 1 to 6 weeks) require a 2-week loading dose of 200 mg once daily in the typical patient. If treatment was interrupted for longer than 8 weeks, a 2-week loading dose (400 mg once daily) was needed to reach the proposed efficacy target, slightly exceeding the safety limit. In conclusion, we here propose a strategy for BDQ re-introduction providing guidance to clinicians for safe and efficacious BDQ dosing.
49.	Keutzer, Lina, et al. (författare) Individualized Dosing With High Inter-Occasion Variability Is Correctly Handled With Model-Informed Precision Dosing : Using Rifampicin as an Example 2020 Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11 Tidskriftsartikel (refereegranskat)abstract Rifampicin exhibits complexities in its pharmacokinetics (PK), including high inter-occasion variability (IOV), which is challenging for dose individualization. Model-informed precision dosing (MIPD) can be used to optimize individual doses. In this simulation-based study we investigated the magnitude of IOV in rifampicin PK on an exposure level, the impact of not acknowledging IOV when performing MIPD, and the number of sampling occasions needed to forecast the dose. Subjects with drug-susceptible tuberculosis (TB) were simulated from a previously developed population PK model. To explore the magnitude of IOV, the area under the plasma concentration-time curve from time zero up to 24 h (AUC0–24h) after 35 mg/kg in the typical individual was simulated for 1,000 sampling occasions at steady-state. The impact of ignoring IOV for dose predictions was investigated by comparing the prediction error of a MIPD approach including IOV to an approach ignoring IOV. Furthermore, the number of sampling occasions needed to predict individual doses using a MIPD approach was assessed. The AUC0–24h in the typical individual varied substantially between simulated sampling occasions [95% prediction interval (PI): 122.2 to 331.2 h mg/L], equivalent to an IOV in AUC0–24h of 25.8%, compared to an inter-individual variability of 25.4%. The median of the individual prediction errors using a MIPD approach incorporating IOV was 0% (75% PI: −14.6% to 0.0%), and the PI for the individual prediction errors was narrower with than without IOV (median: 0%, 75% PI: −14.6% to 20.0%). The most common target dose in this population was forecasted correctly in 95% of the subjects when IOV was included in MIPD. In subjects where doses were not predicted optimally, a lower dose was predicted compared to the target, which is favorable from a safety perspective. Moreover, the imprecision (relative root mean square error) and bias in predicted doses using MIPD with IOV decreased statistically significant when a second sampling occasion was added (difference in imprecision: −9.1%, bias: −7.7%), but only marginally including a third (difference in imprecision: −0.1%, bias: −0.1%). In conclusion, a large variability in exposure of rifampicin between occasions was shown. In order to forecast the individual dose correctly, IOV must be acknowledged which can be achieved using a MIPD approach with PK information from at least two sampling occasions.
50.	Keutzer, Lina, et al. (författare) Machine Learning and Pharmacometrics for Prediction of Pharmacokinetic Data : Differences, Similarities and Challenges Illustrated with Rifampicin 2022 Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 14:8 Tidskriftsartikel (refereegranskat)abstract Pharmacometrics (PM) and machine learning (ML) are both valuable for drug development to characterize pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetic/pharmacodynamic (PKPD) analysis using PM provides mechanistic insight into biological processes but is time- and labor-intensive. In contrast, ML models are much quicker trained, but offer less mechanistic insights. The opportunity of using ML predictions of drug PK as input for a PKPD model could strongly accelerate analysis efforts. Here exemplified by rifampicin, a widely used antibiotic, we explore the ability of different ML algorithms to predict drug PK. Based on simulated data, we trained linear regressions (LASSO), Gradient Boosting Machines, XGBoost and Random Forest to predict the plasma concentration-time series and rifampicin area under the concentration-versus-time curve from 0-24 h (AUC(0-24h)) after repeated dosing. XGBoost performed best for prediction of the entire PK series (R-2: 0.84, root mean square error (RMSE): 6.9 mg/L, mean absolute error (MAE): 4.0 mg/L) for the scenario with the largest data size. For AUC(0-24h) prediction, LASSO showed the highest performance (R-2: 0.97, RMSE: 29.1 h center dot mg/L, MAE: 18.8 h center dot mg/L). Increasing the number of plasma concentrations per patient (0, 2 or 6 concentrations per occasion) improved model performance. For example, for AUC(0-24h) prediction using LASSO, the R-2 was 0.41, 0.69 and 0.97 when using predictors only (no plasma concentrations), 2 or 6 plasma concentrations per occasion as input, respectively. Run times for the ML models ranged from 1.0 s to 8 min, while the run time for the PM model was more than 3 h. Furthermore, building a PM model is more time- and labor-intensive compared with ML. ML predictions of drug PK could thus be used as input into a PKPD model, enabling time-efficient analysis.

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