| 1. |
- Ayoun Alsoud, Rami, et al.
(author)
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Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development
- 2023
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In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 14
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Journal article (peer-reviewed)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.
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| 2. |
- Svensson, Elin M., 1985-, et al.
(author)
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The Potential for Treatment Shortening With Higher Rifampicin Doses : Relating Drug Exposure to Treatment Response in Patients With Pulmonary Tuberculosis
- 2018
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In: Clinical Infectious Diseases. - : OXFORD UNIV PRESS INC. - 1058-4838 .- 1537-6591. ; 67:1, s. 34-41
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Journal article (peer-reviewed)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.
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| 3. |
- Stemkens, Ralf, et al.
(author)
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Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis
- 2023
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In: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 67:10
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Journal article (peer-reviewed)abstract
- Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1–15), followed by RIF40 (days 16–30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%–115%); tolbutamide, 80% (74%–86%); omeprazole, 55% (47%–65%); dextromethorphan, 77% (68%–86%); midazolam, 62% (49%–78%), and 117% (105%–130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.
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| 4. |
- Svensson, Robin J., et al.
(author)
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A Population Pharmacokinetic Model Incorporating Saturable Pharmacokinetics and Autoinduction for High Rifampicin Doses
- 2018
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In: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 103:4, s. 674-683
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Journal article (peer-reviewed)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.
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| 5. |
- Svensson, Robin J., et al.
(author)
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Greater Early Bactericidal Activity at Higher Rifampicin Doses Revealed by Modeling and Clinical Trial Simulations
- 2018
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In: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 218:6, s. 991-999
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Journal article (peer-reviewed)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.
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| 6. |
- te Brake, Lindsey H. M., et al.
(author)
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Increased bactericidal activity but dose-limiting intolerability at 50 mg.kg(-1) rifampicin
- 2021
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In: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 58:1
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Journal article (peer-reviewed)abstract
- Accumulating data have indicated that higher rifampicin doses are more effective and shorten tuberculosis treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 7 and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Here we report the results of the final cohorts of PanACEA HIGHRIF1, a dose-escalation study in treatment-naive adult smear-positive patients with tuberculosis. Patients received, in consecutive cohorts, 40 or 50mg/kg rifampicin once daily in monotherapy (day 1-7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between day 8-14. In the 40mg/kg cohort (n=15), 13 patients experienced a total of 36 adverse events (AEs) during monotherapy, resulting in one treatment discontinuation. In the 50mg/kg group (n=17), all patients experienced AEs during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. AEs were mostly mild/moderate and tolerability-rather than safety-related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean AUC(0-24h) for 50mg/kg compared to 40mg/kg; 571 mg/L*h (range 320-995) versus 387 mg/L*h (201-847), while peak exposures saw proportional increases. Protein-unbound exposure after 50mg/kg (11%, 8-17%) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (day-3 Spearman's rho 0.670, p<0.001). EBA increased considerably with dose, with the highest seen after 50mg/kg; 14-day EBA -0.427 logCFU/mL/day (95%CI -0.500, -0.355). In conclusion, although associated with an increased bactericidal effect, the 50mg/kg dose was not well tolerated. Rifampicin at 40mg/kg was well tolerated and therefore selected for evaluation in a phase IIC treatment shortening trial.
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| 7. |
- Van Wijk, Rob C, 1991-, et al.
(author)
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Seasonal influence on respiratory tract infection severity including COVID-19 quantified through Markov Chain modeling
- 2023
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In: CPT. - : John Wiley & Sons. - 2163-8306. ; 12:9, s. 1250-1261
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Journal article (peer-reviewed)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.
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| 8. |
- Abulfathi, Ahmed Aliyu, et al.
(author)
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Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis
- 2019
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In: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 58:9, s. 1103-1129
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Research review (peer-reviewed)abstract
- The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6months when combined with pyrazinamide in the first 2months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600mg (8-12mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of >= 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600mg. Rifampicin maximum (peak) concentration (C-max) > 8.2 mu g/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of >= 8 mu g/mL. A higher rifampicin C-max is required for severe forms TB such as TB meningitis, with C-max >= 22 mu g/mL and area under the concentration-time curve (AUC) from time zero to 6h (AUC(6)) >= 70 mu g.h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35mg/kg were found to be safe and well-tolerated over a period of 12weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as C-max/MIC (minimum inhibitory concentration) and AUC/MIC.
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| 9. |
- Alffenaar, Jan-Willem C., et al.
(author)
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Pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs : An evaluation of in vitro, in vivo methodologies and human studies
- 2022
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In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13
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Research review (peer-reviewed)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.
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| 10. |
- De Jager, Veronique, et al.
(author)
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Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis : The COMRADE Randomized, Phase 2A Clinical Trial
- 2022
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In: American Journal of Respiratory and Critical Care Medicine. - : American Thoracic Society. - 1073-449X .- 1535-4970. ; 205:10, s. 1228-1235
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Journal article (peer-reviewed)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.
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| 11. |
- Faraj, Alan, et al.
(author)
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Drug effect of clofazimine on persisters explain an unexpected increase in bacterial load from patients
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Other publication (other academic/artistic)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.
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| 12. |
- Faraj, Alan, et al.
(author)
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Drug Effect of Clofazimine on Persisters Explains an Unexpected Increase in Bacterial Load in Patients
- 2020
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In: Antimicrobial Agents and Chemotherapy. - : AMER SOC MICROBIOLOGY. - 0066-4804 .- 1098-6596. ; 64:5
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Journal article (peer-reviewed)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.
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| 13. |
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| 14. |
- Koele, Simon E., et al.
(author)
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Early bactericidal activity studies for pulmonary tuberculosis : A systematic review of methodological aspects
- 2023
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In: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 61:5
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Research review (peer-reviewed)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.
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| 15. |
- Litjens, Carlijn H. C., et al.
(author)
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Protein binding of rifampicin is not saturated when using high-dose rifampicin
- 2019
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In: Journal of Antimicrobial Chemotherapy. - : OXFORD UNIV PRESS. - 0305-7453 .- 1460-2091. ; 74:4, s. 986-990
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Journal article (peer-reviewed)abstract
- Background Higher doses of rifampicin are being investigated as a means to optimize response to this pivotal TB drug. It is unknown whether high-dose rifampicin results in saturation of plasma protein binding and a relative increase in protein-unbound (active) drug concentrations. Objectives To assess the free fraction of rifampicin based on an in vitro experiment and data from a clinical trial on high-dose rifampicin. Methods Protein-unbound rifampicin concentrations were measured in human serum spiked with increasing total concentrations (up to 64mg/L) of rifampicin and in samples obtained by intensive pharmacokinetic sampling of patients who used standard (10mg/kg daily) or high-dose (35mg/kg) rifampicin up to steady-state. The performance of total AUC(0-24) to predict unbound AUC(0-24) was evaluated. Results The in vitro free fraction of rifampicin remained unaltered (approximate to 9%) up to 21mg/L and increased up to 13% at 41mg/L and 17% at 64mg/L rifampicin. The highest (peak) concentration in vivo was 39.1mg/L (high-dose group). The arithmetic mean percentage unbound to total AUC(0-24)in vivo was 13.3% (range=8.1%-24.9%) and 11.1% (range=8.6%-13.6%) for the standard group and the high-dose group, respectively (P=0.214). Prediction of unbound AUC(0-24) based on total AUC(0-24) resulted in a bias of -0.05% and an imprecision of 13.2%. Conclusions Plasma protein binding of rifampicin can become saturated, but exposures after high-dose rifampicin are not high enough to increase the free fraction in TB patients with normal albumin values. Unbound rifampicin exposures can be predicted from total exposures, even in the higher dose range.
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| 16. |
- Mockeliunas, Laurynas, et al.
(author)
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Risk Factors for COVID-19 and Respiratory Tract Infections during the Coronavirus Pandemic
- 2024
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In: Vaccines. - : MDPI. - 2076-393X. ; 12:3
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Journal article (peer-reviewed)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.
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| 17. |
- Mockeliunas, Laurynas, et al.
(author)
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Standards for model-based early bactericidal activity analysis and sample size determination in tuberculosis drug development
- 2023
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In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 14
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Journal article (peer-reviewed)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.
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| 18. |
- Upton, Caryn M., et al.
(author)
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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
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In: eClinicalMedicine. - : Elsevier. - 2589-5370. ; 48
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Journal article (peer-reviewed)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.
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| 19. |
- Van Wijk, Rob C, 1991-, et al.
(author)
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Reproducibility in pharmacometrics applied in a phase III trial of BCG-vaccination for COVID-19
- 2023
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In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13
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Journal article (peer-reviewed)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.
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| 20. |
- Abdelwahab, Mahmoud Tareq, et al.
(author)
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Effect of Clofazimine Concentration on QT Prolongation in Patients Treated for Tuberculosis
- 2021
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In: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 65:7
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Journal article (peer-reviewed)abstract
- Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300mg daily for 3 days, followed by 100mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect (Emax) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (DQTcF. 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with Delta QTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.
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| 21. |
- Abulfathi, Ahmed A., et al.
(author)
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Probability of mycobactericidal activity of para-aminosalicylic acid with novel dosing regimens
- 2020
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In: European Journal of Clinical Pharmacology. - : Springer Nature. - 0031-6970 .- 1432-1041. ; 76:11, s. 1557-1565
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Journal article (peer-reviewed)abstract
- Purpose Para-aminosalicylic acid (PAS) is currently one of the add-on group C medicines recommended by the World Health Organization for multidrug-resistant tuberculosis treatment. At the recommended doses (8-12 g per day in two to three divided doses) of the widely available slow-release PAS formulation, studies suggest PAS exposures are lower than those reached with older PAS salt formulations and do not generate bactericidal activity. Understanding the PASER dose-exposure-response relationship is crucial for dose optimization. The objective of our study was to establish a representative population pharmacokinetics model for PASER and evaluate the probability of bactericidal and bacteriostatic target attainment with different dosing regimens.Methods To this end, we validated and optimized a previously published population pharmacokinetic model on an extended dataset. The probability of target attainment was evaluated for once-daily doses of 12 g, 14 g, 16 g and 20 g PASER. Results The final optimized model included the addition of variability in bioavailability and allometric scaling with body weight on disposition parameters. Peak PAS concentrations over minimum inhibitory concentration of 100, which is required for bactericidal activity are achieved in 53%, 65%, 72% and 84% of patients administered 12, 14, 16 and 20 g once-daily PASER, respectively, when MIC is 1 mg/L. For the typical individual, the exposure remained above 1 mg/L for >= 98% of the dosing interval in all the evaluated PASER regimens.Conclusion The pharmacokinetic/pharmacodynamic parameters linked to bactericidal activity should be determined for 14 g, 16 g and 20 g once-daily doses of PASER.
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| 22. |
- Abulfathi, Ahmed A., et al.
(author)
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The pharmacokinetics of para-aminosalicylic acid and its relationship to efficacy and intolerance
- 2020
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In: British Journal of Clinical Pharmacology. - : WILEY. - 0306-5251 .- 1365-2125. ; 86:11, s. 2123-2132
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Research review (peer-reviewed)abstract
- Following its introduction as an antituberculosis agent close to 75 years ago, the use of para-aminosalicylic acid (PAS) has been limited by gastrointestinal intolerance and multiple formulations were produced in attempts to reduce its occurrence. More recently, an enteric-coated, granular, slow-release PAS formulation (PASER) was introduced and is now in wide-spread use for the treatment of drug-resistant tuberculosis. The current PASER dosing regimen is based on recommendations derived from older studies using a variety of different PAS formulations and relegate PAS to a role as an exclusively bacteriostatic agent. However, there is ample evidence that if sufficiently high serum concentrations are reached, PAS can be bactericidal and that intolerance following once daily dosing, that aids the achievement of such concentrations, is no worse than that following intermittent daily dosing. In particular, prevention of resistance to companion drugs appears to be dependent on the size of the single dose, and hence the peak concentrations, and not on maintaining serum levels consistently above minimum inhibitory concentration. We present a narrative review of the development of PAS formulations, dosing practices, and published data regarding pharmacokinetics and pharmacodynamics and the relationship of PAS dosage to intolerance and efficacy. Our conclusions suggests that we are at present not using PAS to its maximum ability to contribute to regimen efficacy and protect companion drugs.
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| 23. |
- Abulfathi, Ahmed A., et al.
(author)
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The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis
- 2021
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In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 12
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Journal article (peer-reviewed)abstract
- Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5-1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise.Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified.Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.
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| 24. |
- Svensson, Elin, 1985-, et al.
(author)
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Relative bioavailability of bedaquiline tablets suspended in water : Implications for dosing in children
- 2018
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In: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 84:10, s. 2384-2392
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Journal article (peer-reviewed)abstract
- Aims: Bedaquiline is an important novel drug for treatment of multidrug-resistant tuberculosis, but no paediatric formulation is yet available. This work aimed to explore the possibility of using the existing tablet formulation in children by evaluating the relative bioavailability, short-term safety, acceptability and palatability of suspended bedaquiline tablets compared to whole tablets.Methods: A randomized, open-label, two-period cross-over study was conducted in 24 healthy adult volunteers. Rich pharmacokinetic sampling over 48h was conducted at two occasions 14days apart in each participant after administration of 400mg bedaquiline (whole or suspended in water). The pharmacokinetic data were analysed with nonlinear mixed-effects modelling. A questionnaire was used to assess palatability and acceptability.Results: There was no statistically significant difference in the bioavailability of the suspended bedaquiline tables compared to whole. The nonparametric 95% confidence interval of the relative bioavailability of suspended bedaquiline tablets was 94-108% of that of whole bedaquiline tablets; hence, the predefined bioequivalence criteria were fulfilled. There were no Grade 3 or 4 or serious treatment emergent adverse events recorded in the study and no apparent differences between whole tablets and suspension regarding taste, texture or smell.Conclusions: The bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole and the suspension was well tolerated. This suggests that the currently available bedaquiline formulation could be used to treat multidrug-resistant tuberculosis in children, to bridge the gap between when paediatric dosing regimens have been established and when a paediatric dispersible formulation is routinely available.
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| 25. |
- Tanneau, Lénaïg, et al.
(author)
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Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens
- 2022
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In: Clinical Pharmacology and Therapeutics. - : Wiley-Blackwell. - 0009-9236 .- 1532-6535. ; 112:4, s. 873-881
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Journal article (peer-reviewed)abstract
- Delamanid and bedaquiline are two drugs approved to treat drug-resistant tuberculosis, and each have been associated with corrected QT interval (QTc) prolongation. We aimed to investigate the relationships between the drugs' plasma concentrations and the prolongation of observed QT interval corrected using Fridericia's formula (QTcF) and to evaluate their combined effects on QTcF, using a model-based population approach. Furthermore, we predicted the safety profiles of once daily regimens. Data were obtained from a trial where participants were randomized 1:1:1 to receive delamanid, bedaquiline, or delamanid + bedaquiline. The effect on QTcF of delamanid and/or its metabolite (DM- -6705) and the pharmacodynamic interactions under coadministration were explored based on a published model between bedaquiline's metabolite (M2) and QTcF. The metabolites of each drug were found to be responsible for the drug-related QTcF prolongation. The final drug-effect model included a competitive interaction between M2 and DM-6705 acting on the same cardiac receptor and thereby reducing each other's apparent potency, by 28% (95% confidence interval (CI), 22-40%) for M2 and 33% (95% CI, 24-54%) for DM-6705. The generated combined effect was not greater but close to "additivity" in the analyzed concentration range. Predictions with the final model suggested a similar QT prolonging potential with simplified, once-daily dosing regimens compared with the approved regimens, with a maximum median change from baseline QTcF increase of 20 milliseconds in both regimens. The concentrations-QTcF relationship of the combination of bedaquiline and delamanid was best described by a competitive binding model involving the two main metabolites. Model predictions demonstrated that QTcF prolongation with simplified once daily regimens would be comparable to currently used dosing regimens.
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| 26. |
- Tanneau, Lénaïg, 1989-, et al.
(author)
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Pharmacodynamic interaction of bedaquiline and delamanid co-administration on QTcF interval prolongation
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Other publication (other academic/artistic)abstract
- Bedaquiline and delamanid are two drugs approved to treat drug-resistant tuberculosis, and each have been associated with QTc prolongation. We aimed to investigate the relationships between the drugs’ plasma concentrations and observed QTcF prolongation and to evaluate their combined effects on QTcF, using a model-based population approach. Furthermore, we predicted the safety profiles of once daily regimens. Data were obtained from a trial where participants were randomized 1:1:1 to receive bedaquiline , delamanid or bedaquiline+delamanid. The effect on QTcF of delamanid and/or its metabolite (DM-6705) and the pharmacodynamic interactions under co-administration, were explored based on a published model between bedaquiline’s metabolite (M2) and QTcF. The metabolites of each drug were found to be responsible for the drug-related QTcF prolongation. The final drug-effect model included a competitive interaction between M2 and DM-6705 acting on the same cardiac receptor and thereby reducing each other’s apparent potency, by 28% (95CI 22%-40%) for M2 and 33% (95CI 24%-54%) for DM-6705. The generated combined effect was not greater but close to “additivity” in the analysed concentration range. Predictions with the final model suggested a similar QT prolonging potential with novel simplified regimens with novel once daily dosing compared to the approved regimens, with a maximum median change from baseline QTcF increase of 20 ms in both regimens. The concentrations-QTcF relationship of the combination of bedaquiline and delamanid was best described by a competitive binding model involving the two main metabolites, and predictions from the model support the use of these drugs together in once daily regimens.
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| 27. |
- Tanneau, Lénaïg, et al.
(author)
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Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline
- 2022
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In: Clinical Pharmacokinetics. - : Springer. - 0312-5963 .- 1179-1926.
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Journal article (peer-reviewed)abstract
- Background: Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis. Delamanid is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-resistant tuberculosis and to explore a potential drug-drug interaction with bedaquiline when co-administered. Methods: Delamanid and DM-6705 concentrations after oral administration, from 52 participants (of whom 26 took bedaquiline concurrently and 20 were HIV-1 positive) enrolled in the DELIBERATE trial were analyzed using nonlinear mixed-effects modeling.Results: Delamanid PK was described by a one-compartment disposition model with transit compartment absorption (mean absorption time of 1.45 h (95% confidence interval 0.501–2.20)) and linear elimination. The PK of DM-6705 metabolite, was described by a one-compartment disposition model with delamanid clearance as input and linear elimination. Predicted terminal half-life values for delamanid and DM-6705 were 15.1 hours and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline co-administration did not affect delamanid PK. Other than allometric scaling with body weight, no patients’ demographics were significant (including HIV). Conclusions: This is the first published joint PK model of delamanid and its DM-6705 metabolite. As such, it can be utilized in future exposure-response or exposure-safety analyses. Importantly, albumin concentrations, bedaquiline co-administration, and HIV co-infection (dolutegravir co-administration) did not have an effect on delamanid and DM-6705 PK.
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