| 1. |
- Keutzer, Lina, et al.
(author)
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A modeling-based proposal for safe and efficacious reintroduction of bedaquiline after dose interruption : A population pharmacokinetics study
- 2022
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In: CPT. - : John Wiley & Sons. - 2163-8306. ; 11:5, s. 628-639
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Journal article (peer-reviewed)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.
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| 2. |
- Ayoun Alsoud, Rami, et al.
(author)
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Model-based effect evaluation of a novel Mmpl3 inhibitor in C3HeB/FeJ compared to BALB/c mouse models and translation to humans
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Other publication (other academic/artistic)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.
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| 3. |
- Keutzer, Lina, et al.
(author)
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Derivation and Clinical Utility of Safety Targets for Linezolid-Related Adverse Events in Drug-Resistant Tuberculosis Treatment
- 2023
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In: Pharmaceuticals. - : MDPI. - 1424-8247. ; 16:11
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Journal article (peer-reviewed)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.
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| 4. |
- Keutzer, Lina, et al.
(author)
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Individualized Dosing With High Inter-Occasion Variability Is Correctly Handled With Model-Informed Precision Dosing : Using Rifampicin as an Example
- 2020
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In: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Journal article (peer-reviewed)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.
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| 5. |
- Keutzer, Lina, et al.
(author)
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Machine Learning and Pharmacometrics for Prediction of Pharmacokinetic Data : Differences, Similarities and Challenges Illustrated with Rifampicin
- 2022
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In: Pharmaceutics. - : MDPI. - 1999-4923. ; 14:8
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Journal article (peer-reviewed)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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| 6. |
- Keutzer, Lina, et al.
(author)
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Mobile Health Apps for Improvement of Tuberculosis Treatment : Descriptive Review
- 2020
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In: JMIR mhealth and uhealth. - : JMIR Publications Inc.. - 2291-5222. ; 8:4
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Research review (peer-reviewed)abstract
- Background: Mobile health (mHealth) is a rapidly emerging market, which has been implemented in a variety of different disease areas. Tuberculosis remains one of the most common causes of death from an infectious disease worldwide, and mHealth apps offer an important contribution to the improvement of tuberculosis treatment. In particular, apps facilitating dose individualization, adherence monitoring, or provision of information and education about the disease can be powerful tools to prevent the development of drug-resistant tuberculosis or disease relapse. Objective: The aim of this review was to identify, describe, and categorize mobile and Web-based apps related to tuberculosis that are currently available. Methods: PubMed, Google Play Store, Apple Store, Amazon, and Google were searched between February and July 2019 using a combination of 20 keywords. Apps were included in the analysis if they focused on tuberculosis, and were excluded if they were related to other disease areas or if they were games unrelated to tuberculosis. All apps matching the inclusion criteria were classified into the following five categories: adherence monitoring, individualized dosing, eLearning/information, diagnosis, and others. The included apps were then summarized and described based on publicly available information using 12 characteristics. Results: Fifty-five mHealth apps met the inclusion criteria and were included in this analysis. Of the 55 apps, 8 (15%) were intended to monitor patients' adherence, 6 (11%) were designed for dosage adjustment, 29 (53%) were designed for eLearning/information, 3 (6%) were focused on tuberculosis diagnosis, and 9 (16%) were related to other purposes. Conclusions: The number of mHealth apps related to tuberculosis has increased during the past 3 years. Although some of the discovered apps seem promising, many were found to contain errors or provided harmful or wrong information. Moreover, the majority of mHealth apps currently on the market are focused on making information about tuberculosis available (29/55, 53%). Thus, this review highlights a need for new, high-quality mHealth apps supporting tuberculosis treatment, especially those supporting individualized optimized treatment through model-informed precision dosing and video observed treatment.
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| 7. |
- Mockeliunas, Laurynas, et al.
(author)
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Model-Informed Precision Dosing of Linezolid in Patients with Drug-Resistant Tuberculosis
- 2022
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In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:4
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Journal article (peer-reviewed)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.
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| 8. |
- Pieterman, Elise D., et al.
(author)
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Superior Efficacy of a Bedaquiline, Delamanid, and Linezolid Combination Regimen in a Mouse Tuberculosis Model
- 2021
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 224:6, s. 1039-1047
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Journal article (peer-reviewed)abstract
- Background: The treatment success rate of drug-resistant (DR) tuberculosis is alarmingly low. Therefore, more effective and less complex regimens are urgently required.Methods: We compared the efficacy of an all oral DR tuberculosis drug regimen consisting of bedaquiline (25 mg/kg), delamanid (2.5 mg/kg), and linezolid (100 mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of tuberculosis-infected mice during a treatment period of 24 weeks. This treatment was compared with the standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). Relapse was assessed 12 weeks after treatment. Two logistic regression models were developed to compare the efficacy of both regimens.Results: Culture negativity in the lungs was achieved at 8 and 20 weeks of treatment with BDL and HRZE, respectively. After 14 weeks of treatment only 1 mouse had relapse in the BDL group, while in the H RZE group relapse was still observed at 24 weeks of treatment. Predictions from the final mathematical models showed that a 95% cure rate was reached after 20.5 and 28.5 weeks of treatment with BDL and HRZE, respectively.Conclusion: The BDL regimen was observed to be more effective than HRZE and could be a valuable option for the treatment of DR tuberculosis.
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