How long will treatment guidelines for TB continue to overlook variability in drug exposure?

BACKGROUND: Despite wide clinical acceptance, the use of weight-banded dosing regimens for the treatment of TB in adults has been defined on an empirical basis. The potential impact of known covariate factors on exposure to different drugs has not been taken into account. OBJECTIVES: To evaluate the effect of demographic factors on the exposure to standard of care drugs after weight-banded dosing, as currently recommended by TB treatment guidelines. In addition, we aim to identify alternative dosing regimens that ensure comparable systemic exposure across the overall patient population. METHODS: Clinical trial simulations were performed to assess the differences in systemic exposure in a cohort of virtual patients. Secondary pharmacokinetic parameters were used to evaluate the adequacy of each regimen along with the percentage of patients achieving predefined thresholds. RESULTS: Our results show that patients weighing less than 40 kg are underexposed relative to patients with higher body weight. The opposite trend was observed following a crude weight band-based dosing regimen with 50 kg as the cut-off point. Simulations indicate that a fixed-dose regimen based on three (70 kg) tablets of 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide and 275 mg ethambutol reduces variability in exposure, increasing the overall probability of favourable long-term outcome across the population. CONCLUSIONS: These findings suggest the need to revisit current guidelines for the dose of standard of care drugs for TB treatment in adults. The proposed fixed-dose regimen should be considered in future clinical trials

Bacterial growth dynamics and PKPD relationships of rifampicin and bedaquiline in BALB/c mice

Background and Purpose: Translational efforts in the evaluation of novel anti-tubercular drugs demand better integration of pharmacokinetic–pharmacodynamic data arising from preclinical protocols. However, parametric approaches that discriminate drug effect from the underlying bacterial growth dynamics have not been fully explored, making it difficult to translate and/or extrapolate preclinical findings to humans. This analysis aims to develop a drug-disease model that allows distinction between drug- and system-specific properties. Experimental Approach: Given their clinical relevance, rifampicin and bedaquiline were used as test compounds. A two-state model was used to describe bacterial growth dynamics. The approach assumes the existence of fast- and slow-growing bacterial populations. Drug effect on the growth dynamics of each subpopulation was characterised in terms of potency (EC50-F and EC50-S) and maximum killing rate. Key Results: The doubling time of the fast- and slow-growing population was estimated to be 25 h and 42 days, respectively. Rifampicin was more potent against the fast-growing (EC50-F = 4.8 mg·L−1), as compared with the slow-growing population (EC50-S = 60.2 mg·L−1). Bedaquiline showed higher potency than rifampicin (EC50-F = 0.19 mg·L−1; EC50-S = 3.04 mg·L−1). External validation procedures revealed an effect of infection route on the apparent potency of rifampicin. Conclusion and Implications: Model parameter estimates suggest that nearly maximum killing rate is achieved against fast-growing, but not against slow-growing populations at the tested doses. Evidence of differences in drug potency for each subpopulation may facilitate the translation of preclinical findings and improve the dose rationale for anti-tubercular drugs in humans

Characterising QT interval prolongation in early clinical development: a case study with methadone

Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modelling can be used to assess the probability of QTc interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate non-clinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of prodromic drug effects in humans. ECG and drug concentration data from safety pharmacology study in dogs were analysed using nonlinear mixed effects modelling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration vs. time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QTc interval of ≥ 5 and ≥10 ms. Point estimates for the slope in dogs suggested low probability of ≥10 ms prolongation in humans. However, an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals the drug-specific parameter in dogs. In addition, our analysis show that understanding of interspecies differences in drug disposition is required to accurately predict the QT prolonging effects in humans. Extrapolation of the effects of parent compound may not be sufficient to describe the increase in QT interval observed after administration of methadone in humans. Assessment of the contribution of enantioselective metabolism and active metabolites is critical

Model-informed repurposing of medicines for SARS-CoV-2: extrapolation of antiviral activity and dose rationale for paediatric patients

Repurposing of remdesivir and other drugs with potential antiviral activity has been the basis of numerous clinical trials aimed at SARS-CoV-2 infection in adults. However, expeditiously designed trials without careful consideration of dose rationale have often resulted in treatment failure and toxicity in the target patient population, which includes not only adults but also children. Here we show how paediatric regimens can be identified using pharmacokinetic-pharmacodynamic (PKPD) principles to establish the target exposure and evaluate the implications of dose selection for early and late intervention. Using in vitro data describing the antiviral activity and published pharmacokinetic data for the agents of interest, we apply a model-based approach to assess the exposure range required for adequate viral clearance and eradication. Pharmacokinetic parameter estimates were subsequently used with clinical trial simulations to characterise the probability target attainment (PTA) associated with enhanced antiviral activity in the lungs. Our analysis shows that neither remdesivir, nor anti-malarial drugs can achieve the desirable target exposure range based on a mg/kg dosing regimen, due to a limited safety margin and high concentrations needed to ensure the required PTA. To date, there has been limited focus on suitable interventions for children affected by COVID-19. Most clinical trials have defined doses selection criteria empirically, without thorough evaluation of the PTA. The current results illustrate how model-based approaches can be used for the integration of clinical and nonclinical data, providing a robust framework for assessing the probability of pharmacological success and consequently the dose rationale for antiviral drugs for the treatment of SARS-CoV-2 infection in children

Dose rationale for amoxicillin in neonatal sepsis when referral is not possible

Background: Despite the widespread use of amoxicillin in young children, efforts to establish the feasibility of simplified dosing regimens in resource-limited settings have relied upon empirical evidence of efficacy. Given the antibacterial profile of beta-lactams, understanding of the determinants of pharmacokinetic variability may provide a more robust guidance for the selection of a suitable regimen. Here we propose a simplified dosing regimen based on pharmacokinetic-pharmacodynamic principles, taking into account the impact of growth, renal maturation and disease processes on the systemic exposure to amoxicillin. Materials and Methods: A meta-analytical modeling approach was applied to allow the adaptation of an existing pharmacokinetic model for amoxicillin in critically ill adults. Model parameterization was based on allometric concepts, including a maturation function. Clinical trial simulations were then performed to characterize exposure, as defined by secondary pharmacokinetic parameters (AUC, Cmax, Cmin) and T>MIC. The maximization of the T>MIC was used as criterion for the purpose of this analysis and results compared to current WHO guidelines. Results: A two-compartment model with first order absorption and elimination was found to best describe the pharmacokinetics of amoxicillin in the target population. In addition to the changes in clearance and volume distribution associated with demographic covariates, our results show that sepsis alters drug distribution, leading to lower amoxicillin levels and longer half-life as compared to non-systemic disease conditions. In contrast to the current WHO guidelines, our analysis reveals that amoxicillin can be used as a fixed dose regimen including two weight bands: 125 mg b.i.d. for patients with body weight < 4.0 kg and 250 mg b.i.d. for patients with body weight ≥ 4.0 kg. Conclusions: In addition to the effect of developmental growth and renal maturation, sepsis also alters drug disposition. The use of a model-based approach enabled the integration of these factors when defining the dose rationale for amoxicillin. A simplified weight-banded dosing regimen should be considered for neonates and young infants with sepsis when referral is not possible

Prediction of disease progression, treatment response and dropout in chronic obstructive pulmonary disease (COPD).

Drug development in chronic obstructive pulmonary disease (COPD) has been characterised by unacceptably high failure rates. In addition to the poor sensitivity in forced expiratory volume in one second (FEV1), numerous causes are known to contribute to this phenomenon, which can be clustered into drug-, disease- and design-related factors. Here we present a model-based approach to describe disease progression, treatment response and dropout in clinical trials with COPD patients

Clinical Trial Diversity: An Opportunity for Improved Insight into the Determinants of Variability in Drug Response

Although the number of countries participating in pivotal trials submitted to enable drug registration has nearly doubled over the past 25 years, there has not been a substantial increase in the diversity of clinical trial populations. In parallel, our understanding of factors that influence medicine response and variability has continued to evolve. The notion of intrinsic and extrinsic sources of variability has been embedded into different regulatory guidelines, including the recent guideline on the importance of enhancing the diversity of clinical trial populations. In addition to presenting the clinical and scientific reasons for ensuring that clinical trial populations represent the demographics of patient populations, this overview outlines the efforts of regulatory agencies, patient advocacy groups and clinical researchers to attain this goal through strategies to meet representation in recruitment targets and broaden eligibility criteria. Despite these efforts, challenges to participation in clinical trials remain, and certain groups continue to be underrepresented in development programmes. These challenges are amplified when the representativeness of specific groups may vary across countries and regions in a global clinical programme. Whilst enhanced trial diversity is a critical step towards ensuring that results will be representative of patient populations, a concerted effort is required to characterise further the factors influencing interindividual and regional differences in response for global populations. Quantitative clinical pharmacology principles should be applied to allow extrapolation of data across groups or regions as well as provide insight into the effect of patient-specific characteristics on a medicine's dose rationale and efficacy and safety profiles

Implications of drug-induced phenotypical resistance : is isoniazid radicalizing M. tuberculosis?

Funding: This study was funded by a grant from the British Society for Antimicrobial Chemotherapy (GA2015-172R).Background: Treatment duration is long and does not guarantee eradication of infection. Shorter treatment regimens are a critical research objective to improve uptake and reduce the risk of relapse and bacterial resistance. The explanation for the need to continue treatment after patients are culture negative remains elusive. We have previously shown that the presence of lipid inclusions in mycobacterial cells is associated with an increase in antibiotic resistance. Aim: We investigate the bactericidal effect of isoniazid and rifampicin and the expression of lipid inclusions and the associated phenotypic antibiotic resistance to a range of anti-tuberculosis agents in current use. Methods: Antibiotic killing effect for both M. tuberculosis and M. komossense were investigated by both hollow fiber bioreactor (HFS) studies and static time kill curve (STKC) experiments. Following STKC cultures were stained with resazurin, Sytox green and Nile red to establish their live/dead (resazurin positive/Sytox positive) and lipid inclusion status respectively. In addition, M. komossense was studied in the hollow fiber bioreactor model (HFS) and exposed to isoniazid (H) and rifampicin (R). The MIC of current antituberculosis agents for cells from the treated hollow fiber experiments were tested. Results: Antibiotic killing was similar for both species. For M. komossense; isoniazid was ineffective at the established MIC (1mg/L) in the hollow fiber bioreactor but rifampicin reduced the viable count rapidly at MIC (0.4mg/L). When the two drugs were combined at their respective MICs the killing effect was significant and greater than separately. Cells exposed to isoniazid (1x & 9x MIC) for 168 hours showed considerable numbers of recoverable viable cells when compared with a combination of 1x MIC R & H where there were no viable cells detectable. For both drugs the number of lipid body positive cells increased over time and this effect was most pronounced for isoniazid and was associated with phenotypic resistance to multiple anti-tuberculosis drugs. Conclusion: Our results showed that isoniazid is a potent stimulator of lipid body accumulation, culture persistence, and phenotypic resistance to multiple anti-tuberculosis drugs. These findings emphasise the importance of understanding mechanisms of drug-drug interactions and phenotypic resistance in regimen building.Publisher PDFPeer reviewe

Simplified Dosing Regimens for Gentamicin in Neonatal Sepsis

Background: The effectiveness of antibiotics for the treatment of severe bacterial infections in newborns in resource-limited settings has been determined by empirical evidence. However, such an approach does not warrant optimal exposure to antibiotic agents, which are known to show different disposition characteristics in this population. Here we evaluate the rationale for a simplified regimen of gentamicin taking into account the effect of body size and organ maturation on pharmacokinetics. The analysis is supported by efficacy data from a series of clinical trials in this population. Methods: A previously published pharmacokinetic model was used to simulate gentamicin concentration vs. time profiles in a virtual cohort of neonates. Model predictive performance was assessed by supplementary external validation procedures using therapeutic drug monitoring data collected in neonates and young infants with or without sepsis. Subsequently, clinical trial simulations were performed to characterize the exposure to intra-muscular gentamicin after a q.d. regimen. The selection of a simplified regimen was based on peak and trough drug levels during the course of treatment. Results: In contrast to current World Health Organization guidelines, which recommend gentamicin doses between 5 and 7.5 mg/kg, our analysis shows that gentamicin can be used as a fixed dose regimen according to three weight-bands: 10 mg for patients with body weight <2.5 kg, 16 mg for patients with body weight between 2.5 and 4 kg, and 30 mg for those with body weight >4 kg. Conclusion: The choice of the dose of an antibiotic must be supported by a strong scientific rationale, taking into account the differences in drug disposition in the target patient population. Our analysis reveals that a simplified regimen is feasible and could be used in resource-limited settings for the treatment of sepsis in neonates and young infants with sepsis aged 0–59 days