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

L'esercizio terapeutico nel trattamento della tendinopatia Achillea: revisione sistematica della letteratura

Background: La tendinopatia Achillea è una condizione che causa dolore, rigidità e alterazione della funzione del tendine d’Achille. La patogenesi è degenerativa. Il trattamento conservativo verte soprattutto sulla ricerca di stimoli che promuovano la sintesi di collagene e incrementino la forza tensile del tendine d’Achille. Per questo motivo, l’esercizio è una delle modalità più studiate. Obiettivi: Valutare l’efficacia dell’esercizio terapeutico, in termini di miglioramento dei sintomi di dolore e funzione, nel trattamento della tendinopatia achillea cronica della porzione media. Disegno dello studio: Revisione sistematica seguendo la checklist del PRISMA statement. Criteri di eleggibilità: Studi Trial Clinici Randomizzati e non, che indagano il cambiamento di dolore e funzione in pazienti affetti da tendinopatia achillea cronica della porzione media trattati con esercizio terapeutico. Fonti di ricerca: PUBMED, PEDro, CINAHL complete, PsycARTICLES, Psychology and Behavioral Sciences Collection, PsycINFO, SPORTDiscus, Cochrane Central Register of Controlled Trial. Risultati: 13 studi inclusi. In tutti, l’esercizio terapeutico produce miglioramenti significativi di dolore e funzione. Il protocollo di esercizio eccentrico di Alfredson (HECT) è più efficace della guarigione spontanea, dell’esercizio concentrico isolato, e del programma di Stanish. Inoltre, unito a massaggio trasverso profondo ed ultrasuoni provoca miglioramenti statisticamente significativi rispetto a queste terapie isolate. Non ci sono differenze significative fra l’HECT e: l’AirHeel brace, le onde d’urto, gli ultrasuoni, il PRP, il “pressure massage”, e l’esercizio isotonico in palestra (HSR). L’HECT ridotto di volume e frequenza produce gli stessi miglioramenti. Conclusioni: L’esercizio è un trattamento efficace per la tendinopatia achillea cronica della porzione media. Il suo utilizzo consente di scegliere programmi di lavoro ugualmente validi come l’HECT (classico o ridotto) e l’HSR