No abstract

This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0–τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0–14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.)

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 (<40 kg), four (40–70 kg) or five (>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.

Despite evidence of the efficacy of anti-tubercular drug regimens in clinical practice, the rationale underpinning the selection of doses and companion drugs for combination therapy remains empirical. Novel methods are needed to optimise the antibacterial activity in combination therapies. A drug-disease modelling framework for rational selection of dose and drug combinations in tuberculosis is presented here. Methods: A model-based meta-analysis was performed to assess the antibacterial activity of different combinations in infected mice. Data retrieved from the published literature were analysed using a two-state bacterial growth dynamics model, including fast-and slow-growing bacterial populations. The contribution of each drug to the overall antibacterial activity of the combination was parameterised as relative change to the potency of the backbone drug (EC 50-F and/or EC 50-S). Rifampicin and bedaquiline were selected as paradigm drugs to evaluate the predictive performance of the modelling approach. Results: Pyrazinamide increased the potency (EC 50-F and EC 50-S) of rifampicin (RZ) and bedaquiline (BZ) by almost twofold. By contrast, pretomanid and isoniazid were found to worsen the antibacterial activity of BZ and RZ, respectively. Following extrapolation of in vivo pharmacokinetic-pharmacodynamic relationships, the dose of rifampicin showing maximum bactericidal effect in tuberculosis patients was predicted to be 70 mgÁkg −1 when given in combination with pyrazinamide. Conclusions: The use of a drug-disease modelling framework may provide a more robust rationale for extrapolation and selection of dose and companion drugs in humans. Our analysis demonstrates that RZ and BZ should be considered as a backbone therapy in prospective novel combination regimens against tuberculosis.