Morris Muliaditan (1), Oscar Della Pasqua (1,2)
(1) UCL School of Life and Medical Sciences, London, UK, (2) GlaxoSmithKline, London, UK.
Objectives: Despite promising advances in tuberculosis (TB) drug development, new integrated methods are still required to efficiently transition the growing number of novel compounds that are needed to shorten current first-line therapy. Clinical trial simulation (CTS) can be a valuable tool for informing robust study designs with respect to the population and dose rationale. This project aims to present the first component of a simulation-based framework for the evaluation of combination therapies in TB. A model for simulation of virtual patients was developed in conjunction with existing population pharmacokinetic (PK) models for all first-line drugs, with the objective of highlighting the implications of covariate effect on variability in systemic drug exposure following different dosing regimens.
Methods: Virtual demographic characteristics were simulated from a database using the multivariate distribution method [1]. Existing population PK models were used to simulate concentration versus time profiles based on WHO recommendations and crude weight band. The goodness of predictions was assessed against literature values. The adequacy of each regimen was measured based on the variability in the simulated AUC0-24 and percentage of patients achieving the recommended minimum Cmax [2]. The development of the population demographic model was performed in R. Population PK simulations were performed using a non-linear mixed effects approach, as implemented in NONMEM 7.2.
Results: The use of a multivariate distribution method yielded a virtual population with comparable covariate correlations to those in the database and published studies. Evaluation of the weight bands revealed that WHO recommended regimens yielded the lowest exposure in patients weighing less than 40 kg. Median simulated AUC0-24 of the first-line drugs was found to be approximately 1.2, 1.3 or 1.4 fold lower when compared to patients weighing respectively 40-54 kg, 55-70 kg or >70 kg. The opposite trend was observed following crude weight band-based dosing regimen.
Conclusion: A population demographic model was developed that can be integrated into a TB CTS framework. Our results show potential limitations of WHO recommended regimen, in that patients with low body weight are potentially underexposed. Moreover, a fixed dose regimen based on three (<40 kg), four (40-70 kg) or five (>70 kg) tablets was proposed to ensure comparable drug levels across all the population.
References:
[1] Tannenbaum, S. J., Holford, N. H., Lee, H., Peck, C. C., & Mould, D. R. (2006). Simulation of correlated continuous and categorical variables using a single multivariate distribution. J Pharmacokinet Pharmacodyn, 33(6), 773-794
[2] Peloquin, C. (2002). Therapeutic Drug Monitoring in the Treatment of Tuberculosis. Drugs, 62(15), 2169-2183.
Reference: PAGE 24 () Abstr 3421 [www.page-meeting.org/?abstract=3421]
Poster: Drug/Disease modeling - Other topics