Mahmoud Tareq Abdewahab (1), Sean Wasserman (1,2), James CM Brust (3), Gary Maartens (1,2), Paolo Denti (1)
1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. 2) Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa 3) Divisions of General Internal Medicine & Infectious Diseases, Albert Einstein College of Medicine, New York, United States of America
Objectives: Clofazimine is a key component of the short regimen for drug-resistant tuberculosis (TB) but there is currently no evidence base for the standard 100 mg daily dose of clofazimine in widespread use. A model-based approach that can account for the unusual PK characteristics of clofazimine and predict individual exposures for linkage to clinical outcome data is required to inform dose optimization. We present a model to describe the population PK of clofazimine, and characterize covariate effects on PK variability, in a large cohort of South African patients with drug resistant TB.
Methods: Adult drug-resistant TB patients with or without HIV co-infection were enrolled in a prospective, observational cohort study (PROBeX). At recruitment, participants were on drug-resistant TB therapy (usually including clofazimine at a dose of 100 mg daily); follow-up was for 24 months, and included PK visits at months 1, 2 and 6 after study entry with a single sample collected approximately 6-12 hours after the previous dose (time reported by the participant). A subset of participants underwent intensive sampling at month 2 with blood draws pre- and 1, 2, 3, 4, 5, 6, 8, and 24 hours post-observed dose. Plasma clofazimine concentrations were measured using a validated LC-MS/MS assay with 0.00781 mg/L as the lower limit of quantification. Clofazimine plasma concentrations are available for 81 participants, 22 of whom contributed rich PK samples. PK data were analysed using NONMEM 7.4 with FOCE-I; PsN was used for model run execution and R software was used for data preparation. xpose4 and Pirana were used for post-processing results.
Results: Data from the intensive PK-sub study (22-participants & 186 observations) were used to develop the population PK model. No steady-state assumption was made and all doses since treatment initiation were captured. Eleven participants were male and 9 HIV-infected. Median weight was 55.2 kg (IQR 48.4-63.9), fat-free mass 47.3 kg (IQR 38.7-47.6) and fat mass 7.6 kg (IQR 21.1-7.36) and fat mass by sex; females: 22.7 kg (15.0-31.5), males: 7.29 kg (4.93-7.68). The median the duration on clofazimine at the intensive PK visit was 71 days (IQR 62-80). There were no concentrations below the limit of quantification (BLQ). A two-compartment disposition model with first-order elimination and transit compartment absorption fitted the data well (with no separate estimate for absorption rate constant). Female participants had lower exposure on visual plots, and we tried to explain this difference using body composition via allometric scaling as opposed to sex per se. The best size descriptors for scaling of disposition parameters were total body weight (WT) for central clearance (CL) and inter-compartmental clearance (Q), fat-free mass (FFM) for central compartment volume (Vc) and fat mass (FAT) for the peripheral compartment (Vp). To overcome instability of Vp parameters, we added a weakly-informative Bayesian prior on Vp based on a previous report of clofazimine in healthy volunteers and leprosy patients.1 The prior was log-normally distributed with typical values of 3960 L and ~70% uncertainty. In the final model the typical (median values of WT, FAT and FFM) value of CL was 9.25 L/hr, Vc 1090 L, Q 13.8 L/h, and Vp 7259 L. Based on these values, the typical terminal half-life was derived to be ~40 days (~76 days for a typical female and 31 days for a typical male).
Conclusions: Our model characterized PK of clofazimine in South African patients with drug-resistant tuberculosis. Our results are physiologically plausible and consistent with the (limited) information available on clofazimine PK, i.e., its long terminal half-life and accumulation in fat cells. The difference in exposure between males and females is ascribed to differences in body size and composition. The female participants in our cohort had a higher proportion of body fat, and thus a larger peripheral volume of distribution when compared to males. This extends the terminal half-life of the drug in females and prolongs the number of repeated daily doses necessary to achieve steady state. Because the PK profiles observed in this study were not at steady state, but the drug was still accumulating, females in our study have lower concentrations. Furthermore, the model can be used to simulate different scenarios for loading and maintenance dosing to reduce the time needed to achieve steady state.
References:
- Ganesan, S., Sunkara, G., Mcneeley, D. & Hughes, D. Identification of optimal dose and dosing regimen of clofazimine for the treatment of multi-drug resistant tuberculosis (MDR-TB) based on pharmacokinetic modeling. Poster session presented at The Union World Health Conference on Lung Cancer (2015).
Reference: PAGE 28 (2019) Abstr 8980 [www.page-meeting.org/?abstract=8980]
Poster: Drug/Disease Modelling - Infection