Clofazimine pharmacokinetics in patients with TB: dosing implications

Abstract

Background: Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization.

Objectives: To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients.

Patients and methods: Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L.

Results: We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant.

Conclusions: Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.

Figure 1.

Schematic of the final clofazimine population PK model. The dose is assumed to go through a series of transit compartments, where NN describes the number of transit compartments and the transit rate constant (Ktr) the transfer rate, calculated as NN + 1 divided by the mean transit time (MTT). Drug is then absorbed into the central compartment (representing the plasma concentration of clofazimine), described by the absorption rate constant (Ka). Bidirectional equilibration (Q1 and Q2) occurs with two peripheral tissue compartments, deep (V_p1) and shallow (V_p2), while drug is eliminated from the central compartment with first-order kinetics (CL). Cmpt, compartment. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Prediction-corrected visual predictive check for pooled clofazimine concentration versus time (time after dose), stratified by sex. Circles represent original data, dashed and solid lines are the 5th, 50th and 95th percentiles of the original data, and the shaded areas are the corresponding 95% CI for the same percentiles, as predicted by the model. Vertical yellow lines on the x-axis represent bins for sampling timepoints. An appropriate model is expected to have most observed percentiles within the simulated CIs. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Box and whisker plots showing secondary model-derived non-compartmental parameters, stratified by sex. The dots represent individual values; the central lines in boxes represent median values; upper and lower horizontal lines of boxes are 75th and 25th percentiles, respectively; and whiskers are 2.5th and 97.5th percentiles. n = 22 for PROBeX, sampled at ∼2 months; n = 57 for the Phase 2A trial, sampled at Day 14.

Figure 4.

Predicted clofazimine concentrations at steady-state with standard dosing (100 mg daily), stratified for typical male/female participants in the cohort. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 5.

Simulated exposures with standard dosing and loading dose for typical male, typical female and all TB patients in the cohort. Dashed lines represent the suggested target concentration (0.25 mg/L); the central lines in boxes represents median values; upper and lower horizontal lines are 75th and 25th percentiles, respectively; and whiskers are 2.5th and 97.5th percentiles. Orange shaded boxplots represent the loading dose period. Note, time is truncated at 26 weeks for improved visualization. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.