Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB

Abstract

Objectives: We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB.

Methods: Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400 mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and again 4 weeks after treatment completion, when given alone as a single dose. Moxifloxacin concentration-time data were analysed using non-linear mixed-effects models.

Results: We included 58 patients; 42 (72.4%) were HIV co-infected and 40 (95%) of these were on efavirenz-based ART. Moxifloxacin pharmacokinetics was best described using a two-compartment disposition model with first-order lagged absorption and elimination using a semi-mechanistic model describing hepatic extraction. Oral clearance (CL/F) of moxifloxacin during rifampicin-based TB treatment was 24.3 L/h for a typical patient (fat-free mass of 47 kg), resulting in an AUC of 16.5 mg·h/L. This exposure was 7.8% lower than the AUC following the single dose of moxifloxacin given alone after TB treatment completion. In HIV-co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4%, resulting in a further 30% reduction in moxifloxacin AUC.

Conclusions: Moxifloxacin clearance was high and plasma concentrations low in our patients overall. Moxifloxacin AUC was further decreased by co-administration of efavirenz-based ART and, to a lesser extent, rifampicin. The clinical relevance of the low moxifloxacin concentrations for TB treatment outcomes and the need for moxifloxacin dose adjustment in the presence of rifampicin and efavirenz co-treatment need further investigation.

© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Figure 1

Schematic diagram of the semi-mechanistic model describing the pharmacokinetics of moxifloxacin in patients with drug-susceptible recurrent TB. Tlag, absorption lag time; Fpre-H, pre-hepatic bioavailability; Ka, absorption rate constant; EH, hepatic extraction; CLint, (hepatic) clearance intrinsic; fu, free (unbound) fraction of drug in plasma; QH, hepatic plasma flow; CLH, hepatic clearance; VC, volume of central compartment; VP, volume of peripheral compartment; Q, inter-compartmental clearance; QH, hepatic plasma flow.

Figure 2

Visual predictive check (VPC) stratified by co-administration with rifampicin and/or efavirenz. The dashed and solid lines are the 5th percentile, median and 95th percentile of the observed concentrations, while the shaded regions represent the corresponding 95% CIs for the same percentiles. The sub-plot in each stratum shows the same VPC with a logarithmic transformation applied to the y-axis. SS, steady-state; SD, single dose; MXF, moxifloxacin; RIF, rifampicin; EFV, efavirenz. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3

Model-based moxifloxacin exposure stratified by co-administration of rifampicin and/or efavirenz. The left panel shows AUC0–∞ (for steady-state dosing) or AUC0–24 (for single dose), while the right panel shows Cmax. The dots are the model-predicted individual exposures observed in the study cohort and based on empirical Bayes estimates; geometric means were used to summarize multiple values from the same subject. The box summarizes the median and IQR, while the whiskers are the 2.5%–97.5% range. SS, steady-state; SD, single dose; MXF, moxifloxacin; RIF, rifampicin; EFV, efavirenz.