A semi-physiological model for moxifloxacin pharmacokinetics which includes the effect of co-administered drugs and genetic polymorphisms
Maxwell Chirehwa (1), Anushka Naidoo (2), Veron Ramsuran (2,3), Helen McIlleron (1), Kogieleum Naidoo (2,4), Nonhlanhla Yende-Zuma (2), Ravesh Singh (5), Sinaye Ngapu (2), Michael S. Pepper (6), Mamoonah Chaudhry (6), Nesri Padayatchi (2,4), Paolo Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa, (2) Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa, (3) School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa, (4) MRC-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, (5) Department of Microbiology, National Health Laboratory Services, KZN Academic Complex, Inkosi Albert Luthuli Central Hospital, Durban, South Africa, (6) Department of Immunology and the Institute for Cellular and Molecular Medicine; South African Medical Research Council Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
Objectives: Moxifloxacin (MOXI) is currently recommended for the treatment of MDR-TB [1]. It could potentially reduce the time to culture conversion in patients with drug‑susceptible TB [2]. We describe the pharmacokinetics (PK) of MOXI and identify the effect of selected covariates on PK parameters.
Methods: Blood samples were collected from 58 tuberculosis (TB) patients from South Africa recruited in the PK sub‑study of the IMPRESS study. Patients received 400 mg of MOXI for 6 months together with weight-adjusted doses of rifampicin and isoniazid, and pyrazinamide in the first 2 months of treatment. HIV+ patients received ART, mostly efavirenz-based. PK sampling was conducted on 2 visits in the intensive phase and on 1 day in the continuation phase. Additional PK sampling was done after administration of a single dose of MOXI, one month after completion of TB treatment. On a PK sampling day, four serial blood samples were collected prior to dosing and at 2.5, 6 and 24 hours post-dose. Plasma moxifloxacin was quantified using HPLC-MS/MS, and the LLOQ was 0.05 mg/L. Data were analysed using nonlinear mixed effects modelling in NONMEM 7.3 and FOCE-I.
Results: PK of MOXI was best described using a 2‑compartment disposition model, and a semi-mechanistic model to capture liver first-pass effect (ΔOFV 24 vs. no first-pass effect). The hepatic volume of distribution and plasma flow (QH) were fixed to 1 L and 50 L/h, and MOXI unbound fraction was fixed to 50% [3]. Priors were included on Ka and ALAG to using parameter estimates from Zvada et al. [4]. Allometric scaling using FFM on all clearance and volume parameters was supported by the data. The model identified the effect of rifampicin co-administration, efavirenz co-administration, and genotypes of rs8175347 and rs3755319 on exposure. The liver extraction ratio (EH) was highest (44%) for patients that were administered rifampicin based anti-TB treatment, efavirenz-based ART, and have AC or AA genotype for rs3755319. Intrinsic clearance after a single dose of MOXI was 29% less compared to steady‑state with rifampicin co-administration. However, the model also estimated a 22% reduced pre-hepatic bioavailability after a single dose of MOXI.
Conclusions: A semi-mechanistic model with hepatic extraction describes the data adequately. The clinical significance of the effects found warrants further investigation on the proportion of patients attaining therapeutic exposure using MIC distributions determined and the currently recommended dose of 400 mg.
References:
[1] WHO. 2016. Global Tuberculosis Report.
[2] Conde MB, Efron A, Loredo C, De Souza GRM, Graça NP, Cezar MC, Ram M, Chaudhary MA, Bishai WR, Kritski AL, Chaisson RE. 2009. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet 373:1183–1189.
[3] MacGowan AP. 1999. Moxifloxacin (Bay 12-8039): a new methoxy quinolone antibacterial. Expert Opin Investig Drugs 8:181–199.
[4] Zvada SP, Denti P, Sirgel FA, Chigutsa E, Hatherill M, Charalambous S, Mungofa S, Wiesner L, Simonsson USH, Jindani A, Harrison T, McIlleron HM. 2014. Moxifloxacin population pharmacokinetics and model-based comparison of efficacy between moxifloxacin and ofloxacin in African patients. Antimicrob Agents Chemother 58.
