Moxifloxacin Population Pharmacokinetics in Patients with Pulmonary Tuberculosis and the Effect of Intermittent High-Dose Rifapentine

Abstract

dWe described the population pharmacokinetics of moxifloxacin and the effect of high-dose intermittent rifapentine in patients with pulmonary tuberculosis who were randomized to a continuation-phase regimen of 400 mg moxifloxacin and 900 mg rifapentine twice weekly or 400 mg moxifloxacin and 1,200 mg rifapentine once weekly. A two-compartment model with transit absorption best described moxifloxacin pharmacokinetics. Although rifapentine increased the clearance of moxifloxacin by 8% during antituberculosis treatment compared to that after treatment completion without rifapentine, it did not result in a clinically significant change in moxifloxacin exposure. The duration of standard therapy for pulmonary tuberculosis is at least 6 months, and direct observation of treatment doses is promoted to support treatment adherence. Strategies aiming to shorten the duration of treatment or reduce the frequency of treatment doses are desirable. Rifapentine has a long half-life (7) and has superior in vitro activity against Mycobacterium tuberculosis compared to rifampin (9). Moxifloxacin has demonstrated potent bactericidal and sterilizing activity against M. tuberculosis in vitro and in mouse models (11,12). Like rifapentine, moxifloxacin has a long half-life (9 to 12 h) (8, 18), making it an attractive companion drug to prevent selection of rifapentine-resistant strains when the drugs are administered intermittently. However, moxifloxacin is a substrate of p glycoprotein (6), sulfotransferases (17), and glucuronosyltransferases (19), which may be induced by rifapentine, thus reducing systemic concentrations of moxifloxacin.To investigate the effects of rifapentine on moxifloxacin pharmacokinetics, we enrolled 28 adults diagnosed with pulmonary tuberculosis who were participating in the RIFAQUIN study (ISRCTN 44153044; http://ipc.nxgenomics.org/intertb /download/RIFAQUIN_Protocol_v_1.8_15_April_2011_FINAL .pdf) at the study site in Worcester, South Africa. Separate written informed consent for the pharmacokinetic study was obtained from RIFAQUIN study participants who were randomized to the two investigational arms with continuation-phase regimens of 1,200 mg rifapentine and 400 mg moxifloxacin once weekly or 900 mg rifapentine and 400 mg moxifloxacin twice weekly. The study protocol was reviewed and approved by the Research Ethics Committee of the University of Cape Town and the Medicines Control Council of South Africa.Plasma concentration data were collected during coadministration of moxifloxacin and rifapentine in the fourth month of tuberculosis treatment and again after a single 400-mg moxifloxacin dose 4 to 8 weeks after completion of tuberculosis treatment. At each occasion, blood samples were collected immediately before and at 1,3,5,7,10,12, 26, and 50 h after the dose.Plasma moxifloxacin concentrations were determined using a validated liquid chromatography-tandem mass spectrometry assay method developed in the Division of Clinical Pharmacology, University of Cape Town. The samples were processed with a protein...

Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

“…The 241 patients on moxifloxacin provided 856 concentration-time points, and only 4% were below LLOQ. As in our previous analysis (13), the population pharmacokinetics of moxifloxacin was well described by a two-compartment model with first-order elimination and transit absorption compartments. FFM was used for allometric scaling of CL, Q and V c , while V p was better scaled with FAT.…”

“…After blood collection, plasma was separated and immediately stored at Ϫ80°C. Moxifloxacin concentrations were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as previously described (13). The lower limit of quantification was 0.063 mg/liter.…”

“…The execution of runs was through Perlspeaks-NONMEM (29), and graphical diagnostics were created using Xpose 4 (30). The use of allometric scaling testing total body weight (WT), fat-free mass (FFM) (31), and fat mass (FAT) as predictors was applied on clearance (CL), intercompartmental clearance (Q), and volume of distribution of the central (V c ) and peripheral (V p ) compartments, as previously described (13). Various structural models were tested, including one-or two-compartment distribution with first-order absorption and elimination rate constants, absorption lag time, and transit compartment absorption (32).…”

“…Moxifloxacin is a substrate of inducible p-glycoprotein (10), sulfotransferases (11), and glucuronosyltransferases (12). Coadministration of moxifloxacin with rifapentine (enzyme and transporter inducer) gave 17.2% (8) and 8% (13) decreases in moxifloxacin exposure in healthy volunteers (dosed three times a week) and tuberculosis patients (dosed once or twice weekly), respectively. Ofloxacin is rapidly absorbed, with peak concentrations reached within 2 h and with a half-life of 6 h, and those characteristics are comparable between healthy volunteers (14) and infected patients (15).…”

Activities of Drug Combinations against Mycobacterium tuberculosis Grown in Aerobic and Hypoxic Acidic Conditions

“…Drugs (100 l) were added to A5 cultures by micropipette and to H5, H12, and H19 cultures by syringe (13,14). R, I, E, MX, AK, MZ, NZ, NC, and PA were used at their maximum drug concentration in serum (C max ) at 8, 2, 4, 4, 8, 8, 10, 0.3, and 2 g/ml, respectively (9,(22)(23)(24)(25)(26). Pyrazinamide was used at 100 g/ml (19).…”