The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

Simulations based on our models suggest that with the new WHO dosing guidelines and utilizing available paediatric fixed-dose combinations, children will receive adequate rifampicin exposures when compared with adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. Further studies are needed to confirm these findings in children administered the revised dosages and to optimize pragmatic approaches to dosing.

BackgroundEfavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics. Plasma concentrations below 1 μg/ml may result in virologic failure and above 4 μg/ml, may result in central nervous system adverse effects. This study used population pharmacokinetics modeling to explore the influence of demographic and pharmacogenetic factors including efavirenz-rifampicin interaction on EFV pharmacokinetics, towards safer dosing of EFV.MethodsPatients receiving an EFV-based regimen for their antiretroviral therapy and a rifampicin-containing anti-TB regimen were recruited. EFV plasma concentrations were measured by HPLC and genomic DNA genotyped for variants in the CYP2B6, CYP2A6 and ABCB1 genes. All patients were evaluated for central nervous system adverse effects characterised as sleep disorders, hallucinations and headaches using the WHO ADR grading system. A pharmacokinetic model was built in a forward and reverse procedure using nonlinear mixed effect modeling in NONMEM VI followed by model-based simulations for optimal doses.ResultsCYP2B6*6 and *18 variant alleles, weight and sex were the most significant covariates explaining 55% of inter-individual variability in EFV clearance. Patients with the CYP2B6*6TT genotype had a 63% decrease in EFV clearance despite their CYP2B6*18 genotypes with females having 22% higher clearance compared to males. There was a 21% increase in clearance for every 10 kg increase in weight. The effect of TB/HIV co-treatment versus HIV treatment only was not statistically significant. No clinically relevant association between CYP2B6 genotypes and CNS adverse effects was seen, but patients with CNS adverse effects had a 27% lower clearance compared to those without. Model- based simulations indicated that all carriers of CYP2B6*6 TT genotype would be recommended a dose reduction to 200 mg/day, while the majority of extensive metabolisers may be given 400 mg/day and still maintain therapeutic levels.ConclusionThis study showed that screening for CYP2B6 functional variants has a high predictability for efavirenz plasma levels and could be used in prescribing optimal and safe EFV doses.

Rifapentine and its primary metabolite, 25-desacetyl rifapentine, are active against mycobacterium tuberculosis. The objectives of this study were to describe the population pharmacokinetics of rifapentine and 25-desacetyl rifapentine in fasting and fed states. Thirty-five male healthy volunteers were enrolled in an open-label, randomized, sequential, five-way crossover study. Participants received a single 900-mg dose of rifapentine after meals with high fat (meal A), bulk and low fat (meal B), bulk and high fat (meal C), high fluid and low fat (meal D), or 200 ml of water (meal E). Venous blood samples were collected over 72 h after each rifapentine dose, and plasma was analyzed for rifapentine and 25-desacetyl rifapentine using high-performance liquid chromatography. Pharmacokinetic data were analyzed by nonlinear mixed-effect modeling using NONMEM. Compared with the fasting state, meal A had the greatest effect on rifapentine oral bioavailability, increasing it by 86%. Meals B, C, and D resulted in 33%, 46%, and 49% increases in rifapentine oral bioavailability, respectively. Similar trends were observed for 25-desacetyl rifapentine. As meal behavior has a substantial impact on rifapentine exposure, it should be considered in the evaluation of optimal dosing approaches.Rifapentine (RFP), a cyclopentyl rifamycin, is an orally administered drug registered by the Food and Drug Administration (FDA) for the treatment of pulmonary tuberculosis (TB). It exerts its antibacterial activity through inhibition of DNAdependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis (32). RFP has a microbiologically active metabolite, 25-desacetyl rifapentine (25-DRFP) (10). RFP has a long half-life (5, 17) and superior in vitro potency against M. tuberculosis in comparison with rifampin and rifabutin (10), making it an attractive candidate for shortening and simplifying antitubercular therapy.Currently, RFP is dosed at 600 mg either once weekly or twice weekly in human immunodeficiency virus (HIV)-negative patients with noncavitary TB (2). There is concern that the development of acquired rifamycin monoresistance (ARR), treatment failure, and relapse may be associated with intermittent dosing (4, 20), insufficient companion drug exposure (33), or low rifamycin concentrations (9, 21). RFP's sterilizing effect has been shown to be dose dependent in murine studies which suggest that daily doses of RFP may reduce treatment duration to just 3 months (25,26,37), and higher doses of RFP are associated with improved early bactericidal activity in humans (29). Clinical trials are currently evaluating new antituberculosis regimens containing higher doses of RFP used intermittently or daily doses of RFP. Concomitant food has a marked effect on RFP absorption (6). The effect of food on systemic RFP exposure may therefore impact treatment activity and safety. The aim of this study was to investigate the effect of meals differing in fat and bulk content on the rate and extent of RFP absorption and 25-DRFP disposition. The ...

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...