Arylacetamide deacetylase (AADAC) gene polymorphism and HIV infection affect the exposure of Rifapentine: a population pharmacokinetics analysis. [Experimental Therapeutics]

Rifapentine is a rifamycin used to treat tuberculosis. As for rifampicin, plasma exposures of rifapentine are associated with treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, PXR, CAR, and AADAC on rifapentine exposure. Two studies evaluating novel regimens amongst Southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In RIFAQUIN, rifapentine was administered in the continuation phase of antituberculosis treatment in 1200mg once-weekly or 900mg twice-weekly doses. In Daily-RPE 450 or 600mg were given daily during the intensive-phase of treatment. Nonlinear mixed-effects modelling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1144 drug-concentration measurements, from 326 patients, were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight of 56kg, fat-free-mass of 45kg), the values of clearance and volume of distribution were 1.33L/h and 25L, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have 10.4% lower clearance. HIV+ infected patients had 21.9% lower bioavailability. Once weekly doses of 1200 mg were associated reduced clearance (-13.2%), compared to more frequently administered doses. Bioavailability was 23.3% lower amongst patients participating in the Daily-RPE study compared to RIFAQUIN. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the different food concomitant to the dose. HIV coinfected patients had lower rifapentine exposures.

http://bit.ly/2R4pBWZ