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A Population Pharmacokinetic Analysis Shows that Arylacetamide Deacetylase (AADAC) Gene Polymorphism and HIV Infection Affect the Exposure of Rifapentine.

Francis, J; Zvada, SP; Denti, P; Hatherill, M; Charalambous, S; Mungofa, S; Dawson, R; Dorman, S; Gupte, N; Wiesner, L; et al. Francis, J; Zvada, SP; Denti, P; Hatherill, M; Charalambous, S; Mungofa, S; Dawson, R; Dorman, S; Gupte, N; Wiesner, L; Jindani, A; Harrison, TS; Olagunju, A; Egan, D; Owen, A; McIlleron, HM (2019) A Population Pharmacokinetic Analysis Shows that Arylacetamide Deacetylase (AADAC) Gene Polymorphism and HIV Infection Affect the Exposure of Rifapentine. Antimicrob Agents Chemother, 63 (4). ISSN 1098-6596 https://doi.org/10.1128/AAC.01964-18
SGUL Authors: Harrison, Thomas Stephen Jindani, Amina

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Abstract

Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the 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, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 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, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have a 10.4% lower clearance. HIV-infected patients had a 21.9% lower bioavailability. Once-weekly doses of 1,200 mg were associated with a reduced clearance (13.2%) compared to that achieved with more frequently administered doses. Bioavailability was 23.3% lower among patients participating in the Daily RPE study than in those participating in the RIFAQUIN study. 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 differences in food intake concomitant with the dose. HIV-coinfected patients had lower rifapentine exposures.

Item Type: Article
Additional Information: Copyright © 2019 Francis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).
Keywords: AADAC, SLCO1B1, pharmacogenetics, population pharmacokinetics, rifapentine, tuberculosis, AADAC, SLCO1B1, pharmacogenetics, population pharmacokinetics, rifapentine, tuberculosis, 0605 Microbiology, 1108 Medical Microbiology, 1115 Pharmacology And Pharmaceutical Sciences, Microbiology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Antimicrob Agents Chemother
ISSN: 1098-6596
Language: eng
Dates:
DateEvent
27 March 2019Published
22 January 2019Published Online
14 December 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
CT.2004.32011.002European and Developing Countries Clinical Trials Partnershiphttp://dx.doi.org/10.13039/501100001713
RO1FD003524US Food and Drug Administration Orphan Products ProgramUNSPECIFIED
WT081199/Z/06/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
UM1 AI068634National Institute of Allergy and Infectious Diseaseshttp://dx.doi.org/10.13039/100000060
UM1 AI068636National Institute of Allergy and Infectious Diseaseshttp://dx.doi.org/10.13039/100000060
UM1 AI106701National Institute of Allergy and Infectious Diseaseshttp://dx.doi.org/10.13039/100000060
U01 AI068632National Institute of Allergy and Infectious Diseaseshttp://dx.doi.org/10.13039/100000060
AI068632National Institute of Mental Healthhttp://dx.doi.org/10.13039/100000025
206379/Z/17/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
204776/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
IFR170227223728South African National Research FoundationUNSPECIFIED
PubMed ID: 30670438
Web of Science ID: WOS:000462474100019
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/110572
Publisher's version: https://doi.org/10.1128/AAC.01964-18

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