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

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) Arylacetamide deacetylase (AADAC) gene polymorphism and HIV infection affect the exposure of Rifapentine: a population pharmacokinetics analysis. Antimicrob Agents Chemother. 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 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.

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: 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
22 January 2019Published Online
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
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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