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Pharmacogenetics of...
Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa
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- Haas, David W. (author)
- Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN USA.;Meharry Med Coll, Dept Internal Med, Nashville, TN USA
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- Abdelwahab, Mahmoud Tareq (author)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa
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- van Beek, Stijn W. (author)
- Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands
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- Baker, Paxton (author)
- Vanderbilt Univ, Med Ctr, Vanderbilt Technol Adv Genom, Nashville, TN USA
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- Maartens, Gary (author)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa
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- Bradford, Yuki (author)
- Univ Penn, Dept Genet, Philadelphia, PA USA
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- Ritchie, Marylyn D. (author)
- Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA USA.;Univ Penn, Inst Biomed Informat, Perelman Sch Med, Philadelphia, PA USA
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- Wasserman, Sean (author)
- Univ Cape Town, Dept Med, Div Infect Dis, Cape Town, South Africa
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- Meintjes, Graeme (author)
- Univ Cape Town, Wellcome Ctr Infect Dis Res Africa, Inst Infect Dis & Mol Med, Cape Town, South Africa.;Univ Cape Town, Dept Med, Cape Town, South Africa
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- Beeri, Karen (author)
- Vanderbilt Univ, Med Ctr, Vanderbilt Technol Adv Genom, Nashville, TN USA
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- Gandhi, Neel R. (author)
- Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA USA.;Emory Univ, Dept Global Hlth, Rollins Sch Publ Hlth, Atlanta, GA USA.;Emory Univ, Emory Sch Med, Dept Med, Div Infect Dis, Atlanta, GA USA
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- Svensson, Elin, 1985- (author)
- Uppsala universitet,Institutionen för farmaci,Radboud Univ Nijmegen Med Ctr, Radboud Inst Hlth Sci, Dept Pharm, Nijmegen, Netherlands
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- Denti, Paolo (author)
- Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa
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- Brust, James C. M. (author)
- Albert Einstein Coll Med, Dept Med, Div Gen Internal Med, Bronx, NY USA
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Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN USA;Meharry Med Coll, Dept Internal Med, Nashville, TN USA Univ Cape Town, Dept Med, Div Clin Pharmacol, Cape Town, South Africa (creator_code:org_t)
- 2022-01-29
- 2022
- English.
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In: Journal of Infectious Diseases. - : Oxford University Press. - 0022-1899 .- 1537-6613. ; 226:1, s. 147-156
- Related links:
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https://academic.oup...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- In a cohort of patients treated for drug-resistant tuberculosis in South Africa, CYP3A5*3was associated with slower plasma bedaquiline clearance. Different CYP3A5*3minor allele frequencies among populations may help explain the more rapid bedaquiline clearance previously reported with African ancestry.Background Plasma bedaquiline clearance is reportedly more rapid with African ancestry. Our objective was to determine whether genetic polymorphisms explained between-individual variability in plasma clearance of bedaquiline, its M2 metabolite, and clofazimine in a cohort of patients treated for drug-resistant tuberculosis in South Africa.Methods Plasma clearance was estimated with nonlinear mixed-effects modeling. Associations between pharmacogenetic polymorphisms, genome-wide polymorphisms, and variability in clearance were examined using linear regression models.Results Of 195 cohort participants, 140 were evaluable for genetic associations. Among 21 polymorphisms selected based on prior genome-wide significant associations with any drug, rs776746 (CYP3A5*3) was associated with slower clearance of bedaquiline (P = .0017) but not M2 (P = .25). CYP3A5*3 heterozygosity and homozygosity were associated with 15% and 30% slower bedaquiline clearance, respectively. The lowest P value for clofazimine clearance was with VKORC1 rs9923231 (P = .13). In genome-wide analyses, the lowest P values for clearance of bedaquiline and clofazimine were with RFX4 rs76345012 (P = 6.4 x 10(-7)) and CNTN5 rs75285763 (P = 2.9 x 10(-8)), respectively.Conclusions Among South Africans treated for drug-resistant tuberculosis, CYP3A5*3 was associated with slower bedaquiline clearance. Different CYP3A5*3 frequencies among populations may help explain the more rapid bedaquiline clearance reported in Africans. Associations with RFX4 and CNTN5 are likely by chance alone.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Mikrobiologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Microbiology in the medical area (hsv//eng)
Keyword
- bedaquiline
- clofazimine
- pharmacogenomics
- tuberculosis
- pharmacokinetics
Publication and Content Type
- ref (subject category)
- art (subject category)
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Haas, David W.
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Abdelwahab, Mahm ...
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van Beek, Stijn ...
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Baker, Paxton
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Maartens, Gary
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Bradford, Yuki
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Ritchie, Marylyn ...
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Wasserman, Sean
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Meintjes, Graeme
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Beeri, Karen
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Gandhi, Neel R.
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Svensson, Elin, ...
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Denti, Paolo
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Brust, James C. ...
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- MEDICAL AND HEALTH SCIENCES
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and Basic Medicine
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Journal of Infec ...
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Uppsala University