Pharmacogenetics of Between-Individual Variability in Plasma Clearance of Bedaquiline and Clofazimine in South Africa

Abstract

Objective Plasma bedaquiline clearance is reportedly more rapid with African ancestry. We examined 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 non-linear mixed-effects modelling. 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 = 0.0017) but not M2 (p = 0.25). CYP3A5*3 heterozygosity and homozygosity were associated with 15% and 30% slower bedaquiline clearance, respectively. The lowest P-value for clofazimine clearance was VKORC1 rs9923231 (p = 0.13). In genome-wide analyses, the lowest P-values for clearance of bedaquiline and clofazimine were RFX4 rs76345012 (p = 6.4x10 -7) and CNTN5 rs75285763 (p = 2.9x10 -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.

Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment

“…Black race was much more prevalent in the PROBeX study compared with the phase II studies (82% vs 36%). Black race has been associated with increased clearance of bedaquiline and M2 and lower concentrations of both as a result [ 13 , 22 , 23 ].…”

Human Cytochrome P450 1, 2, 3 Families as Pharmacogenes with Emphases on Their Antimalarial and Antituberculosis Drugs and Prevalent African Alleles

“…With regards to TB, clearance of bedaquiline was 52% faster in Africans using a population pharmacokinetic model [ 211 ], which may be due to Africans expressing significantly more CYP3A5 compared to other populations [ 212 ]. Although bedaquiline is metabolized by CYP3A4, substrate specificity frequently overlaps between CYP3A4 and CYP3A5.…”

Promoting Pharmacogenomics in Africa: Perspectives From Variation in G6PD and Other Pharmacogenes

“…The distributions of CYP3A5*1 (normal function) and CYP3A5*3 (nonfunctional) alleles are significant factors in the variability of tacrolimus response (immunosuppression during organ transplant). In a recent study among South Africans, Haas et al 9 reported that CYP3A5*3 was associated with slower bedaquiline clearance during TB treatment. Remarkably, the frequency of CYP3A5*3 in African populations (16-18%) is far lower than the *1 frequency (about 56%).…”

“…(b) The frequency distribution of selected actionable G6PD and CYP2D6 alleles across African populations. 7,9 Allele frequencies are indicated as relative percentages (%), but are not to scale. The illustrated genetic heterogeneity across Africa emphasizes that a single African population cannot proxy the entire continent in implementation of clinical pharmacogenomics.…”

“…The paucity of information on the pharmacological use of these medications and limited access to them in African communities are major barriers to clinical pharmacogenomics implementation. ( b ) The frequency distribution of selected actionable G6PD and CYP2D6 alleles across African populations 7,9 . Allele frequencies are indicated as relative percentages (%), but are not to scale.…”