Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB-rifampicin sensitivity among Ugandan patients

Background: Suboptimal anti-TB drugs exposure may cause multidrug-resistant TB. The role of African predominant SLCO1B1 variant alleles on rifampicin pharmacokinetics and the subsequent effect on the occurrence of Mycobacterium tuberculosis-rifampicin sensitivity needs to be defined. We describe the rifampicin population pharmacokinetics profile and investigate the relevance of SLCO1B1 genotypes to rifampicin pharmacokinetics and rifampicin-TB sensitivity status. Methods: Fifty patients with TB (n=25 with rifampicin-resistant TB and n=25 with rifampicin-susceptible TB) were genotyped for SLOC1B1 rs4149032 (g.38664C>T), SLOC1B1(*)1B (c.388A>G) and SLOC1B1(*)5 (c.521 T>C). Steady state plasma rifampicin levels were determined among patients infected with rifampicin-sensitive TB. Data were analysed using NONMEM to estimate population rifampicin pharmacokinetics as well as the effect of SLOC1B1 genotypes on rifampicin pharmacokinetics and on rifampicin-TB sensitivity status. Results: Overall allele frequencies of SLOC1B1 rs4149032, (*)1B and (*)5 were 0.66, 0.90 and 0.01, respectively. Median (IQR) C-max and T-max were 10.2 (8.1-12.5) mg/L and 1.7 (1.125-2.218) h, respectively. Twenty-four percent of patients exhibited C-max below the recommended 8-24 mg/L range. SLOC1B1 genotypes, gender and age did not influence rifampicin pharmacokinetics or TB-rifampicin sensitivity. Conclusions: Although SLOC1B1 genotype, age and gender do not influence either rifampicin pharmacokinetics or rifampicin-TB sensitivity status, one in every four Ugandan TB patients achieve subtherapeutic plasma rifampicin concentrations.