Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB-rifampicin sensitivity among Ugandan patients.
Jackson K Mukonzo, Allan Kengo, Bisaso Kutesa, Sarah Nanzigu, Anton Pohanka, Timothy D McHugh, Alimuddin Zumla, Eleni Aklillu
Author Information
Jackson K Mukonzo: Department of Pharmacology & Therapeutics, Makerere University, P.O. Box 7072 Kampala, Uganda.
Allan Kengo: Department of Pharmacology & Therapeutics, Makerere University, P.O. Box 7072 Kampala, Uganda.
Bisaso Kutesa: Department of Pharmacology & Therapeutics, Makerere University, P.O. Box 7072 Kampala, Uganda.
Sarah Nanzigu: Department of Pharmacology & Therapeutics, Makerere University, P.O. Box 7072 Kampala, Uganda.
Anton Pohanka: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital-Huddinge, SE-141 86 Stockholm, Sweden.
Timothy D McHugh: Center for Clinical Microbiology, Division of Infection and Immunology, University College London, Royal Free Hospital, Rowland Hill Street, NW3 2PF London, UK.
Alimuddin Zumla: Center for Clinical Microbiology, Division of Infection and Immunology, University College London, Royal Free Hospital, Rowland Hill Street, NW3 2PF London, UK.
Eleni Aklillu: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital-Huddinge, SE-141 86 Stockholm, Sweden.
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) Cmax and Tmax were 10.2 (8.1-12.5) mg/L and 1.7 (1.125-2.218) h, respectively. Twenty-four percent of patients exhibited Cmax 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.
