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

Author:

Mukonzo Jackson K1,Kengo Allan1,Kutesa Bisaso1,Nanzigu Sarah1,Pohanka Anton2,McHugh Timothy D3,Zumla Alimuddin34,Aklillu Eleni2

Affiliation:

1. Department of Pharmacology & Therapeutics, Makerere University, P.O. Box 7072 Kampala, Uganda

2. Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital-Huddinge, SE-141 86 Stockholm, Sweden

3. Center for Clinical Microbiology, Division of Infection and Immunology, University College London, Royal Free Hospital, Rowland Hill Street, NW3 2PF London, UK

4. NIHR Biomedical Research Center at UCL Hospitals NHS Foundation Trust, 162 City Rd, EC1V 2PD London, Bungereza

Abstract

Abstract 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.

Funder

International AIDS Society

Swedish Research Council

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Public Health, Environmental and Occupational Health,General Medicine,Parasitology

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