Population pharmacokinetic model of rifampicin for personalized tuberculosis pharmacotherapy: Effects of SLCO1B1 polymorphisms on drug exposure

• Published in: International journal of antimicrobial agents 2024-02, Vol.63 (2), p.107034-107034, Article 107034
• Main Authors: Hoa, Pham Quang, Kim, Hyun Kuk, Jang, Tae Won, Seo, Hyewon, Oh, Jee Youn, Kim, Ho Cheol, Shin, Ah Young, Min, Jinsoo, Jayanti, Rannissa Puspita, Hung, Tran Minh, Anh, Nguyen Ky, Ahn, Sangzin, Long, Nguyen Phuoc, Cho, Yong-Soon, Shin, Jae-Gook
• Format: Article
• Language: English
• Subjects: Pharmacogenetics; Population pharmacokinetics; Rifampicin; Therapeutic drug monitoring; Tuberculosis
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2023.107034

•Wild-type SLCO1B1 rs4149056 had a 16% higher RIF CL/F than variant patients.•The SLCO1B1 rs2306283 polymorphism had no considerable influence on RIF exposure.•For successful treatment, higher RIF doses were necessitated in all WHO weight bands.•In particular to patients weighing >70 kg, a dose of 1050 mg should be administered. Rifampicin (RIF) exhibits high pharmacokinetic (PK) variability among individuals; a low plasma concentration might result in unfavorable treatment outcomes and drug resistance. This study evaluated the contributions of non- and genetic factors to the interindividual variability of RIF exposure, then suggested initial doses for patients with different weight bands. This multicenter prospective cohort study in Korea analyzed demographic and clinical data, the solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotypes, and RIF concentrations. Population PK modeling and simulations were conducted using nonlinear mixed-effect modeling. In total, 879 tuberculosis (TB) patients were divided into a training dataset (510 patients) and a test dataset (359 patients). A one-compartment model with allometric scaling for effect of body size best described the RIF PKs. The apparent clearance (CL/F) was 16.6% higher among patients in the SLCO1B1 rs4149056 wild-type group than among patients in variant group, significantly decreasing RIF exposure in the wild-type group. The developed model showed better predictive performance compared with previously reported models. We also suggested that patients with body weights of 70 kg patients receive RIF doses of 450, 600, 750, and 1050 mg/day, respectively. Total body weight and SLCO1B1 rs4149056 genotypes were the most significant covariates that affected RIF CL/F variability in Korean TB patients. We suggest initial doses of RIF based on World Health Organization weight-band classifications. The model may be implemented in treatment monitoring for TB patients.