Development of population pharmacokinetics model and Bayesian estimation of rifampicin exposure in Indonesian patients with tuberculosis

• Published in: Tuberculosis (Edinburgh, Scotland) Vol. 139; p. 102325
• Main Authors: Soedarsono, Soedarsono, Jayanti, Rannissa Puspita, Mertaniasih, Ni Made, Kusmiati, Tutik, Permatasari, Ariani, Indrawanto, Dwi Wahyu, Charisma, Anita Nur, Lius, Elvina Elizabeth, Yuliwulandari, Rika, Quang Hoa, Pham, Ky Phat, Nguyen, Thu, Vo Thuy Anh, Ky Anh, Nguyen, Ahn, Sangzin, Phuoc Long, Nguyen, Cho, Yong-Soon, Shin, Jae-Gook
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01.03.2023
• Subjects: Aged; Antitubercular Agents - therapeutic use; Bayes Theorem; Humans; Indonesia; Liver-Specific Organic Anion Transporter 1; Mycobacterium tuberculosis; Pharmacogenetic; Population pharmacokinetics; Rifampicin; Rifampin - therapeutic use; Therapeutic drug monitoring; Tuberculosis; Tuberculosis - drug therapy; Indonesia; Therapeutic drug monitoring; Population pharmacokinetics; Pharmacogenetic; Tuberculosis; Rifampicin
• ISSN: 1472-9792; 1873-281X
• DOI: 10.1016/j.tube.2023.102325

Interindividual variability in the pharmacokinetics (PK) of anti-tuberculosis (TB) drugs is the leading cause of treatment failure. Herein, we evaluated the influence of demographic, clinical, and genetic factors that cause variability in RIF PK parameters in Indonesian TB patients. In total, 210 Indonesian patients with TB (300 plasma samples) were enrolled in this study. Clinical data, solute carrier organic anion transporter family member-1B1 (SLCO1B1) haplotypes *1a, *1b, and *15, and RIF concentrations were analyzed. The population PK model was developed using a non-linear mixed effect method. A one-compartment model with allometric scaling adequately described the PK of RIF. Age and SLCO1B1 haplotype *15 were significantly associated with variability in apparent clearance (CL/F). For patients in their 40s, each 10-year increase in age was associated with a 10% decrease in CL/F (7.85 L/h). Patients with the SLCO1B1 haplotype *15 had a 24% lower CL/F compared to those with the wild-type. Visual predictive checks and non-parametric bootstrap analysis indicated good model performance. Age and SLCO1B1 haplotype *15 were significant covariates of RIF CL/F. Geriatric patients with haplotype *15 had significantly greater exposure to RIF. The model could optimize TB pharmacotherapy through its application in therapeutic drug monitoring (clinical trial no. NCT05280886). •LBW, age, and SLCO1B1 *15 were significantly associated with RIF PK variability.•Geriatric Indonesian TB patients had high exposure of RIF.•Sparse sampling at random post-dose time points enables good estimation of RIF PK.•SLCO1B1 *15 haplotype was associated with 24% lower clearance of RIF.