Eun Sun Kim (1,4), Seonghae Yoon (2), Jong Sun Park (1,4), Jae-Yong Chung(2,5), Soo Hyun Seo (3,6), Kyoung Un Park (3,6), Junghan Song (3.6), Jae Ho Lee (1,4)
(1) Department of Internal Medicine, (2) Clinical Trials Center, (3) Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea, (4) Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, (5) Department of Clinical Pharmacology and Therapeutics, (6) Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
Introduction: Tuberculosis (TB) is one of the top 10 causes of death worldwide and its prevalence rate is high in Korea. Rifampin is a first-line anti-TB drug that displays concentration-dependent bactericidal effects. It is transported into the liver by organic anion transporting polypeptide 1B1 (OATP1B1), which is encoded by the SLCO1B1 gene and excreted into bile. Some studies have shown that single nucleotide polymorphisms (SNPs) of SLCO1B1 have an impact on rifampin concentrations [1-3], but that remains controversial.
Objectives: We aimed to investigate how the relationship between genetic polymorphisms of SLCO1B1 and rifampin exposure may impact the clinical outcomes for patients with active pulmonary TB. To estimate the exposure of rifampin in patients with a single rifampin concentration, we developed a population pharmacokinetic (PK) model of rifampin.
Methods: From February 2016 to December 2019, patients with active pulmonary TB were enrolled in this study. Serial or one-time blood sampling was conducted to determine rifampin concentrations. Serial blood samples were taken up to 24 h post rifampin administration. The genotypes of 4 SNPs of SLCO1B1 were determined. A nonlinear mixed-effects modelling for population PK analysis was performed with 300 concentrations from 110 patients who received either 450 or 600 mg of rifampin. The first-order conditional estimation with interaction method implemented by NONMEM (version 7.3.0) [4] was used, followed by standard goodness-of-fit diagnostics and a visual predictive check for qualification evaluation of the model’s predictions. The apparent clearance (CL/F) of rifampin for each individual was estimated and the area under the curve (AUC) was calculated using the following equation: AUC=Dose/(CL/F). Clinical outcomes were evaluated using the duration of acid fast bacilli (AFB) culture conversion and the change of the chest X-ray score from baseline. The exposure among different SLCO1B1 genotypes was compared and the relationship between drug exposure and clinical outcomes was explored.
Results: A total of 105 patients (70 males and 35 females) were included in the final analysis. The mean age was 55.4 years. A one-compartment model with first-order absorption and first-order elimination characterized the rifampin PK. Body weight was included as a covariate for the apparent clearance. The typical population estimates (inter-individual variabilities shown as coefficients of variation, CV%) of the CL/F and volume of distribution (Vd/F) were 12.1 L/h (63.1%) and 44.9 L (64.4%), respectively. Inter-individual variabilities were quite large and it might be due to non-linear PK of rifampin. The absorption rate was fixed at 1.12 h-1, which was estimated from the serial sampling population. The genetic polymorphisms of SLCO1B1 were deemed unrelated to rifampin clearance or exposure. The drug exposure and chest X-ray changes had a linear relationship (p <0.001); as the drug exposure increased, the change in chest X-ray score increased. However, the duration of AFB culture conversion was not related to the drug exposure.
Conclusions: A population PK model for rifampin was developed to estimate drug exposure. The model showed that the exposure of rifampin had no significant relationship with the genotype of SLCO1B1. The change in chest X-ray score was related to rifampin exposure, suggesting that appropriate drug exposure might improve clinical outcomes for TB patients.
References:
[1] Dompreh A, Tang X, Zhou J, et al. Effect of Genetic Variation of NAT2 on Isoniazid and SLCO1B1 and CES2 on Rifampin Pharmacokinetics in Ghanaian Children with Tuberculosis. Antimicrobial agents and chemotherapy. Mar 2018;62(3).
[2] Ramesh K, Hemanth Kumar AK, Kannan T, Vijayalakshmi R, Sudha V, Manohar Nesakumar S, et al. SLCO1B1 gene polymorphisms do not influence plasma rifampicin concentrations in a South Indian population. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2016;20(9):1231-5.
[3] Chigutsa E, Visser ME, Swart EC, Denti P, Pushpakom S, Egan D, et al. The SLCO1B1 rs4149032 polymorphism is highly prevalent in South Africans and is associated with reduced rifampin concentrations: dosing implications. Antimicrobial agents and chemotherapy. 2011;55(9):4122-7
[4] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2015. Icon Development Solutions, Gaithersburg, Maryland, USA.
Reference: PAGE () Abstr 9343 [www.page-meeting.org/?abstract=9343]
Poster: Drug/Disease Modelling - Infection