Evidence-based evaluation for race difference of pirfenidone using population pharmacokinetics model
Seongwon Park (1), Woojin Jung (1), Jeongmin Ha (1), Jung-woo Chae＊(1,2), Hwi-yeol Yun* (1,2), JaeWoo Kim* (3)
(1) College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea (2) Department of Bio-AI convergence, Chungnam National University, Daejeon, Republic of Korea (3) H Plus Yangji Hospital, Seoul 08779, Republic of Korea *Those of authors contributed equally as correspondence.
Introduction:
Idiopathic pulmonary fibrosis (IPF), with a significantly high mortality rate, is a chronic, progressive disease primarily in the elderly. Pirfenidone is an orphan drug known to prevent disease progression in IPF patients. It has been used in different dosing regimens in Western (Caucasian, Black/African American) and Asian countries based on Arata Azuma et al. study. [1] However, there is still controversy about the origin of differences in race-related regimens. The FDA review of pirfenidone states that the clearance of pirfenidone is affected by body weight, age, sex, smoking, and disease status, not race. [2] However, there were just 4 Asians among all 282 subjects in the studies. So, we aim to reassess the effect of race on the pharmacokinetics of pirfenidone using a merged dataset for Asian-rich populations and population pharmacokinetic (popPK) analysis. The detailed objectives of this study are the following:
• Develop the popPK model of pirfenidone for healthy Asian subjects and confirm the published popPK model for healthy Western subjects.
• Re-evaluate the difference between the two healthy populations using popPK model derived non-compartmental analysis (NCA) pharmacokinetic parameters (Cmax and AUC) statistically.
Methods:
The Westerners dataset, which was collected by Webplotdigitizer from the FDA review document, [2] (mean age and body weight are 40 years and 80 kg, respectively, with 16 men and a total of 159 blood samples)was merged with that of 50 Asians (mean age and body weight are 27.6 years and 68.2 kg, with 37 men and 13 women and a total of 941 blood samples in the in-house dataset) and separated by races using FLAG. The structure of the popPK model for Westerners was described in FDA documents, and the popPK model for Asians was developed referring to the published pirfenidone popPK model structure and parameters. [3] Using the popPK models for both populations, individual virtual data were generated with the same dosing and PK sampling scenario for each model. The NCA pharmacokinetic parameters Cmax and AUC were evaluated statistically for the two groups with two independent sample t-test.
Results:
The healthy Asian popPK model was developed as a two-compartment model with first-order absorption with lagtime and first-order elimination. Inter-individual variability (IIV) was modeled exponentially, and a residual variability was applied with a combined error model.
The final popPK models were used to simulate PK data for the same dose regimen, and the derived NCA parameters were compared for the two populations. There were statistical differences for Cmax and AUC between the healthy Asian and Western populations. In a single-dose simulation of 200 mg, 400 mg, 600 mg, and 800 mg, the predicted mean of Cmax and AUC values were about 150–160% higher in the Asian than the Westerner population, at the same dose level, respectively. The maximum tolerable daily doses for Caucasians and Asians are acceptable as 800 mg and 600 mg, respectively. A comparison of the maximum dose amount for Asian and Western populations found that Cmax and AUC were 119% higher in Asians than in Westerners.
Conclusions:
A popPK model of pirfenidone was developed using data from healthy Asians and it was confirmed via simulations that Asians have higher exposure than Westerners. Using the accepted maximum tolerable dose of 800 mg in Caucasians as a comparator, a maximum dose of 500 mg is suggested as the clinically applicable optimal dose for Asians. It should result in similar exposure (which assumes a similar PK/PD relationship). The differences in systemic exposure to pirfenidone for the two population groups are supposed to come from race, including differences in body weight or metabolic enzyme activity. The published information on genetic differences in the metabolization of pirfenidone is available. [4], [5] CYP2C19, one of the CYP enzymes that metabolize pirfenidone, has variable expression among ethnicities and is known to have different frequencies of CYP2C19 polymorphism. [5] Prediction of the pharmacokinetics of pirfenidone could be improved by considering genetic differences between populations.
In future studies, the pirfenidone model for healthy subjects could be modified for IPF patients by including disease status or appropriate demographic data of IPF patients.
References:
[1] Arata Azuma et al., Double-blind, Placebo-controlled Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis, Am J Respir Crit Care Med, 2005.
[2] FDA CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S), 022535Orig1s000, May 23, 2014.
[3] Lina Marcela Barranco-Garduno et al., Pharmacokinetic evaluation of two pirfenidone formulations in patients with idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis, Heliyon, 2020.
[4] Shigeki Saito et al., Ethnic differences in idiopathic pulmonary fibrosis: The Japanese perspective, Respiratory Investigation, 2018.
[5] Ulrich M. Zanger, Matthias Schwab, Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation, Pharmacology & Therapeutics, 2013.