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KMID : 1146920230530060857
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Journal of Pharmaceutical Investigation
2023 Volume.53 No. 6 p.857 ~ p.868
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A population pharmacokinetic model for individualized regimens of finasteride according to CYP3A5 genotype and liver function
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Jang Ji-Hun
Jeong Seung-Hyun
Lee Yong-Bok
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Abstract
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Purpose : Finasteride, a 5α-reductase inhibitor, is used in clinical practice to treat benign prostatic hyperplasia and androgenetic alopecia. However, scientific and quantitative dosage regimen studies for finasteride are lacking. This study explored effective finasteride covariates related to inter-individual pharmacokinetic (PK) variability through population PK modeling and their quantitative correlations.
Methods : We used bioequivalence PK results from healthy Korean males for modeling. We considered the physiological and biochemical parameters obtained from each individual and CYP3A5 genotyping information in the covariate search process. We investigated the genetic polymorphisms of CYP3A5 and alanine transaminase (ALT) as effective covariates for clearance (CL/F) in inter-individual finasteride PK variability.
Results : The homozygous (*3/*3) CYP3A5*3 allele had approximately 34% lower CL/F than the *1 allele carriers (*1/*1 and *1/*3), and the CL/F decreased as ALT increased. The established model explained the data sets of multiple-dose groups and subjects derived from external sources. The model simulation revealed that the mean finasteride plasma or serum concentration at steady state was significantly increased by approximately 1.59?1.83 fold with the *3/*3 genotype of CYP3A5, and the ALT level was higher than 40 IU/L.
Conclusion : This suggests that the CYP3A5 genotype is *3 allele homozygous or that, with increased hepatic impairment, continued exposure to high doses of finasteride can lead to adverse side effects. It was quantitatively confirmed that the dosage might have to be adjusted, considering the CYP3A5 and ALT genotypes. Thus, this study will aid in the clinical application of finasteride.
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KEYWORD
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Finasteride, Population pharmacokinetic modeling, Inter-individual variability, Alanine transaminase, CYP3A5, Model simulation
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