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Effect of SRD5A2 genotype on pharmacodynamics of 5‐alpha‐reductase inhibitor analyzed by PK‐PD modeling
Author(s) -
Chung J.,
Cho J.,
Lim H.,
Oh D.,
Yi S.,
Jang I.,
Shin S.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.044
Subject(s) - dutasteride , pharmacodynamics , 5 alpha reductase inhibitor , pharmacology , finasteride , chemistry , genotype , pharmacokinetics , reductase , dihydrotestosterone , ic50 , medicine , endocrinology , androgen , enzyme , biochemistry , in vitro , prostate , gene , cancer , hormone
Dihydrotesterone (DHT) converted by 5‐alpha‐reductase from testosterone is thought to be the androgen primarily responsible for the development of Benign Prostatic Hyperplasia. Dutasteride is a potent and specific irreversible competitive inhibitor of 5‐alpha‐reductase type 1 and type 2 for control of BPH. The aim of this study is to evaluate the effect of genetic polymorphism of SRD5A2 on the pharmacodynamics of dutasteride by PK‐PD modeling approach. We conducted a phase I clinical study of a single oral 0.5mg dose of dutasteride in 30 healthy Korean male volunteers. We also obtained genotype of SRD5A2 V89L, coding gene of 5‐alpha‐reductase type 2. Data were analyzed by nonlinear mixed effect modeling using NONMEM. We used a indirect response model to explain the PK‐PD characteristics. PK parameters were similar to those of other previous studies (ka = 2.79 h‐1, Vd = 530 l, Cl = 10.7 lh‐1). Drug concentration corresponding to 50% suppression of enzyme activity(IC50) was about 3 fold smaller in SRD5A2 V89L homomutant group(L/L) than wild type group(V/V) in PK‐PD model incorporated genotype as covariate to IC50. (IC50: V/V=0.375 ng/ml, L/L=0.102 ng/ml) These findings suggest dutasteride can be more potently acting in person who have SRD5A2 V89L mutation. It is consistent with the result of in vitro inhibition study. A PK/PD modeling approach was useful to find the effect of genetic polymorphism on the PD of 5‐alpha‐reductase inhibitor. Clinical Pharmacology & Therapeutics (2004) 75 , P12–P12; doi: 10.1016/j.clpt.2003.11.044