Abstract
Dutasteride and tamsulosin are one of the first-line combination therapies for the management of benign prostatic hyperplasia (BPH). Despite being more effective than monotherapies, they produce frequent adverse drug reactions (ADRs). Institutions such as Food and Drug Administration and European Medicines Agency recommend precaution with CYP2D6 poor metabolizers (PMs) that receive CYP3A4 inhibitors and tamsulosin. However, no specific pharmacogenetic guideline exists for tamsulosin. Furthermore, to date, no pharmacogenetic information is available for dutasteride. Henceforth, we studied the pharmacokinetics and safety of dutasteride/tamsulosin 0.5 mg/0.4 mg capsules according to 76 polymorphisms in 17 candidate pharmacogenes. The study population comprised 79 healthy male volunteers enrolled in three bioequivalence, phase-I, crossover, open, randomized clinical trials with different study designs: the first was single dose in fed state, the second was a single dose in fasting state, and the third was a multiple dose. As key findings, CYP2D6 PMs (i.e., *4/*4 and *4/*5 subjects) and intermediate metabolizers (IMs) (i.e., *1/*4, *1/*5, *4/*15 individuals) presented higher AUC (p = 0.004), higher t1/2 (p = 0.008), and lower Cl/F (p = 0.006) when compared with NMs (*1/*1 individuals) and UMs (1/*1 × 2 individuals) after multiple testing correction. Moreover, fed volunteers showed significantly higher tmax than fasting individuals. Nominally significant associations were observed between dutasteride exposure and CYP3A4 and CYP3A5 genotype and between tamsulosin and ABCG2, CYP3A5, and SLC22A1 genotypes. No association between the occurrence of adverse drug reactions and genotype was observed. Nonetheless, higher incidence of adverse events was found in a multiple-dose clinical trial. Based on our results, we suggest that dose adjustments for PMs and UMs could be considered to ensure drug safety and effectiveness, respectively. Further studies are warranted to confirm other pharmacogenetic associations.
Highlights
Dutasteride and tamsulosin are one of the first-line combination therapies for the management of benign prostatic hyperplasia (BPH)
Our goal was to conduct a candidate gene pharmacogenetic study evaluating 76 polymorphisms in 17 pharmacogenes, including CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP3A4, CYP3A5, and CYP4F2 and transporters such as ABCB1, ABCC2, ABCG2, SLC22A1, SLC28A3, SLCO1B1, and UGT1A1 in healthy volunteers participating in bioequivalence clinical trials
All polymorphisms analyzed were in Hardy–Weinberg equilibrium, except for CYP1A2 *1C, CYP2A6 *9, CYP2B6 *4, ABCB1 rs2032582, CYP2C8 *8, and CYP3A4 *22
Summary
Dutasteride and tamsulosin are one of the first-line combination therapies for the management of benign prostatic hyperplasia (BPH). Dutasteride belongs to 5-α reductase inhibitors (5-ARIs), which prevent dihydrotestosterone production and, delay prostatic tissue growth. At 0.5 mg daily doses, the elimination is slower, reaching a t1/2 of 3–5 weeks It is extensively metabolized by cytochrome P450 (CYP) isoforms CYP3A4 and CYP3A5 into four major metabolites: two of them less active than dutasteride and two other that are active to the parent drug. They are primarily excreted in stools and marginally in urine; only between 1 and 15.4% of the dutasteride dose is excreted unmetabolized in feces. It has been reported that dutasteride is not metabolized in vitro by human cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 (FDA, 2010)
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