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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 t 1/2  ( 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 t max  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.

Effects of Cytochrome P450 and Transporter Polymorphisms on the Bioavailability and Safety of Dutasteride and Tamsulosin