Tadalafil and finasteride are used in combination for the management of benign prostatic hyperplasia (BPH). Genetic variations in genes involved in the metabolism and transport of tadalafil or finasteride (i.e., pharmacogenes) could affect their pharmacokinetic processes altering their drug exposure, efficacy, and toxicity. The main objective of this study was to investigate the effects of variants in pharmacogenes on the pharmacokinetics of tadalafil and finasteride. An exploratory candidate gene study involving 120 variants in 33 genes was performed with 66 male healthy volunteers from two bioequivalence clinical trials after administration of tadalafil/finasteride 5 mg/5 mg under fed or fasting conditions. Afterwards, a confirmatory study was conducted with 189 male and female volunteers receiving tadalafil 20 mg formulations in seven additional bioequivalence clinical trials. Regarding tadalafil, fed volunteers showed higher area in the time-concentration curve (AUC_∞), maximum plasma concentration (C_max), and time to reach C_max (t_max) compared to fasting volunteers; male volunteers also showed higher AUC_∞ and C_max compared to female volunteers. Furthermore, fed volunteers presented higher finasteride AUC_∞, C_max and t_max compared to fasting individuals. Variants in ABCC3, CYP1A2, CES1, NUDT15, SLC22A1/A2 and UGT2B10 were nominally associated with pharmacokinetic variation in tadalafil and/or finasteride but did not remain significant after correction for multiple comparisons. Genetic variation did not demonstrate to clinically impact on the pharmacokinetics of finasteride and tadalafil; however, additional studies with larger sample sizes are needed to assess the effect of rare variants, such as CYP3A4*20 or *22, on tadalafil and finasteride pharmacokinetics.

Background: Psoriasis is a skin disease characterized by the presence of erythematous, scaly plaques on the extensor surfaces of the body. Treatment varies according to the stage of the disease, with the most severe cases being treated with biologic treatments that differ in efficacy and persistence over time. This study aimed to evaluate the 10-year persistence of biologic drugs (adalimumab, etanercept, infliximab and ustekinumab) in the treatment of moderate-to-severe plaque psoriasis. Methods: A total of 143 patients (61 women and 82 men) were evaluated; data were collected from the electronic clinical history, and statistical analysis was performed using the SPSS program. In addition, 115 of them were genotyped in a previous study for 173 immune system genetic polymorphisms. Results: The persistence of biologic drugs at 10 years was 25.9% (95% CI: 17.2–34.5%). Adalimumab was the most persistent drug (41.5%), followed by ustekinumab (34.8%), infliximab (28%) and etanercept (9.3%). The main reason for discontinuation was insufficient efficacy (51%). Adalimumab allowed an increase in the dosing interval in 82.4% of patients who persisted and ustekinumab allowed an increase in 37.5%. The 10-year persistence was related to sex (higher in men, p < 0.001), biologic drug (p = 0.002) and polymorphisms in LMO4 (rs983332) (p = 0.014) and IL20RA (rs1167846) (p = 0.013). Conclusion: The results show that 25% of psoriasis patients treated with first-line biologics persisted at 10 years.

Drug combination therapy is the most common pharmacological strategy for hypertension management. No pharmacogenetic biomarkers for guiding hypertension pharmacotherapy are available to date. The study population were 64 volunteers from seven bioequivalence trials investigating formulations with valsartan, olmesartan and/or hydrochlorothiazide. Every volunteer was genotyped for 10 genetic variants in different transporters’ genes. Additionally, valsartan-treated volunteers were genotyped for 29 genetic variants in genes encoding for different metabolizing enzymes. Variability in pharmacokinetic parameters such as maximum concentration (C_max) and time to reach it (t_max), the incidence of adverse drug reactions (ADRs) and blood pressure measurements were analyzed as a function of pharmacogenetic and demographic parameters. Individuals with the ABCB1 rs1045642 T/T genotype were associated with a higher valsartan t_max compared to those with T/G and G/G genotypes (p < 0.001, β = 0.821, R² = 0.459) and with a tendency toward a higher postural dizziness incidence (11.8% vs. 0%, p = 0.070). A higher hydrochlorothiazide dose/weight (DW)-corrected area under the curve (AUC_∞/DW) was observed in SLC22A1 rs34059508 G/A volunteers compared to G/G volunteers (p = 0.050, β = 1047.35, R² = 0.051), and a tendency toward a higher postural dizziness incidence (50% vs. 1.6%, p = 0.063). Sex impacted valsartan and hydrochlorothiazide pharmacokinetics, showing a lower exposure in women, whereas no significant differences were found for olmesartan pharmacokinetics.

Statins are the primary drugs used to prevent cardiovascular disease by inhibiting the HMG-CoA reductase, an enzyme crucial for the synthesis of LDL cholesterol in the liver. A significant number of patients experience adverse drug reactions (ADRs), particularly musculoskeletal problems, which can affect adherence to treatment. Recent clinical guidelines, such as those from the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2022, recommend adjusting rosuvastatin doses based on genetic variations in the ABCG2 and SLCO1B1 genes to minimize ADRs and improve treatment efficacy. Despite these adjustments, some patients still experience ADRs. So, we performed a candidate gene study to better understand the pharmacogenetics of rosuvastatin. This study included 119 healthy volunteers who participated in three bioequivalence trials of rosuvastatin alone or in combination with ezetimibe at the Clinical Trials Unit of the Hospital Universitario de La Princesa (UECHUP). Participants were genotyped using a custom OpenArray from ThermoFisher that assessed 124 variants in 38 genes associated with drug metabolism and transport. No significant differences were observed according to sex or biogeographic origin. A significant increase in t_1/2 (p_multivariate(p_mv) = 0.013) was observed in the rosuvastatin plus ezetimibe trial compared with the rosuvastatin alone trials. Genetic analysis showed that decreased (DF) and poor function (PF) volunteers for the ABCG2 transporter had higher AUC_∞/DW (adjusted dose/weight), AUC_72h/DW and C_max/DW compared to normal function (NF) volunteers (p_mv< 0.001). DF and PF volunteers for SLCO1B1 showed an increase in AUC_72h/DW (p_mv = 0.020) compared to increased (IF) and NF individuals. Results for ABCG2 and SLCO1B1 were consistent with the existing literature. In addition, AUC_∞/DW, AUC_72h/DW and C_max/DW were increased in intermediate (IA) and poor (PA) NAT2 acetylators (p_mv = 0.001, p_mv< 0.001, p_mv< 0.001, respectively) compared to rapid acetylators (RA), which could be associated through a secondary pathway that was previously unknown.

Background/Objectives: Pregabalin is a useful therapeutic option for patients with anxiety or neuropathic pain. Genetic variants in certain genes encoding for transporters related to absorption and distribution could have an impact on the efficacy and safety of the drug. Furthermore, extreme phenotypes in metabolic enzymes could alter pregabalin-limited metabolism. Methods: In this study, we included 24 healthy volunteers participating in a bioequivalence clinical trial and administered pregabalin 300 mg orally; 23 subjects were genotyped for 114 variants in 31 candidate genes, and we explored their impact on pregabalin pharmacokinetics and safety. Results: The uncorrected mean (±SD) of AUC_∞ and C_max were 61,097 ± 14,762 ng*h/mL and 7802 ± 1659 ng/mL, respectively, which were significantly higher in females than in males (p = 0.002 and p = 0.001, respectively), with no differences in dose/weight (DW)- corrected exposure metrics. NAT2 slow acetylators (SAs) showed a 16–18% increase in exposure compared to intermediate (IAs) and normal (NAs) acetylators; NAT2 SAs exhibited a 25% higher t_1/2 as compared with NAT2 IAs and 58% higher compared to NAT2 NAs. In contrast, neither the NAT2 phenotype nor other genetic variants were related to pregabalin adverse drug reaction (ADR) occurrence. On the contrary, sex and sex-related exposure differences (i.e., females and their higher exposure compared to males) were the main predictors of ADR occurrence. Conclusions: Our findings suggest that NAT2 could be partially responsible for the minor proportion of pregabalin metabolism, but the effect of NAT2 phenotype does not seem clinically relevant. Therefore, pharmacogenetic biomarkers appear to play a restrained role in pregabalin pharmacotherapy.

Mirabegron is a drug used in overactive bladder (OAB) treatment. Genetic variation in pharmacogenes might alter its pharmacokinetics, affecting its efficacy and safety. This research aimed to analyze the impact of genetic variation on mirabegron pharmacokinetics and safety. Volunteers from three bioequivalence trials (n = 79), treated with a single or a multiple dose of mirabegron 50 mg under fed or fasting conditions, were genotyped for 115 variants in pharmacogenes and their phenotypes were inferred. A statistical analysis was performed, searching for associations between genetics, pharmacokinetics and safety. CYP2D6 intermediate metabolizers showed a higher elimination half-life (t_1/2) (univariate p-value (p_uv) = 0.018) and incidence of adverse reactions (ADRs) (p_uv = 0.008, multivariate p (p_mv) = 0.010) than normal plus ultrarapid metabolizers. The UGT1A4 rs2011425 T/G genotype showed a higher t_1/2 than the T/T genotype (p_uv = 0.002, p_mv = 0.003). A lower dose/weight corrected area under the curve (AUC/DW) and higher clearance (CL/F) were observed in the SLC6A2 rs12708954 C/C genotype compared to the C/A genotype (p_uv = 0.015 and 0.016) and ADR incidence was higher when the SLCO1B1 function was decreased (p_uv = 0.007, p_mv = 0.010). The lower elimination and higher ADR incidence when CYP2D6 activity is reduced suggest it might be a useful biomarker in mirabegron treatment. UGT1A4, SLC6A2 and SLCO1B1 might also be involved in mirabegron pharmacokinetics.