Within‐subject coefficient of variation (CV_w) plays a decisive role in the determination of sample size in bioequivalence clinical trials. Highly variable drugs may require the participation of a large number of subjects. The aim of this study was to investigate whether gender and polymorphisms in CYP2D6 affect the CV_w of risperidone. Two single‐dose, two‐period crossover studies of risperidone (n = 70) were reanalysed to calculate CV_w for AUC_t and C_max. Subjects were classified into four different CYP2D6 phenotype groups [poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM)]. The effect of gender was evaluated in EM and IM. CV_w was lower in PM (13.3% for AUC_t and 10.9% for C_max) and UM (17.4% and 8.7%) than in EM (28.7% and 34.7%) and IM (33.2% and 27.3%). Variability was slightly lower in women (27.9% for AUC_t and 25.7% for C_max) than in men (33.3% and 37.2%, respectively). Genetic polymorphisms affect within‐subject variability more than gender and could considerably affect sample size calculation. Therefore, subjects participating in bioequivalence trials should be genotyped.

Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson’s disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in other CYP enzymes (e.g., CYP2C19), UGT enzymes (e.g., UGT1A1) or other enzymes (e.g., NAT2), and transporters (e.g., SLCO1B1) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. CYP1A2 alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with ABCB1 rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC_0-∞/DW) than those with the G/G genotype (p = 0.012) and lower volume of distribution (V_d/F) and clearance (Cl/F) (p = 0.001 and p = 0.012, respectively). Subjects with the ABCC2 rs2273697 A/A genotype presented lower t_max (i.e., the time to reach the maximum concentration, C_max) compared to those with G/G+G/A genotypes (p = 0.001). Volunteers with the SLC22A1 *1/*5 genotype exhibited lower C_max/DW and higher t_max (p = 0.003 and p = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline.

A cost analysis of thiopurine treatment was carried out in 257 patients, with 153 preemptively genotyped for TPMT and 104 retrospectively genotyped in a Spanish setting. The healthcare cost was significantly higher in patients retrospectively genotyped compared to those who were preemptively genotyped (p < 0.001). TPMT intermediate metabolizers (IMs) (n = 23) showed a 3.3-fold higher healthcare cost when compared to normal metabolizers (NMs) (p < 0.001). The healthcare cost in patients with a TPMT IM phenotype whose physician adhered to the genotype-informed recommendation was similar than the cost in TPMT NMs and was significantly lower than IMs whose physician did not adhere to the therapeutic recommendation (3.8-fold, p = 0.016). Myelotoxicity occurrence was significantly lower in patients preemptively vs. retrospectively genotyped (2.0% and 21.2%, respectively, p < 0.001). Patients who developed myelotoxicity showed a significantly higher healthcare cost than those who did not (4.10-fold, p < 0.001). Overall, 87% of patients whose dose was not adjusted despite being TPMT IMs suffered myelotoxicity, while only one of the eight patients (13%) whose dose was adjusted suffered myelotoxicity (p < 0.001). In conclusion, TPMT preemptive genotyping and physician adherence to genotype-informed therapeutic recommendations prevents myelotoxicity and significantly reduces the healthcare cost, and it is therefore essential for the sustainability of the Spanish healthcare system.

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: Pharmacogenetics (PGx) may improve drug safety and effectiveness, but its integration into routine care remains heterogeneous across the Spanish National Health System (NHS). This article presents BioFRAM PGx, a multicentre implementation framework that defines the methodological and operational basis for subsequent observational validation in cardiovascular and mental-health care settings. Methods: The framework was developed by healthcare centres from eight Spanish Autonomous Communities through a structured review of PharmGKB/ClinPGx clinical annotations, CPIC and DPWG guidelines, and national regulatory resources. Gene–drug pairs were prioritized according to clinical actionability, therapeutic relevance, applicability to the Spanish population, and analytical feasibility. BioFRAM PGx defines a panel of seven pharmacogenes and 35 drugs, standardized genotyping and phenotype-assignment procedures, pharmacovigilance and clinical variables, healthcare-resource measures, and centralized data management. The proposed non-interventional validation phase includes adults receiving at least one selected drug in hospital or primary-care settings, with a minimum six-month follow-up. PGx results are not returned to clinicians and do not modify treatment. Its primary objective is to assess the predictive value of PGx genotyping for adverse drug reactions (ADRs); secondary objectives include ADR incidence and implementation feasibility. Results: The main outputs are the proposed multicentre observational design, the prioritized gene–drug panel, harmonized analytical and pharmacovigilance workflows, standardized data domains, and a centralized data-management strategy. No patient-level clinical, implementation, or economic outcomes are presented. Conclusions: BioFRAM PGx provides a structured multicentre framework for harmonizing pharmacogenetic procedures across the Spanish NHS. Its clinical effectiveness, influence on prescribing, scalability, and economic outcomes remain to be assessed in subsequent studies.

Purpose: Bortezomib (BTZ) is widely used in multiple myeloma (MM), but its toxicity shows marked interindividual variability. This study aimed to identify pharmacogenetic and clinical factors associated with BTZ-related adverse drug reactions (ADRs). Methods: A retrospective and prospective observational study was conducted in 127 MM patients treated with BTZ-based regimens. Polymorphisms in CYP enzymes and ABCB1 were genotyped using qPCR. Associations between genetic variants, treatment response, and ADRs were assessed using univariate and multivariate analyses with Benjamini–Hochberg correction. Results: ADRs occurred in 98.4% of patients, most commonly gastrointestinal toxicity (49%), general toxicity (46%), and peripheral neuropathy (39%). Women showed higher rates of gastrointestinal toxicity and non-peripheral neurotoxicity. Multivariate analysis identified the ABCB1 C1236T A/G genotype as protective against gastrointestinal toxicity, while the CYP3A4 intermediate metabolizer phenotype was associated with increased psychiatric toxicity. TP53 mutations were independently associated with hematologic and renal toxicity. Kaplan–Meier analysis showed earlier onset of peripheral neuropathy and respiratory toxicity in CYP3A4 intermediate and poor metabolizers. Conclusions: Genetic variation in ABCB1 and CYP3A4, together with clinical factors such as TP53 mutation and sex, may contribute to interindividual variability in BTZ safety in MM. These findings should be considered exploratory given the sample size and require confirmation in larger cohorts. Nonetheless, they suggest a potential role for pharmacogenomics in supporting future approaches to treatment personalization.