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Introduction: Ezetimibe inhibits cholesterol uptake by modulation of intestinal sterol absorption. Currently, although some studies have shown alterations in ezetimibe levels caused by alterations in the ABCG5 , ABCG8 , NPC1L1 or UGT1A1 genes, there are no pharmacogenetic guidelines to confirm these biomarkers. The aim of this work was to evaluate the effect of 49 variants in 22 pharmacogenes related to metabolism and transport., Methods: A total of 96 healthy volunteers from four bioequivalence clinical trials of ezetimibe as monotherapy or in combination with simvastatin were studied. Blood samples were extracted for unconjugated ezetimibe plasma quantification and genotyping., Results and Discussion: No association of metabolizing enzyme variants with ezetimibe pharmacokinetic parameters was found. The results show some trends in the univariate analysis for ABCB1 rs2032582 or ABCC2 rs2273697 and C max ( p univariate ( p uv ) = 0.056 and 0.087, respectively), which finally reach significance in the multivariate analysis ( p multivariate ( p mv ) = 0.049 and 0.048, respectively). Nevertheless, these results need to be validated in future studies., Competing Interests: FA-S and DO have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Aptatargets, Chemo, Cinfa, FAES, Farmal' der, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern, Moderna, MSD, Normon, Novartis, Servier, Silver Pharma, Teva and Zambon. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 González-Iglesias, Ochoa, Navares-Gómez, Zubiaur, Aldama, Torre, Ríos-Rodríguez, Soria-Chacartegui, Rodríguez-Lopez, Abad-Santos and Novalbos.)

Introduction: Fesoterodine is one of the most widely used antimuscarinic drugs to treat an overactive bladder. Fesoterodine is extensively hydrolyzed by esterases to 5-hydroxymethyl tolterodine (5-HMT), the major active metabolite. CYP2D6 and CYP3A4 mainly metabolize 5-HMT and are, therefore, the primary pharmacogenetic candidate biomarkers. Materials and Methods: This is a candidate gene study designed to investigate the effects of 120 polymorphisms in 33 genes (including the CYP, COMT, UGT, NAT2, and CES enzymes, ABC and SLC transporters, and 5-HT receptors) on fesoterodine pharmacokinetics and their safety in 39 healthy volunteers from three bioequivalence trials. Results: An association between 5-HMT exposure (dose/weight corrected area under the curve (AUC/DW) and dose/weight corrected maximum plasma concentration (C max /DW)), elimination (terminal half-life (T 1/2 ) and the total drug clearance adjusted for bioavailability (Cl/F)), and CYP2D6 activity was observed. Poor/intermediate metabolizers (PMs/IMs) had higher 5-HMT AUC/DW (1.5-fold) and C max /DW (1.4-fold) values than the normal metabolizers (NMs); in addition, the normal metabolizers (NMs) had higher 5-HMT AUC/DW (1.7-fold) and C max /DW (1.3-fold) values than the ultrarapid metabolizers (UMs). Lower 5-HMT exposure and higher T 1/2 were observed for the CYP3A4 IMs compared to the NMs, contrary to our expectations. Conclusions: CYP2D6 might have a more important role than CYP3A4 in fesoterodine pharmacokinetics, and its phenotype might be a better predictor of variation in its pharmacokinetics. An association was observed between different genetic variants of different genes of the UGT family and AUC, C max , and CL/F of 5-HMT, which should be confirmed in other studies.

Introduction: Bioequivalence clinical trials are conducted in healthy volunteers whose blood tests should be within normal limits; individuals with Gilbert syndrome (GS) are excluded from these studies on suspicion of any liver disease, even if the change is clinically insignificant. GS is a benign genetic disorder characterized by elevated bilirubin levels, the primary cause of which is the presence of polymorphisms in UGT1A1 gene. In this work, subjects with UGT1A1 intermediate (IM) or poor (PM) metabolizer genotype-informed phenotypes were investigated to determine whether they have a higher incidence of liver disease or other biochemical parameters. Methods: The study population comprised 773 healthy volunteers who underwent biochemical analysis at baseline and at the end of the study which were genotyped for UGT1A1*80 (rs887829), as an indicator of UGT1A1*80+*28 (rs887829 and rs3064744), and UGT1A1*6 (rs4148323). Results: Bilirubin levels were higher in subjects IMs and PMs compared to normal metabolizers (NMs). Decreased uric acid levels was observed in PMs compared to NMs. No associations were observed in liver enzyme levels according to UGT1A1 phenotype. Discussion: Considering that there is no hepatic toxicity in subjects with UGT1A1 IM or PM phenotype, who are more likely to develop GS, this study suggests that they could be included in bioequivalence clinical trials as their biochemical parameters are not affected outside normal ranges., Competing Interests: FA-S and DO have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Aptatargets, Chemo, Cinfa, FAES, Farmal’ der, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern, Moderna, MSD, Normon, Novartis, Servier, Silver Pharma, Teva, and Zambon. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor JA declared a past co-authorship with the author FA-S., (Copyright © 2024 González-Iglesias, Ochoa, Román, Soria-Chacartegui, Martín-Vilchez, Navares-Gómez, De Miguel, Zubiaur, Rodríguez-Lopez, Abad-Santos and Novalbos.)

Proton pump inhibitors (PPIs) are the first-line drug for eosinophilic esophagitis (EoE), although it is estimated that there is a lack of histological remission in 50% of patients. This research aimed to identify pharmacogenetic biomarkers predictive of PPI effectiveness and to study their association with disease features. Peak eosinophil count (PEC) and the endoscopic reference score (EREFS) were determined before and after an eight-week PPI course in 28 EoE patients. The impact of the signal transducer and activator of transcription 6 ( STAT6 ), CYP2C19 , CYP3A4 , CYP3A5, and ABCB1 genetic variations on baseline PEC and EREFS, their reduction and histological response, and on EoE symptoms and comorbidities was analyzed. PEC reduction was higher in omeprazole-treated patients (92.5%) compared to other PPIs (57.9%, p = 0.003). STAT6 rs12368672 (g.18453G>C) G/G genotype showed higher baseline PEC values compared to G/C and C/C genotypes (83.2 vs. 52.9, p = 0.027). EREFS reduction in STAT6 rs12368672 G/G and G/C genotypes was higher than in the C/C genotype (36.7% vs. -75.0% p = 0.011). However, significance was lost after Bonferroni correction. Heartburn incidence was higher in STAT6 rs167769 (g.27148G>A) G/G patients compared to G/A (54.55% vs. 11.77%, p = 0.030). STAT6 rs12368672G>C and rs167769G>A variants might have a relevant impact on EoE status and PPI response. Further research is warranted to clarify the clinical relevance of these variants.

Tramadol is an important minor opioid prescribed for pain management. In this study, we analyzed the well-known impact of CYP2D6 genetic variation and 60 additional variants in eight candidate genes (i.e., ABCG2, SLCO1B1, CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A5, and CYP3A4) on tramadol efficacy and safety. Some 108 patients with pain after surgery admitted to a post-anesthesia care unit (PACU) and prescribed tramadol were recruited. They were genotyped, and tramadol M1/M2 metabolite concentrations were determined by a newly validated HPLC-MS/MS method. CYP2D6 intermediate (IM) and poor (PM) metabolizers showed lower M1 concentrations adjusted for dose/weight at 30 and 120 min compared to ultrarapid (UM) and normal (NM) metabolizers (univariate p < 0.001 and 0.020, multivariate p < 0.001 and 0.001, unstandardized β coefficients = 0.386 and 0.346, R 2  = 0.146 and 0.120, respectively). CYP2B6 PMs (n = 10) were significantly related to a higher reduction in pain 30 min after tramadol intake (univariate p = 0.038, multivariate p = 0.016, unstandardized β coefficient = 0.224, R 2  = 0.178), to lower PACU admission time (p = 0.007), and to lower incidence of adverse drug reactions (p = 0.038) compared to the other phenotypes. CYP3A4 IMs and PMs showed a higher prevalence of drowsiness and dizziness (p = 0.028 and 0.005, respectively). Our results suggest that the interaction of CYP2B6 and CYP2D6 phenotypes may be clinically relevant, pending validation of these results in large, independent cohorts. Additional research is required to clarify the impact of CYP3A4 genetic variation on tramadol response., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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.

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, R 2 = 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, R 2 = 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.

Methotrexate is an essential drug in the treatment of childhood cancer that is not exempt from toxicities. Glucarpidase is a drug used to reduce the toxic concentration of plasma methotrexate in patients with delayed elimination or at risk of toxicity. We describe the characteristics of a cohort of pediatric patients that received glucarpidase and analyze its role in the treatment of toxicity induced by high doses of methotrexate (HDMTX). Retrospective observational study of all pediatric cancer patients who received glucarpidase between 2012 and 2022 at a single center. Fifteen patients were treated with a single dose of glucarpidase, eleven of them presented with acute lymphoblastic leukemia and received HDMTX at 5 g/m 2 in 24-hour infusion. In eight patients, glucarpidase was administered during the first cycle of HDMTX. The indication in thirteen cases was acute renal failure with delayed elimination of plasma methotrexate. The median maximum creatinine was 1.22 mg/dl (0.68 2.01 mg/dl), with a median increase over its baseline level of 313%. All patients normalized renal function after glucarpidase administration, with a median methotrexate excretion time of 193 hours (42-312 hours). No grade ≥2 adverse events derived from carboxypeptidase administration. Eleven patients received new doses of HDMTX in subsequent cycles, without new episodes of serious toxicity. The use of glucarpidase is effective and safe in the treatment of acute renal failure and methotrexate elimination delay in pediatric cancer patients. Further HDMTX doses may be prescribed without additional toxicities., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Rivaroxaban is a direct inhibitor of factor Xa, a member of direct oral anticoagulant group of drugs (DOACs). Despite being a widely extended alternative to vitamin K antagonists (i.e., acenocoumarol, warfarin) the interindividual variability of DOACs is significant, and may be related to adverse drug reaction occurrence or drug inefficacy, namely hemorrhagic or thromboembolic events. Since there is not a consistent analytic practice to monitor the anticoagulant activity of DOACs, previously reported polymorphisms in genes coding for proteins responsible for the activation, transport, or metabolism of DOACs were studied. The study population comprised 60 healthy volunteers, who completed two randomized, crossover bioequivalence clinical trials between two different rivaroxaban formulations. The effect of food, sex, biogeographical origin and 55 variants (8 phenotypes and 47 single nucleotide polymorphisms) in drug metabolizing enzyme genes (such as CYP2D6, CYP2C9, NAT2) and transporters (namely, ABCB1, ABCG2) on rivaroxaban pharmacokinetics was tested. Individuals dosed under fasting conditions presented lower t max (2.21 h vs 2.88 h, β = 1.19, R 2 =0.342, p = 0.012) compared to fed volunteers. NAT2 slow acetylators presented higher AUC ∞ corrected by dose/weight (AUC ∞ /DW; 8243.90 vs 7698.20 and 7161.25 h*ng*mg /ml*kg, β = 0.154, R 2 =0.250, p = 0.044), higher C max /DW (1070.99 vs 834.81 and 803.36 ng*mg /ml*kg, β = 0.245, R 2 =0.320, p = 0.002), and lower t max (2.63 vs 3.19 and 4.15 h, β = -0.346, R 2 =0.282, p = 0.047) than NAT2 rapid and intermediate acetylators. No other association was statistically significant. Thus, slow NAT2 appear to have altered rivaroxaban pharmacokinetics, increasing AUC ∞ and C max . Nonetheless, further research should be conducted to verify NAT2 involvement on rivaroxaban pharmacokinetics and to determine its clinical significance., Competing Interests: Declaration of Competing Interest Francisco Abad-Santos and Dolores Ochoa have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmal’der, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Janssen-Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

For patients with type 2 diabetes, metformin is the most often recommended drug. However, there are substantial individual differences in the pharmacological response to metformin. To investigate the effect of transporter polymorphisms on metformin pharmacokinetics in an environment free of confounding variables, we conducted our study on healthy participants. This is the first investigation to consider demographic characteristics alongside all transporters involved in metformin distribution. Pharmacokinetic parameters of metformin were found to be affected by age, sex, ethnicity, and several polymorphisms. Age and SLC22A4 and SLC47A2 polymorphisms affected the area under the concentration-time curve (AUC). However, after adjusting for dose-to-weight ratio (dW), sex, age, and ethnicity, along with SLC22A3 and SLC22A4 , influenced AUC. The maximum concentration was affected by age and SLC22A1 , but after adjusting for dW, it was affected by sex, age, ethnicity, ABCG2 , and SLC22A4 . The time to reach the maximum concentration was influenced by sex, like half-life, which was also affected by SLC22A3 . The volume of distribution and clearance was affected by sex, age, ethnicity and SLC22A3 . Alternatively, the pharmacokinetics of metformin was unaffected by polymorphisms in ABCB1 , SLC2A2 , SLC22A2 , or SLC47A1 . Therefore, our study demonstrates that a multifactorial approach to all patient characteristics is necessary for better individualization.

Venlafaxine pharmacokinetic variability and pharmacotherapy outcomes are well known to be related to CYP2D6 pharmacogenetic phenotype. In contrast, scarce pharmacogenetic information is available nowadays concerning desvenlafaxine, its active metabolite first marketed in 2012. The aim of this study was to evaluate the impact of 29 alleles in 12 candidate genes (e.g., CYP enzymes like CYP2D6 , CYP3A4 , or CYP2C19 ; ABC transporters like ABCB1 ; SLCO1B1 ; and UGT enzymes like UGT1A1 ) on desvenlafaxine pharmacokinetic variability and tolerability. Pharmacokinetic parameters and adverse drug reaction (ADR) incidence obtained from six bioequivalence clinical trials ( n = 98) evaluating desvenlafaxine formulations (five with single dose administration and one with multiple-dose administration) were analyzed. No genetic polymorphism was related to pharmacokinetic variability or ADR incidence. Volunteers enrolled in the multiple-dose clinical trial also showed a higher incidence of ADRs, e.g., xerostomia or appetite disorders. Volunteers experiencing any ADR showed a significantly higher area under the time-concentration curve (AUC) than those not experiencing any ADR (5115.35 vs. 4279.04 ng*h/mL, respectively, p = 0.034). In conclusion, the strong dose-dependent relationship with the occurrence of ADRs confirms that the mechanism of action of desvenlafaxine is essentially dose-dependent., Competing Interests: FA-S, DO , and MR have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Aptatargets, Chemo, FAES, Farmalider, Ferrer, Galenicum, GlaxoSmithKline, Gilead, Italfarmaco, Janssen-Cilag, Kern, Normon, Novartis, Servier, Teva, and Zambon. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Calleja, Zubiaur, Ochoa, Villapalos-García, Mejia-Abril, Soria-Chacartegui, Navares-Gómez, de Miguel, Román, Martín-Vílchez and Abad-Santos.)

Amlodipine is an antihypertensive drug with unknown pharmacogenetic biomarkers. This research is a candidate gene study that looked for associations between amlodipine pharmacokinetics and safety and pharmacogenes. Pharmacokinetic and safety data were taken from 160 volunteers from eight bioequivalence trials. In the exploratory step, 70 volunteers were genotyped for 44 polymorphisms in different pharmacogenes. CYP2D6 poor metabolizers (PMs) showed higher half-life (t 1/2 ) (univariate p -value ( p uv ) = 0.039, multivariate p -value ( p mv ) = 0.013, β = -5.31, R 2 = 0.176) compared to ultrarapid (UMs), normal (NMs) and intermediate metabolizers (IMs). SLC22A1 rs34059508 G/A genotype was associated with higher dose/weight-corrected area under the curve (AUC 72 /DW) ( p uv = 0.025; p mv = 0.026, β = 578.90, R 2 = 0.060) compared to the G/G genotype. In the confirmatory step, the cohort was increased to 160 volunteers, who were genotyped for CYP2D6 , SLC22A1 and CYP3A4 . In addition to the previous associations, CYP2D6 UMs showed a lower AUC 72 /DW ( p uv = 0.046, p mv = 0.049, β = -68.80, R 2 = 0.073) compared to NMs, IMs and PMs and the SLC22A1 rs34059508 G/A genotype was associated with thoracic pain ( p uv = 0.038) and dizziness ( p uv = 0.038, p mv = 0.014, log OR = 10.975). To our knowledge, this is the first work to report a strong relationship between amlodipine and CYP2D6 and SLC22A1 . Further research is needed to gather more evidence before its application in clinical practice.

Cinitapride is a gastrointestinal prokinetic drug, prescribed for the treatment of functional dyspepsia, and as an adjuvant therapy for gastroesophageal reflux disease. In this study, we aimed to explore the impact of relevant variants in CYP3A4 and CYP2C8 and other pharmacogenes, along with demographic characteristics, on cinitapride pharmacokinetics and safety; and to evaluate the impact of CYP2C8 alleles on the enzyme's function. Twenty-five healthy volunteers participating in a bioequivalence clinical trial consented to participate in the study. Participants were genotyped for 56 variants in 19 genes, including cytochrome P450 (CYP) enzymes (e.g., CYP2C8 or CYP3A4) or transporters (e.g., SLC or ABC), among others. CYP2C8*3 carriers showed a reduction in AUC of 42% and C max of 35% compared to *1/*1 subjects (p = 0.003 and p = 0.011, respectively). *4 allele carriers showed a 45% increase in AUC and 63% in C max compared to *1/*1 subjects, although these differences did not reach statistical significance. CYP2C8*3 and *4 alleles may be used to infer the following pharmacogenetic phenotypes: ultrarapid (UM) (*3/*3), rapid (RM) (*1/*3), normal (NM) (*1/*1), intermediate (IM) (*1/*4), and poor (PM) metabolizers (*4/*4). In this study, we properly characterized RMs, NMs, and IMs; however, additional studies are required to properly characterize UMs and PMs. These findings should be relevant with respect to cinitapride, but also to numerous CYP2C8 substrates such as imatinib, loperamide, montelukast, ibuprofen, paclitaxel, pioglitazone, repaglinide, or rosiglitazone., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Diazepam is a benzodiazepine (BZD) used worldwide for a variety of conditions. Long-term use of diazepam increases the risk for developing tolerance and dependence and for the occurrence of adverse drug reactions (ADRs). CYP3A4 and CYP2C19 mainly metabolize diazepam and are therefore the primary pharmacogenetic candidate biomarkers. In this work, we aimed to explore the impact of CYP3A4 and CYP2C19 phenotypes and of 99 additional variants in other 31 pharmacogenes (including other CYP, UGT, NAT2 and CES enzymes, ABC and SLC transporters) on diazepam pharmacokinetic variability and safety. 30 healthy volunteers that had participated in a single-dose bioequivalence clinical trial of two diazepam formulations were enrolled in the present candidate gene pharmacogenetic study. CYP2C19 poor metabolizers (PMs) showed an almost 2-fold increase in AUC 0-∞/ DW compared to rapid (RMs) or normal (NM) metabolizers, and a 1.46-fold increase compared to intermediate metabolizers (IMs). CYP2B6 PMs showed a 2,74-fold higher AUC 0-∞ /DW compared to RMs, and 2.10-fold compared to NMs (p < 0.007). A dose reduction of 25-50 % may be appropriate for CYP2C19 or CYP2B6 PMs to avoid ADRs, dependence and tolerance. Combined CYP2C19 +CYP2B6 PMs may not use diazepam or sharper dose adjustments (e.g., a dose reduction of 50-70 %) may be advisable. To our knowledge, this is the first work to report a strong relationship between CYP2B6 phenotype and diazepam pharmacokinetics. Additional nominal associations (i.e., 0.007 

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.

Introduction: Thiopurine drugs are purine nucleoside analogues used for treatment of different immune-related conditions. To date, different studies highlighted the importance of thiopurine methyltransferase (TPMT) genotyping in patients who initiate treatment with thiopurines to make an adequate dose adjustment. We aimed to investigate the influence of TPMT phenotype, concomitant treatments, and demographic characteristics on the incidence of adverse reactions (ADRs) in patients who start treatment with azathioprine (AZA)., Methods: This was an observational and retrospective study. The study population comprised 109 patients who started treatment with AZA following routine TPMT genotyping before June 2019 and who were routinely followed up at Hospital Universitario de La Princesa. The incidence of ADRs and treatment duration were evaluated according to TPMT phenotype., Results: Forty-five men and 64 women were recruited, with a mean age of 67.6 ± 18.5. The medical specialty with the most requests was dermatology (45.9%) and the most frequent disease for which genotyping was requested was bullous pemphigoid (27.5%). All patients were normal metabolizers (NM), except for eight intermediate metabolizers (IM) (7.3%); no poor metabolizers (PM) were found. The initial azathioprine dose was subtherapeutic in both groups (103.2 ± 45.4 mg in NMs and 75 ± 32.3 mg in IMs), increasing during the first months of treatment, especially in NMs (120.3 ± 41.3 vs. 78.6 ± 30.4 mg in IMs, p = 0.011). Most patients (73.4%) received corticosteroids to keep the disease under control; and for 41.2% of NMs, physicians were able to reduce the dose at 6 months post treatment. No IMs completed 6 months of treatment. Hepatotoxicity, gastric intolerance, and blood disorders were the most common ADRs. The incidence of ADRs in the sample was 28.4% (n = 31) with a similar trend between IMs (37.5%) and NMs (27.8%). Patients undergoing concomitant treatment with allopurinol were associated with a higher incidence of ADRs (n = 4, 100% vs. n = 105, 20%; p = 0.002)., Conclusion: TPMT genotyping before AZA prescription reduces ADR incidence in IMs to a similar level as NMs in the Spanish population. However, it is important to note no IMs completed 6 months of treatment, suggesting that there may be some differences in drug tolerability according to phenotype. In addition, most NMs are treated with subtherapeutic doses, are poorly followed up, and thus suffer avoidable ADRs. Finally, concomitant therapies that inhibit the xanthine oxidase enzyme (XDH), such as allopurinol, predispose to ADRs. Therefore, pharmacogenetic testing should be integrated as an additional clinical tool, in such a way that each patient receives personalized, precision treatment, where all factors influencing drug response are considered., (© 2022. The Author(s).)

The process of clinical pharmacogenetics implementation depends on patients' and general population's perceptions. To date, no study has been published addressing Spanish patients' opinions on pharmacogenetic testing, the availability of the results, and the need for signing informed consent. In this work, we contacted 146 patients that had been previously genotyped at our laboratory and 46 healthy volunteers that had participated in a bioequivalence clinical trial at the Clinical Pharmacology Department of Hospital Universitario de La Princesa and consented to pharmacogenetic testing for research purposes. From the latter, 108 and 34, respectively, responded to the questionnaire (i.e., a response rate of 74%); Participants were scheduled for a face-to-face, telephone, or videoconference interview and were asked a total of 27 questions in Spanish. Great or almost complete acceptance of pharmacogenetic testing was observed (99.3%), age and university education level being the main predictors of acceptance rates and understanding (multivariate analysis, p = 0.004, R 2 = 0.17, age being inversely proportional to acceptance rates and understanding and university level being related to higher acceptance rates and understanding compared to other education levels). Mixed perceptions were observed on the requirement of written informed consent (55.6% in favor); therefore, it seems recommendable to continue requesting it for the upcoming years until more perceptions are collected. The majority of participants (95.8%) preferred storing pharmacogenetic results in medical records rather than in electronic sources (55.6%) and highly agreed with the possibility of carrying their results on a portable card (91.5%). Patients agreed to broad genetic testing, including biomarkers unrelated to their disease (93.7%) or with little clinically relevant evidence (94.4%). Patients apparently rely on clinician's or pharmacogeneticist's interpretation and seem, therefore, open to the generation of ethically challenging information. Finally, although most patients (68.3%) agreed with universal population testing, some were reluctant, probably due to the related costs and sustainability of the Spanish Health System. This was especially evident in the group of patients who were older and with a likely higher proportion of pensioners.

Among cancer patients treated with fluoropyrimidines, 10-40% develop severe toxicity. Polymorphism of the dihydropyrimidine dehydrogenase ( DPYD ) gene may reduce DPD function, the main enzyme responsible for the metabolism of fluoropyrimidines. This leads to drug accumulation and to an increased risk of toxicity. Routine genotyping of this gene, which usually includes DPYD *HapB3, *2A, *13 and c.2846A > T (D949V) variants, helps predict approximately 20-30% of toxicity cases. For DPD intermediate (IM) or poor (PM) metabolizers, a dose adjustment or drug switch is warranted to avoid toxicity, respectively. Societies such as the Spanish Society of Pharmacogenetics and Pharmacogenomics (SEFF), the Dutch Pharmacogenetics Working Group (DPWG) or the Clinical Pharmacogenetics Implementation Consortium (CPIC) and regulatory agencies (e.g., the Spanish Medicines Agency, AEMPS) already recommend DPYD routine genotyping. However, the predictive capacity of genotyping is currently still limited. This can be explained by the presence of unknown polymorphisms affecting the function of the enzyme. In this case-control work, 11 cases of severe fluoropyrimidine toxicity in patients who did not carry any of the four variants mentioned above were matched with 22 controls, who did not develop toxicity and did not carry any variant. The DPYD exome was sequenced (Sanger) in search of potentially pathogenic mutations. DPYD rs367619008 (c.187 A > G, p.Lys63Glu), rs200643089 (c.2324 T > G, p.Leu775Trp) and rs76387818 (c.1084G > A, p.Val362Ile) increased the percentage of explained toxicities to 38-48%. Moreover, there was an intronic variant considered potentially pathogenic: rs944174134 (c.322-63G > A). Further studies are needed to confirm its clinical relevance. The remaining variants were considered non-pathogenic.

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., Competing Interests: FA-S and DO have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmal’der, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Janssen-Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Villapalos-García, Zubiaur, Navares-Gómez, Saiz-Rodríguez, Mejía-Abril, Martín-Vílchez, Román, Ochoa and Abad-Santos.)

Quetiapine is an atypical antipsychotic widely used for the treatment of schizophrenia and the depressive episodes of bipolar disorder. The aim of this work was to investigate the effect of variants in relevant pharmacogenes in the pharmacokinetics of quetiapine and to exploratorily evaluate adverse drug reaction (ADR) incidence based on genetic polymorphism. Specifically, 49 healthy volunteers enrolled in two bioequivalence clinical trials were included in this study. In addition, 80 variants in 19 relevant pharmacogenes were genotyped, including cytochrome P450 (CYP) genes, catechol-O-methyl transferase ( COMT ), other enzymes (e.g., UGT1A1 or UGT1A4 ), and transporters (e.g., SLCO1B1, ABCB1 , or ABCG2 ). The COMT rs13306278 T allele was significantly related to quetiapine-increased exposure. We demonstrated the existence of quetiapine derivatives with a catechol-like structure (7,8-dihydroxi-quetiapine and 7,8-dihydroxi-N-desalkyl-quetiapine), which would be COMT metabolites and would explain quetiapine accumulation through CYP2D6 and CYP3A4 negative feedback. Moreover, CYP3A5 and CYP2B6 phenotypes were related to quetiapine exposure variability, which confirms (for CYP3A5) and suggests (for CYP2B6) that these enzymes play an important role in quetiapine's metabolism. Finally, the ABCG2 rs2231142 T allele was related to quetiapine accumulation. Further studies are required to confirm the clinical relevance of our findings.

The implementation of clinical pharmacogenetics in daily practice is limited for various reasons. Today, however, it is a discipline in full expansion. Accordingly, in the recent times, several initiatives promoted its implementation, mainly in the United States but also in Europe. In this document, the genotyping results since the establishment of our Pharmacogenetics Unit in 2006 are described, as well as the historical implementation process that was carried out since then. Finally, this progress justified the constitution of La Princesa University Hospital Multidisciplinary Initiative for the Implementation of Pharmacogenetics (PriME-PGx), promoted by the Clinical Pharmacology Department of Hospital Universitario de La Princesa (Madrid, Spain). Here, we present the initiative along with the two first ongoing projects: the PROFILE project, which promotes modernization of pharmacogenetic reporting (i.e., from classic gene-drug pair reporting to complete pharmacogenetic reporting or the creation of pharmacogenetic profiles specific to the Hospital's departments) and the GENOTRIAL project, which promotes the communication of relevant pharmacogenetic findings to any healthy volunteer participating in any bioequivalence clinical trial at the Clinical Trials Unit of Hospital Universitario de La Princesa (UECHUP).

Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. CYP or UGT ) or transporters (e.g., ABC or SLC ) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men ( p < 0.05 in univariate and multivariate analysis). CYP1A2* 1B allele, CYP2B6 IM/PM and CYP2D6 IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the CYP1A2 *1 allele, CYP2B6 NM/RM and CYP2D6 NM/UM phenotypes ( p < 0.05 in the univariate analysis). ABCB1 C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles ( p < 0.05 in univariate and multivariate analysis). ABCB1 C1236TT allele was also related to lower AUC/DW ( p < 0.05 in multivariate analysis). The remaining studied transporter genes ( ABCC2 , SLC22A1 , and SLCO1B1 ) and metabolizing enzyme genes ( CYP3A5 , CYP2C19 , CYP2C9 , CYP2C8 , CYP3A4 , CYP2A6 , and UGT1A1 ) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in CYP2B6 , CYP2D6 , CYP1A2 and ABCB1 on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines., Competing Interests: FA-S and DO have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. The reminaing authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mejía-Abril, Zubiaur, Navares-Gómez, Villapalos-García, Román, Ochoa and Abad-Santos.)

Abacavir (ABC) is an HIV nucleotide-analogue reverse transcriptase inhibitor that can produce a severe hypersensitivity reaction (ABC-HSR) in about 5% of the patients. The HLA-B*57:01 allele is associated with the development of ABC-HSR. Therefore, HLA-B*57:01 genotyping is required prior to the prescription of ABC. The technique routinely used in our laboratory is the sequence-specific oligonucleotide probes (SSOP) reverse hybridization method followed by Sanger sequencing. This technique is time-consuming and expensive. The single-nucleotide polymorphism (SNP) HCP5 rs2395029 was described to be in complete linkage disequilibrium with HLA-B*57:01. In this study, we aimed to assess the linkage disequilibrium between HCP5 rs2395029 and HLA-B*57:01 in patients receiving medical assistance at our hospital. We selected 226 HIV-infected patients from our hospital who had been routinely genotyped since 2009 with the SSOP and Sanger sequencing method: 49 HLA-B*57:01 positives and 177 negatives. We genotyped them for HCP5 rs2395019 by real time PCR (qPCR). We exploratory performed two copy number variation assays flanking HCP5 rs2395019 to explore possible deletions that could break the linkage disequilibrium with HLA-B*57:01. The concordance between HLA-B*57:01 and the HCP5 rs2395029 G allele was absolute, with a specificity and sensitivity of 100% (95% confidence interval: 93.0-100.0% and 98.0-100.0%, respectively) and estimated positive and negative predictive values of 84.4% (48.1-93.9%) and 99.9% (99.4-100.0%), respectively. No deletions were found at HCP5 flanking regions. The duration and cost of the SSOP-based method was considerably higher than the SNP-based method. Therefore, the HCP5 rs2395029 genotyping method may be alternatively used in the clinical practice., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Atorvastatin, prescribed for the treatment of hypercholesterolemia, demonstrated overwhelming benefits in reducing cardiovascular morbidity and mortality. However, many patients discontinue therapy due to adverse reactions, especially myopathy. The Dutch Pharmacogenetics Working Group (DPWG) recommends an alternative agent to atorvastatin and simvastatin or a dose adjustment depending on other risk factors for statin-induced myopathy in SLCO1B1 rs4149056 CC or TC carriers. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their guideline on simvastatin, but not on atorvastatin. In this work, we aimed to demonstrate the effect of SLCO1B1 phenotype and other variants (e.g., in CYP3A4/5 , UGT enzymes or SLC transporters) on atorvastatin pharmacokinetics. For this purpose, a candidate-gene pharmacogenetic study was proposed. The study population comprised 156 healthy volunteers enrolled in atorvastatin bioequivalence clinical trials. The genotyping strategy comprised a total of 60 variants in 15 genes. Women showed higher exposure to atorvastatin compared to men ( p = 0.001), however this difference disappeared after dose/weight (DW) correction. The most relevant pharmacogenetic differences were the following: AUC/DW and C max /DW based on (a) SLCO1B1 phenotype ( p < 0.001 for both) and (b) CYP3A5 *3 ( p = 0.004 and 0.018, respectively). As secondary findings: SLC22A1 *2/*2 genotype was related to higher C max /DW (ANOVA p = 0.030) and SLC22A1 *1/*5 genotype was associated with higher Vd/F (ANOVA p = 0.032) compared to SLC22A1 *1/*1, respectively. Finally, UGT2B7 rs7439366 *1/*1 genotype was associated with higher t max as compared with the *1/*3 genotype (ANOVA p = 0.024). Based on our results, we suggest that SLCO1B1 is the best predictor for atorvastatin pharmacokinetic variability and that prescription should be adjusted based on it. We suggest that the CPIC should include atorvastatin in their statin-SLCO1B1 guidelines. Interesting and novel results were observed based on CYP3A5 genotype, which should be confirmed with further studies.

Introduction: Aripiprazole and olanzapine are atypical antipsychotics. Both drugs can induce metabolic changes; however, the metabolic side effects produced by aripiprazole are more benign. The aim of the study was to evaluate if aripiprazole and olanzapine alter prolactin levels, lipid and glucose metabolism and hepatic, haematological, thyroid and renal function., Methods: Twenty-four healthy volunteers received a daily oral dose of 10 mg aripiprazole and 5 mg olanzapine tablets for 5 days in a crossover randomised clinical trial and were genotyped for 51 polymorphisms in 18 genes by qPCR. Drug plasma concentrations were measured by LC-MS. The biochemical and haematological analyses were performed by enzymatic methods., Results: Olanzapine induced hyperprolactinaemia but aripiprazole did not. Dopamine D3 receptor (DRD3) Ser/Gly and ATP binding cassette subfamily B member 1 (ABCB1) rs10280101, rs12720067 and rs11983225 polymorphisms and cytochrome P450 3A (CYP3A) phenotype had an impact on plasma prolactin levels. C-peptide concentrations were higher after aripiprazole administration and were influenced by catechol-O-methyltransferase (COMT) rs4680 and rs13306278 polymorphisms. Olanzapine and the UDP glucuronosyltransferase family 1 member A1 (UGT1A1) rs887829 polymorphism were associated with elevated glucose levels. CYP3A poor metabolizers had increased insulin levels. Volunteers' weight decreased significantly during aripiprazole treatment and a tendency for weight gain was observed during olanzapine treatment. Triglyceride concentrations decreased as a result of olanzapine and aripiprazole treatment, and varied on the basis of CYP3A phenotypes and the apolipoprotein C-III (APOC3) rs4520 genotype. Cholesterol levels were also decreased and depended on 5-hydroxytryptamine receptor 2A (HTR2A) rs6314 polymorphism. All hepatic enzymes, platelet and albumin levels, and prothrombin time were altered during both treatments. Additionally, olanzapine reduced the leucocyte count, aripiprazole increased free T4 and both decreased uric acid concentrations., Conclusions: Short-term treatment with aripiprazole and olanzapine had a significant influence on the metabolic parameters. However, it seems that aripiprazole provokes less severe metabolic changes., Trial Registration: Clinical trial registration number (EUDRA-CT): 2018-000744-26.

Background and Objectives: Controversy exists regarding dose adjustment in patients treated with voriconazole due to the severity of the infections for which it is prescribed. The Dutch Pharmacogenetics Working Group (DPWG) recommends a 50% dose increase or decrease for cytochrome P450 (CYP) 2C19 ultrarapid (UM) or poor (PM) metabolizers, respectively. In contrast, for the previous phenotypes, the Clinical Pharmacogenetics Implementation Consortium (CPIC) voriconazole guideline only recommends a change of treatment. Based on observed data from single-dose bioequivalence studies and steady-state observed concentrations, we aimed to investigate voriconazole dose adjustments by means of physiologically based pharmacokinetic (PBPK) modeling., Methods: PBPK modeling was used to optimize voriconazole single-dose models for each CYP2C19 phenotype, which were extrapolated to steady state and evaluated for concordance with the therapeutic range of voriconazole. Based on optimized models, dose adjustments were evaluated for better adjustment to the therapeutic range., Results: Our models suggest that the standard dose may only be appropriate for normal metabolizers (NM), although they would benefit from a 50-100% loading dose increase. Intermediate metabolizers (IMs) and PMs required a daily dose reduction of 50 and 75%, respectively. Rapid metabolizers (RMs) and UMs required a daily dose increase of 100% and 300%, respectively., Conclusion: The prescription of voriconazole in clinical practice should be personalized according to the CYP2C19 phenotype, followed by therapeutic drug monitoring of plasma concentrations to guide dose adjustment.

Objective: To assess adverse events (AEs) and safety of aripiprazole (ARI) and olanzapine (OLA) treatment., Methods: Twenty-four healthy volunteers receiving five daily oral doses of 10 mg ARI and 5 mg OLA in a crossover clinical trial were genotyped for 46 polymorphisms in 14 genes by qPCR. Drug plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Blood pressure (BP) and 12-lead electrocardiogram were measured in supine position. AEs were also recorded., Results: ARI decreased diastolic BP on the first day and decreased QTc on the third and fifth day. OLA had a systolic and diastolic BP, heart rate and QTc lowering effect on the first day. Polymorphisms in ADRA2A, COMT, DRD3 and HTR2A genes were significantly associated to these changes. The most frequent adverse drug reactions (ADRs) to ARI were somnolence, headache, insomnia, dizziness, restlessness, palpitations, akathisia and nausea while were somnolence, dizziness, asthenia, constipation, dry mouth, headache and nausea to OLA. Additionally, HTR2A, HTR2C, DRD2, DRD3, OPRM1, UGT1A1 and CYP1A2 polymorphisms had a role in the development of ADRs., Conclusions: OLA induced more cardiovascular changes; however, more ADRs were registered to ARI. In addition, some polymorphisms may explain the difference in the incidence of these effects among subjects., (© 2020 John Wiley & Sons Ltd.)

Olanzapine is an atypical antipsychotic widely used for the treatment of schizophrenia, which often causes serious adverse drug reactions. Currently, there are no clinical guidelines implementing pharmacogenetic information on olanzapine. Moreover, the Dutch Pharmacogenomics Working Group (DPWG) states that CYP2D6 phenotype is not related to olanzapine response or side effects. Thus, the objective of this candidate-gene study was to investigate the effect of 72 polymorphisms in 21 genes on olanzapine pharmacokinetics and safety, including transporters (e.g. ABCB1, ABCC2, SLC22A1), receptors (e.g. DRD2, HTR2C), and enzymes (e.g. UGT, CYP and COMT), in a cohort of healthy volunteers. Polymorphisms in CYP2C9, SLC22A1, ABCB1, ABCC2, and APOC3 were related to olanzapine pharmacokinetic variability. The incidence of adverse reactions was related to several genes: palpitations to ABCB1 and SLC22A1, asthenia to ABCB1, somnolence to DRD2 and ABCB1, and dizziness to CYP2C9. However, further studies in patients are warranted to confirm the influence of these genetic polymorphisms on olanzapine pharmacokinetics and tolerability., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In December 2019, the severe acute respiratory syndrome virus-2 pandemic began, causing the coronavirus disease 2019. A vast variety of drugs is being used off-label as potential therapies. Many of the repurposed drugs have clinical pharmacogenetic guidelines available with therapeutic recommendations when prescribed as indicated on the drug label. The aim of this review is to provide a comprehensive summary of pharmacogenetic biomarkers available for these drugs, which may help to prescribe them more safely., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Aims: Pupillography is a noninvasive and cost-effective method to determine autonomic nerve activity. Genetic variants in cytochrome P450 (CYP), dopamine receptor (DRD2, DRD3), serotonin receptor (HTR2A, HTR2C) and ATP-binding cassette subfamily B (ABCB1) genes, among others, were previously associated with the pharmacokinetics and pharmacodynamics of antipsychotic drugs. Our aim was to evaluate the effects of aripiprazole and olanzapine on pupillary light reflex related to pharmacogenetics., Methods: Twenty-four healthy volunteers receiving 5 oral doses of 10 mg aripiprazole and 5 mg olanzapine tablets were genotyped for 46 polymorphisms by quantitative polymerase chain reaction. Pupil examination was performed by automated pupillometry. Aripiprazole, dehydro-aripiprazole and olanzapine plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry., Results: Aripiprazole affected pupil contraction: it caused dilatation after the administration of the first dose, then caused constriction after each dosing. It induced changes in all pupillometric parameters (P < .05). Olanzapine only altered minimum pupil size (P = .046). Polymorphisms in CYP3A, HTR2A, UGT1A1, DRD2 and ABCB1 affected pupil size, the time of onset of constriction, pupil recovery and constriction velocity. Aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics were significantly affected by polymorphisms in CYP2D6, CYP3A, CYP1A2, ABCB1 and UGT1A1 genes., Conclusions: In conclusion, aripiprazole and its main metabolite, dehydro-aripiprazole altered pupil contraction, but olanzapine did not have such an effect. Many polymorphisms may influence pupillometric parameters and several polymorphisms had an effect on aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics. Pupillography could be a useful tool for the determination of autonomic nerve activity during antipsychotic treatment., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Dabigatran is a direct oral anticoagulant (DOAC) used for the treatment of several thrombotic conditions. To date, very few pharmacogenetic studies on dabigatran were published. We aimed to investigate the influence of 59 polymorphisms in 15 genes (including CES1, UGT and CYP that encode enzymes and ABCB1 and SLC that encode transporters), concomitant treatment with pantoprazole and demographic characteristics (including sex or race) on dabigatran pharmacokinetics and safety., Methods: This was a candidate gene pharmacogenetic study. The study population comprised 107 volunteers enrolled in two dabigatran bioequivalence clinical trials; they were genotyped with a ThermoFisher QuantStudio 12K Flex OpenArray instrument. SPSS software v.21 was used for statistical analysis., Results: Women showed a higher exposure to dabigatran compared to men. The concomitant treatment with pantoprazole was associated with a decreased exposure to the drug. CYP2D6 poor metabolizers (PMs) were related to lower clearance (Cl/F) (p = 0.049) and a tendency was observed towards higher area under the curve (AUC), maximum concentration (C max ) and to lower volume of distribution (V d /F) (p < 0.10). SLC22A1 haplotype was related to pharmacokinetic variability (p < 0.05). The remaining genes (including CYP, UGT1A1 and ABCB1) had no effect on dabigatran pharmacokinetics (p > 0.10). Women showed more adverse drug reactions (ADR) compared to men (0.40 ± 0.68 vs 0.15 ± 0.41 ADR per person, p = 0.03) and SLC22A1 mutant haplotype was related to a lower risk of nausea (p = 0.02)., Conclusion: Sex, concomitant use of pantoprazole and SLC22A1, CYP2D6 and CYP3A5 polymorphism had an effect on dabigatran pharmacokinetics and safety. Previously published pharmacogenetic predictors, namely CES1 or ABCB1 polymorphisms, had no effect on pharmacokinetics and safety. This study is of interest as it increases the scarce pharmacogenetic information on dabigatran.

Several cytochrome P450 (CYP) CYP3A polymorphisms were associated with reduced enzyme function. We aimed to evaluate the influence of these alleles on the pharmacokinetic parameters (PK) of several CYP3A substrates. We included 251 healthy volunteers who received a single dose of ambrisentan, atorvastatin, imatinib, aripiprazole, fentanyl, amlodipine, donepezil, olanzapine, fesoterodine, or quetiapine. The volunteers were genotyped for CYP3A4 and CYP3A5 polymorphisms by qPCR. To compare the PK across studies, measurements were corrected by the mean of each parameter for every drug and were logarithmically transformed. Neither CYP3A phenotype nor individual CYP3A4 or CYP3A5 polymorphisms were significantly associated with differences in PK. However, regarding the substrates that are exclusively metabolized by CYP3A, we observed a higher normalized AUC ( p = 0.099) and a tendency of lower normalized Cl ( p = 0.069) in CYP3A4 mutated allele carriers what was associated with diminished drug metabolism capacity. CYP3A4 polymorphisms did not show a pronounced influence on PK of the analysed drugs. If so, their impact could be detectable in a very small percentage of subjects. Although there are few subjects carrying CYP3A4 double mutations, the effect in those might be relevant, especially due to the majority of subjects lacking the CYP3A5 enzyme. In heterozygous subjects, the consequence might be less noticeable due to the high inducible potential of the CYP3A4 enzyme.