Effect of high versus low dose of dexamethasone on clinical worsening in patients hospitalised with moderate or severe COVID-19 pneumonia: an open-label, randomised clinical trial.

BACKGROUND: Low-dose dexamethasone demonstrated clinical improvement in patients with coronavirus disease 2019 (COVID-19) needing oxygen therapy; however, evidence on the efficacy of high-dose dexamethasone is limited. METHODS: We performed a randomised, open-label, controlled trial involving hospitalised patients with confirmed COVID-19 pneumonia needing oxygen therapy. Patients were randomly assigned in a 1:1 ratio to receive low-dose dexamethasone (6 mg once daily for 10 days) or high-dose dexamethasone (20 mg once daily for 5 days, followed by 10 mg once daily for an additional 5 days). The primary outcome was clinical worsening within 11 days since randomisation. Secondary outcomes included 28-day mortality, time to recovery and clinical status at day 5, 11, 14 and 28 on an ordinal scale ranging from 1 (discharged) to 7 (death). RESULTS: A total of 200 patients (mean±sd age 64±14 years; 62% male) were enrolled. 32 (31.4%) out of 102 patients enrolled in the low-dose group and 16 (16.3%) out of 98 in the high-dose group showed clinical worsening within 11 days since randomisation (rate ratio 0.427, 95% CI 0.216-0.842; p=0.014). The 28-day mortality was 5.9% in the low-dose group and 6.1% in the high-dose group (p=0.844). There was no significant difference in time to recovery, and in the seven-point ordinal scale at days 5, 11, 14 and 28. CONCLUSIONS: Among hospitalised COVID-19 patients needing oxygen therapy, high dose of dexamethasone reduced clinical worsening within 11 days after randomisation, compared with low dose.

Influence of Genetic Polymorphisms on the Response to Tramadol, Ibuprofen, and the Combination in Patients With Moderate to Severe Pain After Dental Surgery.

PURPOSE: We aimed to elucidate the influence on analgesic effect of genetic polymorphisms in enzymes responsible for biotransformation of tramadol and ibuprofen or other possible genes involved in their mechanism of action. METHODS: The study population comprised 118 patients from a multicenter, randomized, double-blind, placebo-controlled, Phase III clinical trial that assessed the analgesic efficacy and tolerability of a single dose of ibuprofen (arginine)/tramadol 400/37.5 mg compared with ibuprofen arginine 400 mg alone, tramadol 50 mg alone, and placebo in patients with moderate to severe pain after dental surgery. We analyzed 32 polymorphisms in the cytochrome P450 (CYP) enzymes COMT, ABCB1, SLC22A1, OPRM1, and SLC22A1. FINDINGS: We did not find any statistically significant difference among CYP2C9 phenotypes related to ibuprofen response, although CYP2C9 poor metabolizers had a longer effect (higher pain relief at 6 hours). Likewise, we did not find any statistically significant difference among PTGS2 genotypes, contradicting previously publications. IMPLICATIONS: There was not a clear effect of CYP2D6 phenotype on tramadol response, although CYP2D6 poor metabolizers had a slower analgesic effect. Concerning the transport of CYP2D6, we observed a better response in individuals carrying ABCB1 mutated alleles, which might correlate with higher tramadol plasma levels. Finally, we found a statistically significant better response in patients carrying the OPRM1 A118G G allele, which contradicts the previous reports. Measuring the active metabolite O-desmethyl-tramadol formation would be of great importance to better evaluate this association because O-desmethyl-tramadol has a higher µ-opioid receptor affinity compared with the parent drug. EudraCT.ema.europa.eu identifier: 2013-004637-33.

Effect of food on the pharmacokinetics of omeprazole, pantoprazole and rabeprazole.

BACKGROUND: The pharmacokinetics of proton pump inhibitors (PPIs) may be affected by food intake. We aimed to evaluate the effect of food on the pharmacokinetics of omeprazole, rabeprazole, and pantoprazole. SETTING: The study population comprised 186 healthy volunteers participating in 6 bioequivalence clinical trials. METHOD: Subjects were evaluated to determine the effect of a high-fat breakfast on the pharmacokinetics of omeprazole (n = 36), rabeprazole (n = 69), and pantoprazole (n = 81). MAIN OUTCOME MEASURE: Drug plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. RESULTS: Food affected the pharmacokinetics of omeprazole (increased Tmax and decreased AUC and Cmax), pantoprazole (increased Tmax and decreased AUC), and rabeprazole (increased Tmax, Cmax and half-life). Food increased variability in Tmax for all 3 drugs, delaying absorption around 3 to 4 h and until 20 h in some subjects. CONCLUSION: As food delays the absorption of PPIs and increases their variability, it would be better to administer these drugs under fasting conditions. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database: EudraCT : 2004-003863-59 (registration date 05/MAR/2004), EudraCT 2006-001162-17 (registration date 17-MAR-2006), EudraCT: 2007-002489-37 (registration date 12-JUN-2007), EudraCT: 2007-002490-31 (registration date 12-JUN-2007), EudraCT: 2010-024029-19 (registration date 23-NOV-2010).

Histone modifications associated with biological drug response in moderate-to-severe psoriasis.

INTRODUCTION: Epigenetic factors play an important role in psoriasis onset and development. Biological drugs are used to treat moderate-to-severe psoriasis patients resistant to conventional systemic drugs. Although they are safe and effective, some patients do not respond to them. Therefore, it is necessary to find biomarkers that could predict response to these therapies. OBJECTIVE: To find epigenetic biomarkers that could predict response to biological drugs (ustekinumab, secukinumab, adalimumab, ixekizumab). MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from 39 psoriasis patients treated with biological therapies before and after drug administration and from 42 healthy subjects. Afterwards, histones were extracted from PBMCs. Four histone modifications (H3 and H4 acetylation, H3K4 and H3K27 methylation) were determined by ELISA. Data were analysed by IBM-SPSS v.23. RESULTS AND CONCLUSIONS: Psoriasis patients presented reduced levels of acetylated H3 and H4 and increased levels of methylated H3K4 compared to controls. Non-significant changes were observed after treatment administration in any of the histone modifications analysed. Nevertheless, significant changes in methylated H3K27 were found between responders and non-responders to biological drugs at 3 months. As 28% of these patients also presented psoriatic arthritis (PsA), the former analysis was repeated in the subsets of patients with or without PsA. In patients without PsA, significant changes in methylated H3K4 were found between responders and non-responders to biological drugs at 3 and 6 months. Although further studies should confirm these results, these findings suggest that H3K27 and H3K4 methylation may contribute to patients' response to biological drugs in psoriasis.

Polymorphisms associated with adalimumab and infliximab response in moderate-to-severe plaque psoriasis.

AIM: This study evaluated the influence of pharmacogenetics in psoriatic patients treated with adalimumab and/or infliximab. MATERIALS & METHODS: Prospective observational study evaluating the association of 124 polymorphisms with the response to adalimumab or infliximab (PASI75) in patients with moderate-to-severe plaque psoriasis at 3 months (n = 95) and 6 months of treatment (n = 90). Significant SNPs for univariate analysis were subjected to multivariate analysis. RESULTS: Five SNPs were associated with PASI75 at 3 months: rs6661932 (IVL), rs2546890 (IL-12B), rs2145623 (NFKBIA), rs9304742 (ZNF816A) and rs645544 (SLC9A8). Furthermore, rs1061624 (TNFR1B) was associated with PASI75 at 6 months. CONCLUSION: Nevertheless, these biomarkers should be validated in large-scale studies before implementation in clinical practice.

Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers.

Sertraline is a selective serotonin reuptake inhibitor widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P-glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of this study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty-six healthy volunteers (24 men and 22 women) receiving a 100-mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP-binding cassette subfamily B member 1 (ABCB1), solute carrier family 6 member 4 (SLC6A4), 5-hydroxytryptamine receptor 2A (HTR2A) and 5-hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Individuals carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half-life (T1/2 ). Moreover, CYP2C19*17 was related to a decreased AUC and T1/2 . No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate-lowering effect, directly related to maximum concentration (Cmax ) and the presence of ABCB1 minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and individuals with higher AUC of sertraline, such as CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T individuals.

Pharmacogenetics of trazodone in healthy volunteers: association with pharmacokinetics, pharmacodynamics and safety.

AIM: The aim was to evaluate the effect of polymorphisms in metabolizing enzymes and transporters on the pharmacokinetics, pharmacodynamics and adverse effects of trazodone in healthy volunteers. MATERIALS & METHODS: 36 healthy volunteers receiving a single 100-mg oral dose of trazodone were genotyped for 11 variants in CYP3A4, CYP3A5, CYP2D6 and ABCB1 by real-time PCR. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry method. RESULTS & CONCLUSION: Sex affected the pharmacokinetics of trazodone with higher clearance in women. Polymorphisms in ABCB1, but not in CYP3A or CYP2D6, influenced trazodone pharmacokinetics. Trazodone decreased blood pressure and prolonged the corrected QT interval interval. CYP2D6 and ABCB1 polymorphisms were associated with the incidence of dizziness and prolonged corrected QT interval, respectively. Subjects with adverse drug reactions had lower concentrations of trazodone suggesting its metabolite (m-chlorophenylpiperazine) could be responsible for these effects.

Polymorphisms associated with etanercept response in moderate-to-severe plaque psoriasis.

AIM: Few studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with etanercept. MATERIALS & METHODS: We evaluated the association between 124 polymorphisms with the response to etanercept in patients with moderate-to-severe plaque psoriasis at 3 months (n = 78) and 6 months of treatment (n = 68). RESULTS: The results of the multivariate analysis showed an association between polymorphisms rs13437088 (HLA-B/MICA), rs96844 (MAP3K1), rs2431697 (PTTG1), rs9304742 (ZNF816A) and the response to etanercept at 3 months. Besides polymorphisms rs928655 (GBP6) and rs2546890 (IL12B) were associated to response at 6 months. CONCLUSIONS: Nevertheless, these biomarkers should be validated in large-scale studies before its implementation in clinical practice.

Pharmacogenetics of ustekinumab in patients with moderate-to-severe plaque psoriasis.

Aim/Materials & methods: Few studies have evaluated the influence of pharmacogenetics in psoriatic patients treated with ustekinumab. We evaluated 121 polymorphisms to study a possible association between these SNPs and the response to ustekinumab (PASI75 at 4 months; n = 69). RESULTS/CONCLUSION: The adjusted results (false discovery rate) showed an association between five SNPs in TNFRSF1A, HTR2A, NFKBIA, ADAM33 and IL13 genes, and poor response to ustekinumab. Furthermore, six SNPs in CHUK, C17orf51, ZNF816A, STAT4, SLC22A4 and Corf72 genes were associated with better response to ustekinumab. However, there was no significant association between response to ustekinumab and SNPs in HLA-C as it has been recently described. Finally, a higher weight was obtained in nonresponders than responders (p = 0.018). Further studies would be necessary to be closer to personalized medicine.

Evaluation of the Relationship Between Pharmacokinetics and the Safety of Aripiprazole and Its Cardiovascular Effects in Healthy Volunteers.

AIMS: The aim of this study was the evaluation of the possible relationship between pharmacokinetics and the safety of aripiprazole as well as its influence on blood pressure (BP), heart rate (HR), and corrected QT (QTc) interval. METHODS: The study population comprised 157 healthy volunteers from 6 bioequivalence clinical trials. Subjects were administered a single 10-mg oral dose of each formulation separated by a 28-day washout period. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. Blood pressure was measured at the following times: predose and 0.5, 2, 4, 6, and 8 hours postdose. An electrocardiogram was recorded at predose, 4, and 8 hours postdose. RESULTS: Area under the curve (AUC), maximum plasma concentration, half-life, and distribution volume corrected for weight were higher in women. Aripiprazole treatment produced a decrease of BP (9.3 mm Hg on systolic and 6.2 mm Hg on diastolic pressure) and an increase in HR (12.1 beats per minute) and QTc interval (9.1 milliseconds). There were sex differences in BP, HR, and QTc interval. Women and subjects with higher AUC and maximum plasma concentration values were more prone to experience adverse drug reactions and gastrointestinal adverse reactions. The AUC was related with systolic BP and diastolic BP decrease and HR increase but there was no relationship between aripiprazole concentrations and QTc increase. CONCLUSIONS: Aripiprazole decreases BP and increases HR and QTc interval. Pharmacokinetics, pharmacodynamics, and safety of aripiprazole are affected by sex. There is a directly proportional relationship between pharmacokinetic parameters and adverse drug reactions and effect on BP and HR.

Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease.

Tumor necrosis factor (TNF) alpha is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD). Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual genetic differences could contribute to lack of efficacy. Genetic studies have tried to uncover the factors underlying differences in response, however, knowledge remains limited, and the results obtained should be validated, so that pharmacogenetic information can be applied in clinical practice. In this review, we gather current knowledge in the pharmacogenetics of anti-TNF drugs in patients with IBD. We observed a connection between the major genes described as possible predictors of response to anti-TNF drugs in IBD and the cytokines and molecules involved in the T helper (Th) 17 pathway.

Utility of Pilot Studies for Predicting Ratios and Intrasubject Variability in High-Variability Drugs.

Pilot studies can be used to identify adequate test formulations for pivotal bioequivalence trials. The objective of this study was to evaluate the usefulness of pilot studies in predicting ratios and the intrasubject coefficient of variation (CVw ) for pivotal studies of high-variability drugs. Seven cross-over and replicate bioequivalence trials were selected. A hundred simulations of pilot studies were performed for different sample sizes and designs. The pharmacokinetic data of the selected formulations were analysed using WinNonLin based on an analysis of variance (anova). The CVw was estimated using the formula recommended by the European Medicines Agency based on the mean square of the anova. We calculated the predictivity index ± 10% and ± 20% of the real value. The predictivity index of ± 20% in the 2 × 2 design with 12 volunteers was 100% for AUC0-t ratio, 87% for Cmax ratio, 50% for the CVw of AUC0-t and 52% for the CVw of Cmax . The results of the 4 × 4 design with 8 volunteers were similar to those of the 2 × 2 design with 12 volunteers. These results were worse for the predictivity index of ± 10% in both designs. Pilot studies do not seem useful for predicting sample size. However, they were very good for predicting the AUC0-t ratio and good for predicting the Cmax ratio. The most adequate design for pilot studies seems to be the 2 × 2 design with at least 12 volunteers.

Clinical implementation of pharmacogenetics.

In the last decade, pharmacogenetic research has been performed in different fields. However, the application of pharmacogenetic findings to clinical practice has not been as fast as desirable. The current situation of clinical implementation of pharmacogenetics is discussed. This review focuses on the advances of pharmacogenomics to individualize cancer treatments, the relationship between pharmacogenetics and pharmacodynamics in the clinical course of transplant patients receiving a combination of immunosuppressive therapy, the needs and barriers facing pharmacogenetic clinical application, and the situation of pharmacogenetic testing in Spain. It is based on lectures presented by speakers of the Clinical Implementation of Pharmacogenetics Symposium at the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society, held in April 20, 2015.

Effect of Truncating AUC at 12, 24 and 48 hr When Evaluating the Bioequivalence of Drugs with a Long Half-Life.

Bioequivalence studies of drugs with a long half-life require long periods of time for pharmacokinetic sampling. The latest update of the European guideline allows the area under the curve (AUC) truncated at 72 hr to be used as an alternative to AUC0-t as the primary parameter. The objective of this study was to evaluate the effect of truncating the AUC at 48, 24 and 12 hr on the acceptance of the bioequivalence criterion as compared with truncation at 72 hr in bioequivalence trials. The effect of truncated AUC on the within-individual coefficient of variation (CVw) and on the ratio of the formulations was also analysed. Twenty-eight drugs were selected from bioequivalence trials. Pharmacokinetic data were analysed using WinNonLin 2.0 based on the trapezoidal method. Analysis of variance (ANOVA) was performed to obtain the ratios and 90% confidence intervals for AUC at different time-points. The degree of agreement of AUC0-72 in relation to AUC0-48 and AUC0-24, according to the Landis and Koch classification, was 'almost perfect'. Statistically significant differences were observed when the CVw of AUC truncated at 72, 48 and 24 hr was compared with the CVw of AUC0-12. There were no statistically significant differences in the AUC ratio at any time-point. Compared to AUC0-72, Pearson's correlation coefficient for mean AUC, AUC ratio and AUC CVw was worse for AUC0-12 than AUC0-24 or AUC0-48. These preliminary results could suggest that AUC truncation at 24 or 48 hr is adequate to determine whether two formulations are bioequivalent.

Polymorphisms Associated with Age at Onset in Patients with Moderate-to-Severe Plaque Psoriasis.

Psoriasis is a chronic skin disease in which genetics play a major role. Although many genome-wide association studies have been performed in psoriasis, knowledge of the age at onset remains limited. Therefore, we analyzed 173 single-nucleotide polymorphisms in genes associated with psoriasis and other autoimmune diseases in patients with moderate-to-severe plaque psoriasis type I (early-onset, <40 years) or type II (late-onset, ≥40 years) and healthy controls. Moreover, we performed a comparison between patients with type I psoriasis and patients with type II psoriasis. Our comparison of a stratified population with type I psoriasis (n = 155) and healthy controls (N = 197) is the first to reveal a relationship between the CLMN, FBXL19, CCL4L, C17orf51, TYK2, IL13, SLC22A4, CDKAL1, and HLA-B/MICA genes. When we compared type I psoriasis with type II psoriasis (N = 36), we found a significant association between age at onset and the genes PSORS6, TNF-α, FCGR2A, TNFR1, CD226, HLA-C, TNFAIP3, and CCHCR1. Moreover, we replicated the association between rs12191877 (HLA-C) and type I psoriasis and between type I and type II psoriasis. Our findings highlight the role of genetics in age of onset of psoriasis.

The polymorphism rs763780 in the IL-17F gene is associated with response to biological drugs in patients with psoriasis.

Psoriasis improves when IL-17 is blocked. Anti-TNF drugs reduce the IL-17 signaling pathway, and anti-IL-17 drugs are being developed to treat moderate-to-severe psoriasis. We analyzed three SNPs in IL-17A (rs2275913 and rs10484879) and IL-17F (rs763780) to look for an association with psoriasis and/or with response to anti-TNF drugs or ustekinumab. We included 197 healthy controls and 194 patients with moderate-to-severe psoriasis. The results of the univariate analysis showed an association between rs10484879 and psoriasis, although this relationship disappeared after adjustment for HLA-C (rs12191877). We also found an association between rs763780 (IL-17F) and response to ustekinumab (n = 70) and infliximab (n = 37) at 3 and 6 months and an association between rs763780 and the response to adalimumab at 6 months (n = 67).

Effect of gender and CYP2C9 and CYP2C8 polymorphisms on the pharmacokinetics of ibuprofen enantiomers.

AIM: To evaluate the effect of polymorphisms in CYP2C9 and CYP2C8 and gender on the pharmacokinetics of the enantiomeric forms of ibuprofen. MATERIALS & METHODS: 122 healthy volunteers were genotyped for polymorphisms in CY2C8 and CYP2C9 using real-time PCR. RESULTS: CYP2C8 polymorphisms affected neither R- nor S-ibuprofen. CYP2C9*3 and CYP2C9*2 carriers had a lower S-ibuprofen clearance and a higher S-ibuprofen AUC and half-life. R-ibuprofen clearance was decreased in CYP2C9*3 carriers. Gender affected R-ibuprofen and S-ibuprofen pharmacokinetics. Multiple regression analysis showed that CYP2C9*2, CYP2C9*3 and gender were associated with S-ibuprofen clearance, but only CYP2C9*3 was associated with R-ibuprofen clearance. CONCLUSION: The pharmacokinetics of S-ibuprofen and R-ibuprofen is affected by CYP2C9 polymorphisms and gender. CYP2C8 polymorphisms do not have a significant role. Original submitted 6 February 2015; Revision submitted 1 April 2015.

Polymorphisms in CYP2D6 have a greater effect on variability of risperidone pharmacokinetics than gender.

Within-subject coefficient of variation (CVw ) 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 CVw of risperidone. Two single-dose, two-period crossover studies of risperidone (n = 70) were reanalysed to calculate CVw for AUCt and Cmax . 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. CVw was lower in PM (13.3% for AUCt and 10.9% for Cmax ) 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 AUCt and 25.7% for Cmax ) 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.

Pharmacogenetics of quetiapine in healthy volunteers: association with pharmacokinetics, pharmacodynamics, and adverse effects.

Quetiapine is an atypical antipsychotic used for treatment of schizophrenia. Variability in response to this drug may be associated with pharmacogenetics. The aim of this study was to identify genetic markers related to the pharmacokinetics, pharmacodynamics, and adverse effects of quetiapine. The study population comprised 79 healthy volunteers from two bioequivalence trials who were genotyped to identify polymorphisms in genes encoding enzymes, receptors, and transporters. Quetiapine plasma levels were quantified using high-performance liquid chromatography/mass spectrometry. Prolactin plasma levels were detected by indirect chemiluminescence. Possible adverse effects were recorded throughout the study. Factors with P value of 0.1 or less in the univariate analysis were included in a multiple regression analysis (logistic regression for adverse reactions). The area under the curve and clearance of quetiapine were affected by polymorphisms in CYP1A2 and DRD3, respectively. Men had a lower quetiapine area under the curve compared with women. Prolactin iC(max) was higher in volunteers harboring polymorphisms in CYP2C19 and AGT. An association was detected between polymorphisms in CYP1A1 and CYP2C9 and somnolence. Several polymorphisms are responsible for differences in the pharmacokinetics, pharmacodynamics, and safety of quetiapine in healthy individuals.

Evaluation of the relationship between polymorphisms in CYP2C19 and the pharmacokinetics of omeprazole, pantoprazole and rabeprazole.

AIM: To evaluate the possible association between polymorphisms in CYP2C19 and the pharmacokinetics of omeprazole, rabeprazole and pantoprazole. MATERIALS & METHODS: 151 healthy volunteers were evaluated for polymorphisms in the CYP2C19 gene using real-time polymerase chain reaction. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. RESULTS: Carriers of the *2 allele displayed poor metabolism for all the PPIs studied (around 50% decrease in clearance). Subjects with the *17 allele showed a light increase in clearance compared with *1/*1 (not significant). CONCLUSION: CYP2C19*2 is associated with decreased clearance of all the PPIs, that could be associated with higher drug efficacy. CYP2C19*17 could increase clearance of these drugs, although the effect seems small.