Effects of Pharmacogenetic Screening for CYP2D6 Among Elderly Starting Therapy With Nortriptyline or Venlafaxine:A Pragmatic Randomized Controlled Trial (CYSCE Trial)

PURPOSE/BACKGROUND: The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine. METHODS/PROCEDURES: In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks. FINDINGS/RESULTS: No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087). IMPLICATIONS/CONCLUSIONS: The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression

Pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism

To study the impact of the 79A > C polymorphism in the cytidine deaminase (CDA) gene on the pharmacokinetics of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) in non-small-cell lung cancer (NSCLC) patients. Patients (n = 20) received gemcitabine 1,125 mg/m(2) as a 30 min i.v. infusion as part of treatment for NSCLC. Plasma samples were collected during 0-6 h after gemcitabine administration. Gemcitabine and dFdU were quantified by high performance liquid chromatography with ultraviolet detection. The CDA 79A > C genotype was determined with PCR and DNA sequencing. Gemcitabine was rapidly cleared from plasma and undetectable after 3 h. The allele frequency of the 79A > C polymorphism was 0.40. Diplotypes were distributed as A/A n = 8, A/C n = 8 ,and C/C n = 4. No significant differences were found between the different CDA genotypes and gemcitabine or dFdU AUC, clearance, or half-life. The 79A > C polymorphism in the CDA gene does not have a major consistent and signficant impact on gemcitabine pharmacokinetics

Effects of Pharmacogenetic Screening for CYP2D6 Among Elderly Starting Therapy With Nortriptyline or Venlafaxine: A Pragmatic Randomized Controlled Trial (CYSCE Trial)

PURPOSE/BACKGROUND: The duration of untreated depression is a predictor for poor future prognosis, making rapid dose finding essential. Genetic variation of the CYP2D6 isoenzyme can influence the optimal dosage needed for individual patients. The aim of this study was to determine the effectiveness of CYP2D6 pharmacogenetic screening to accelerate drug dosing in older patients with depression initiating nortriptyline or venlafaxine. METHODS/PROCEDURES: In this randomized controlled trial, patients were randomly allocated to one of the study arms. In the intervention arm (DG-I), the specific genotype accompanied by a standardized dosing recommendation based on the patients' genotype and the prescribed drug was directly communicated to the physician of the participant. In both the deviating genotype control arm (DG-C) and the nonrandomized control arm, the physician of the participants was not informed about the genotype and the associated dosing advise. The primary outcome was the time needed to reach adequate drug levels: (1) blood levels within the therapeutic range and (2) no dose adjustments within the previous 3 weeks. FINDINGS/RESULTS: No significant difference was observed in mean time to reach adequate dose or time to adequate dose between DG-I and DG-C. Compared with the nonrandomized control arm group, adequate drug levels were reached significantly faster in the DG-I group (log-rank test; P = 0.004), and there was a similar nonsignificant trend for the DG-C group (log-rank test; P = 0.087). IMPLICATIONS/CONCLUSIONS: The results of this study do not support pharmacogenetic CYP2D6 screening to accelerate dose adjustment for nortriptyline and venlafaxine in older patients with depression

Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency

5-Fluorouracil (5-FU) is rapidly degraded by dihyropyrimidine dehydrogenase (DPD). Therefore, DPD deficiency can lead to severe toxicity or even death following treatment with 5-FU or capecitabine. Different tests based on assessing DPD enzyme activity, genetic variants in DPYD and mRNA variants have been studied for screening for DPD deficiency, but none of these are implemented broadly into clinical practice. We give an overview of the tests that can be used to detect DPD deficiency and discuss the advantages and disadvantages of these test

Cross-national comparison of prescribing patterns in Australian and Dutch nursing homes

Background: Prescribing quality is a major issue in nursing home patients. Few cross-national comparisons of prescribing patterns have been carried out in this population. Objectives: To compare prevalence of medication use in nursing home patients between Australia and The Netherlands. Methods: An analysis of medication use based on pharmacy dispensing data was undertaken for residents in nursing homes in Australia (AU) and the Netherlands (NL). The data included residents >65 years old who remained in a high care nursing home in 2009 in AU (n = 1,560) or NL (n = 2,037). Annual prevalence was defined as the dispensing of 1 or more prescriptions for a drug during the study year expressed as percentage of all residents. Multiple logistic regression was used to calculate the prevalence odds ratios (OR) and associated 95% confidence intervals (CI), adjusted for gender and age. Results: The mean age of residents was 85.8 (SD 7.5) (AU) and 82.8 (SD 7.5) (NL), the majority were female (AU: 70.3%, NL: 68.2%). Residents used a mean of 11.4 (SD 5.3) (AU) and 10.8 (SD 7.0) (NL) drugs. The prevalence of medication use was similar in the two countries for most ATC groups. Major differences were observed in the use of benzodiazepines (anxiolytics: AU: 14.1%, NL: 27.8%, OR 0.41 (0.37-0.53)), osteoporosis medication (AU: 51.2%, NL: 28.9; OR 2.56 (2.22-2.96)). Overall use of antipsychotics (AU: 37.7%, NL: 40.3%; OR 0.91 (0.79-1.04)) was similar, but choice of individual drugs differed, e.g. haloperidol (AU: 8.2%, NL: 19.7%; OR 0.34 (0.27-0.42)) and risperidone (AU: 17.4%, NL: 7.3%; OR 2.86 (2.30-2.57)). Systemic antibacterials (AU: 66.8%, NL 62.4%; OR 1.08 (0.93-1.24)) and cardiovascular system drugs (AU: 73.8%, NL: 72.9%; OR 1.05 (0.90-1.23)) overall were similar but major differences were also found in the choice of agents. Conclusions: There are many similarities, but also striking differences in prescribing patterns for nursing home patients between Australia and the Netherlands. Differences in policies, guidelines, education/training and cultural beliefs are possible explanations. Investigating this further should improve our understanding of the various influences on prescribing in nursing homes.1 page(s