Aberrant CYP2D6 metabolizer phenotypes do not show increased frequency in patients undergoing ECT after antidepressant therapy

Hooman Mirzakhani, Juliët van Dormolen, Karen van der Weide, Henk-Jan Guchelaar, Martijn S. van Noorden, Jesse Swen
<span title="">2015</span> <i title="Ovid Technologies (Wolters Kluwer Health)"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/atm3y57xerhylfpibmy5fk35me" style="color: black;">Pharmacogenetics &amp; Genomics</a> </i> &nbsp;
Major depressive disorder (MDD) and bipolar disorder (BD) are common mental disorders. Antidepressant drugs (ADs) are important first-line treatment options in both unipolar and bipolar major depressive episodes. According to present guidelines, the effective AD for treatment of MDD and BD for each individual patient is identified through trial and error switching in sequential treatments. A substantial proportion of depressive patients do not benefit from treatment due to ineffectiveness of
more &raquo; ... ication therapy or incurring serious side effects such that these patients are indicated for electroconvulsive therapy (ECT). CYP2D6 variants are associated with metabolic profile of ADs and have been investigated as a determinant contributor in treatment resistant depression (TRD). Hereby, we investigate the accumulation of aberrant CYP2D6 genotypes and predicted metabolizer phenotypes (UM, IM, and PM) potentially affecting the antidepressant treatment response in depressive patients indicated for ECT compared to patients with single episode of depression. Method: 84 Dutch Caucasian subjects with unipolar or bipolar treatment resistant major depression who underwent ECT were genotyped using Amplichip ® CYP450 Genotyping Test for CYP2D6 and its metabolizer phenotypes. 208 genotyped patients with single episode of unipolar or bipolar major depression were used as controls to examine differences in prevalence of CYP2D6 phenotypes. Result: The mean age of ECT cases and subjects with single episode of depression was 62 ± 14 [range: 27-87, F/M: 46/29] and 49 ± 19 [range: 15-91, F/M: 91/117], respectively. Prevalence of CYP2D6 phenotypes (PM, IM, EM and UM) was "5.3%, 38.7%, 56% and 0.0%"for ECT patients, and "6.4%, 51%, 42.6% and 0.0%"for depressive patients. The type of depression (OR=0.33, p=0.018) and age (OR=1.55 for a-10 year increase, p<0.001), but not CYP2D6 phenotype were associated with the response to treatment. Conclusion: The frequencies of genotype-predicted phenotypes (UM, IM and PM), potentially affecting the treatment response, did not show increased frequency in patients who received ECT for continuation of depression treatment as compared to patients with single episode of depression. Preemptive genotyping for CYP2D6 currently appears to have no clinical implications in treatment resistance depressive patients undergoing ECT. Further largescale prospective clinical trials are warranted. Background In our exploratory studies we have associated single nucleotide polymorphisms (SNPs) in candidate genes with efficacy and toxicities of sunitinib in metastatic renal cell carcinoma (mRCC). The aim of the present study is to test these SNPs for association with sunitinib treatment outcome in the largest patient cohort to date. Methods mRCC patients treated with sunitinib and a DNA sample available were pooled from 3 exploratory studies conducted in the US, Spain and the Netherlands. A total of 22 SNPs and 6 haplotypes in 10 candidate genes related to pharmacokinetics and pharmacodynamics of sunitinib were tested for associations with toxicity, dose reductions, progression-free survival (PFS), overall survival (OS) and best objective response. Results Three-hundred and thirty-three patients were included. The presence of CYP3A5*1 was associated with dose reductions (OR=2.0, CI=1.0-4.0, P=0.039). Presence of CGT in the ABCB1 haplotype was associated with an increased PFS (HR=1.9, CI=1.3-2.6, P=0.000275) and remained significant after Bonferroni correction. These associations are consistent with prior observations. Similar size and direction of effect were observed for the association of VEGFA rs1570360 with hypertension (OR=1.9, CI=0.8-4.5, P=0.173) and FLT3 rs1933437 with leukopenia (OR=3.6, CI=0.8-16.7, P=0.088). Conclusion The confirmation of previously reported associations between polymorphismsin CYP3A5 and ABCB1 with sunitinib toxicity and efficacy respectively indicates that genotyping of these genetic variants may be useful for guiding sunitinib treatment. Background: Close patient monitoring during interchange of tacrolimus commercial formulations is essential to ensure similar exposure on substitution in pediatric transplant patients. Nonetheless, currently available reports in pediatrics undergoing innovator-to-generic interchange are extremely limited. The aim of this study was to compare the variability in tacrolimus blood levels and laboratory parameters in maintenance pediatric transplant patients undergoing switch and that of de novo patients receiving generic or innovator tacrolimus. Methods: From April to August 2013, the Hospital Pharmacy dispensed a generic product of tacrolimus to the inpatient clinics according to the decision of the National Provision Program which provides treatment to all those patients without health insurance. Ten maintenance pediatric patients after kidney, liver, heart and hematopoietic stem cell transplantation were included if they were receiving the tacrolimus for at least 14 days after the switch. Tacrolimus dose-normalized trough levels (DNL) and laboratory parameters of renal and liver function were recorded before and after the switch. Furthermore, we analyzed DNL and the percent coefficient of variation (CV%) of the DNL in 22 de novo transplant patients receiving innovator (n=11) or generic product (n=11) during the first 4 post-transplant weeks. Both groups were chosen to be comparable in type of transplantation, donor type, age, comorbidities and diagnosis. Results: In the maintenance population, median (range) DNL on the innovator and generic tacrolimus was 75.1(ng/ml)/(mg/kg/day) (14.7-466.2) and 79.3 (ng/ml)/(mg/kg/day) (12.2-723.5), respectively (p>0.05). Routine laboratory values showed no differences in biochemical parameters after the switch (p>0.05). No significant difference was found in DNL and in CV% of DNL between products in de novo transplant patients when comparing the corresponding post-transplant weeks (p>0.05). Conclusions: We report no significant differences in terms of pharmacokinetic or laboratory parameters in the studied pediatric patients subjected to switch between tacrolimus commercial products. We strengthen the need of further studies in bigger groups of patients undergoing substitution of tacrolimus formulations to ensure a safe interchange in this vulnerable population. Despite the small patient number of our study, there are no previous reports about substitution of tacrolimus in pediatric patients. Background Despite the practice of transplant is well regulated in Argentina by the National Authorities of Health, only general requirements are stated for analytical laboratories involved in drug assays for clinical decisions. We decided to perform a nationwide survey on the analytical performance of current immunosuppressants assays in Argentina and identify areas of improvement as a result of the joint effort between the Unit of Clinical Pharmacokinetics (UFC)-Garrahan and the national authority INCUCAI. Methods Based on the list of transplant centers certified by INCUCAI, surveyed centers were those with greater percentage of transplant patients updated to January 2013. Private analytical laboratories were also included. The questionnaire was written in Spanish and previously approved by the IRB of our Hospital. The director of each clinical or analytical center agreed to participate. The survey was designed to obtain information about: facilities and demographics of the analytical laboratory; analytes and sample information; analytical assays and instruments; types and contents of reports; quality assurance. Results 27 respondents were surveyed including 22 clinical centers and 5 private laboratories. Almost all clinical centers monitor calcineurin inhibitors while 86%, 64% and 14% request for sirolimus, everolimus and MPA, respectively. 15/22 clinical centers outsource at least one assay; everolimus was the most common outsource determination. Almost 60% of the samples were analyzed at the private practice. All bioassays were performed in the biochemistry department without the pharmacist participation. 4/24 laboratories provide the therapeutic range in the report and none gave other advice. 92% reported to use immunoassays as assay methodologies; 1 center used HPLC and 60% (3/5) of private practice employed LCMSMS. A quality assurance program was reported in 13/19 (68%) respondents from clinical centers but only 10 (53%) participated in an international QA program for external quality controls. Conclusions The present is the first survey carried out in a developing country and the first step of a national project in collaboration between UFC-INCUCAI to support and promote the development and conduct of bioanalytical assays for clinical decisions according to international consensus to improve TDM and also support the professional development on this field.
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