[Dealing with opioid dependence and withdrawal in hospitals]. / Omgaan met opioïdafhankelijkheid en -onthouding in het ziekenhuis.

BACKGROUND: In opioid addiction tolerance occurs requiring substitution with unusually high doses. A balance must be struck between the risk of overdose with respiratory depression and QTc interval prolongation on one hand and underdosing with withdrawal syndrome on the other hand. An unreliable anamnesis can complicate adequate dosing. CASE DESCRIPTION: A 30-year-old polydrug user with a severe dependence on methadone and heroin was admitted to the Intensive Care Unit after surgery for thoracic surgery. Upon cautious initiation with methadone, severe withdrawal and pain symptoms occurred. Doubling the dose made the withdrawal symptoms disappear without signs of overdose. CONCLUSION: During hospital admission of patients with high opioid tolerance the anamnestic equivalent high opioid dose can be started immediately, provided there is a possibility of monitoring the respiration and heart rhythm. The risk of withdrawal and insufficient pain relief in a hospital is generally greater than the risk of an overdose.

The end of the laboratory developed test as we know it? Recommendations from a national multidisciplinary taskforce of laboratory specialists on the interpretation of the IVDR and its complications.

The in vitro diagnostic medical devices regulation (IVDR) will take effect in May 2022. This regulation has a large impact on both the manufacturers of in vitro diagnostic medical devices (IVD) and clinical laboratories. For clinical laboratories, the IVDR poses restrictions on the use of laboratory developed tests (LDTs). To provide a uniform interpretation of the IVDR for colleagues in clinical practice, the IVDR Task Force was created by the scientific societies of laboratory specialties in the Netherlands. A guidance document with explanations and interpretations of relevant passages of the IVDR was drafted to help laboratories prepare for the impact of this new legislation. Feedback from interested parties and stakeholders was collected and used to further improve the document. Here we would like to present our approach to our European colleagues and inform them about the impact of the IVDR and, importantly we would like to present potentially useful approaches to fulfill the requirements of the IVDR for LDTs.

Pharmacist-Initiated Pre-Emptive Pharmacogenetic Panel Testing with Clinical Decision Support in Primary Care: Record of PGx Results and Real-World Impact.

Logistics and (cost-)effectiveness of pharmacogenetic (PGx)-testing may be optimized when delivered through a pre-emptive panel-based approach, within a clinical decision support system (CDSS). Here, clinical recommendations are automatically deployed by the CDSS when a drug-gene interaction (DGI) is encountered. However, this requires record of PGx-panel results in the electronic medical record (EMR). Several studies indicate promising clinical utility of panel-based PGx-testing in polypharmacy and psychiatry, but is undetermined in primary care. Therefore, we aim to quantify both the feasibility and the real-world impact of this approach in primary care. Within a prospective pilot study, community pharmacists were provided the opportunity to request a panel of eight pharmacogenes to guide drug dispensing within a CDSS for 200 primary care patients. In this side-study, this cohort was cross-sectionally followed-up after a mean of 2.5-years. PGx-panel results were successfully recorded in 96% and 68% of pharmacist and general practitioner (GP) EMRs, respectively. This enabled 97% of patients to (re)use PGx-panel results for at least one, and 33% for up to four newly initiated prescriptions with possible DGIs. A total of 24.2% of these prescriptions had actionable DGIs, requiring pharmacotherapy adjustment. Healthcare utilization seemed not to vary among those who did and did not encounter a DGI. Pre-emptive panel-based PGx-testing is feasible and real-world impact is substantial in primary care.

A pilot study of the implementation of pharmacogenomic pharmacist initiated pre-emptive testing in primary care.

Despite the nationwide availability of pharmacogenomic (PGx) guidelines in electronic medication surveillance systems in The Netherlands, PGx guided prescribing is still uncommon in primary care. We set out to investigate the adoption of pharmacist initiated PGx testing in primary care. Community pharmacists were offered a free PGx test covering 40 variants in 8 genes to test patients receiving an incident prescription (IRx) of a selection of 10 drugs. Results of the PGx test along with predicted phenotypes and a therapeutic recommendation based on the Dutch Pharmacogenetics Working Group (DPWG) guidelines were transferred to the pharmacist and physician. Adoption was defined as the percentage of eligible patients that received genotyping. From November 2014-July 2016, 200 patients were included with an adoption of 18.0%. Of the included patients 57.5% received an IRx for atorvastatin, 14.5% started with simvastatin and 28.0% received an IRx for amitriptyline, (es)citalopram, nortriptyline, or venlafaxine. 90% of the patients carried at least one actionable PGx test result in the selected PGx-panel. In 31.0% of the incident prescriptions a combination between a drug with a known gene-drug interaction and an actionable genotype was present and a therapeutic recommendation was provided. The provided recommendations were accepted by the clinicians in 88.7% of the patients. Pharmacist initiated implementation of PGx in primary care is feasible, and the frequency of actionable gene-drug interactions for the selected drugs is high.

Implementation of Pharmacogenomics in Everyday Clinical Settings.

Currently, germline pharmacogenomics (PGx) is successfully implemented within certain specialties in clinical care. With the integration of PGx in pharmacotherapy multiple stakeholders are involved, which are identified in this chapter. Clinically relevant pharmacogenes with their related PGx test are discussed, along with diagnostic test criteria to guide clinicians and policy makers in PGx test selection. The chapter further reviews the similarities and the differences between the guidelines of the Dutch Pharmacogenetics Working Group and the Clinical Pharmacogenetics Implementation Consortium which both support healthcare professionals in understanding PGx test results and help guiding pharmacotherapy by providing evidence-based dosing recommendations. Finally, clinical studies which provide scientific evidence and information on cost-effectiveness supporting clinical implementation of PGx in clinical care are discussed along with the remaining barriers for adoption of PGx testing by healthcare professionals.

GenoChip CYP2D6 macroarray as a method to genotype for CYP2D6 variants: results of a validation study in a Caucasian population.

AIM: The aim of this study was to investigate the concordance between the novel GenoChip CYP2D6 macroarray and the AmpliChip, which is considered the gold standard in CYP2D6 genotyping. MATERIALS & METHODS: Germline DNA of 200 patients was genotyped with both the AmpliChip and the GenoChip CYP2D6 macroarray. RESULTS: One hundred and ninety-eight samples (99%) showed concordance. In two discordant samples the AmpliChip identified a *41 allele while the GenoChip CYP2D6 macroarray did not. Sanger sequencing showed that the 2988G>A mutation and thus the *41 allele was not present in both samples. CONCLUSION: We conclude that that the GenoChip CYP2D6 macroarray is a valid method for detecting genetic variants of CYP2D6 in a Caucasian population. Original submitted 10 November 2014; Revision submitted 23 February 2015.

The effect of complementary and alternative medicines on CYP3A4-mediated metabolism of three different substrates: 7-benzyloxy-4-trifluoromethyl-coumarin, midazolam and docetaxel.

OBJECTIVE: Concomitant use of complementary and alternative medicine (CAM) and anticancer drugs can affect the pharmacokinetics of anticancer drugs by inhibiting the metabolizing enzyme cytochrome P450 3A4 (CYP3A4) (EC 1.14.13.157). Several in vitro studies determined whether CAM can inhibit CYP3A4, but these studies revealed contradictory results. A plausible explanation for these conflicting results is the use only of a single model CYP3A4 substrate in each study. Therefore, the objective was to determine the potential of selected CAM (ß-carotene, Echinacea, garlic, Ginkgo biloba, ginseng, grape seed extract, green tea extract, milk thistle, saw palmetto, valerian, vitamin B6, B12 and C) to inhibit CYP3A4-mediated metabolism of different substrates: 7-benzyloxy-4-trifluoromethyl-coumarin (BFC), midazolam and docetaxel. The effect of CAM on CYP3A4-mediated metabolism of an anticancer drug has never been determined before in vitro, which makes this study unique. The oncolytic CYP3A4 substrate docetaxel was used to establish the predictive value of the model substrates for pharmacokinetic interactions between CAM and anticancer drugs in vitro, and to more closely predict these interactions in vivo. METHODS: The inhibition of CYP3A4-mediated metabolism of 7-benzyloxy-4-trifluoromethyl-coumarin (BFC) by CAM was assessed in Supersomes, using the fluorometric CYP3A4 inhibition assay. In human liver microsomes (HLM) the inhibition of CYP3A4-mediated metabolism of midazolam and docetaxel was determined, using liquid-chromatography coupled to tandem mass spectrometry (LC-MS/MS). KEY FINDINGS: The results confirmed grape seed and green tea as potent inhibitors and milk thistle as moderate inhibitor of CYP3A4-mediated metabolism of BFC, midazolam and docetaxel. CONCLUSION: Clinical studies are required to determine the clinical relevance of the determined CYP3A4 inhibition by grape seed, green tea and milk thistle.