Pharmacist and physician perception of pharmacogenetic testing.

OBJECTIVES: To assess the perception of pharmacists and physicians towards pharmacogenetic testing. METHODS: A self-administered questionnaire was developed, validated, tested for reliability and disseminated to pharmacists and physicians in Malta. KEY FINDINGS: The study population consisted of 292 participants; 61% pharmacists (64% female, 38% practicing >10 years) and 39% physicians (50% female, 54% practicing >10 years). Pharmacists and physicians felt they lack sufficient competence in the area (95.0% and 97.4%, respectively; P > 0.05) and agreed that further training is required (92.7% and 91.2%, respectively; P > 0.05). CONCLUSIONS: The need for further training was identified by the participants to support competency development and sustain confidence on the topic, hence facilitating the clinical implementation of pharmacogenetic testing.

The interplay between pharmacogenetics, concomitant drugs and blood levels of amitriptyline and its main metabolites.

Background: The research considers the impact of genotype-inferred variability on blood levels of amitriptyline and its main metabolites, as may be moderated by phenocopying. Patients & methods:CYP2D6 and CYP2C19 genotypes, and serum concentrations of amitriptyline, nortriptyline and hydroxymetabolites, were determined in 33 outpatients. Co-medications were reviewed to identify CYP inhibition risk. Results: CYP2C19 metabolizer status explained interpatient variation in nortriptyline to amitriptyline concentration ratios. The hydroxymetabolite to parent ratios increased with higher CYP2D6 activity scores and lower CYP2D6 inhibition risk. In patients at high CYP2D6 inhibition risk, the amitriptyline + nortriptyline concentration was, on average, 52% above the higher end of expected ranges. Conclusion: Practical construal of pharmacogenetics and drug interactions tantamount to aberrant metabolism can facilitate patient-tailored use of the established drug.

Amitriptyline is an established drug in managing depression and neuropathic pain. Body exposure to amitriptyline and its by-products is influenced by enzymes activities, which are subject to genetic variation, whereas other medications in a patient's treatment regimen may alter drug breakdown. To study these implications, genetic testing was conducted in 33 outpatients on amitriptyline therapy, alongside measurement of drug concentrations in blood and consideration of any co-administered medications. Breakdown of amitriptyline to nortriptyline was associated with the genetically determined status of patients. Subjects at high risk of having their rate for further breakdown delayed by other drugs had higher blood levels than expected in normal cases. A proportion of variation observed in blood drug concentrations across individuals with same genetic results could be explained by actions of drugs received concurrently. Supportive evidence is provided on the integration of drug interaction information with insights from genetic testing for patient-tailored pharmacotherapy that attempts to mitigate the possibility of missing an intended benefit or the risk of adverse events due to altered blood levels.

Practical liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of amitriptyline, nortriptyline and their hydroxy metabolites in human serum.

Amitriptyline (AMI) has been in use for decades in treating depression and more recently for the management of neuropathic pain. A highly sensitive and specific LC-tandem mass spectrometry method was developed for simultaneous determination of AMI, its active metabolite nortriptyline (NOR) and their hydroxy-metabolites in human serum, using deuterated AMI and NOR as internal standards. The isobaric E-10-hydroxyamitriptyline (E-OH AMI), Z-10-hydroxyamitriptyline (Z-OH AMI), E-10-hydroxynortriptyline (E-OH NOR) and Z-10-hydroxynortriptyline (Z-OH NOR), together with their parent compounds, were separated on an ACE C18 column using a simple protein precipitation method, followed by dilution and analysis using positive electrospray ionisation with multiple reaction monitoring. The total run time was 6 min with elution of E-OH AMI, E-OH NOR, Z-OH AMI, Z-OH NOR, AMI (+ deuterated AMI) and NOR (+ deuterated NOR) at 1.21, 1.28, 1.66, 1.71, 2.50 and 2.59 min, respectively. The method was validated in human serum with a lower limit of quantitation of 0.5 ng/mL for all analytes. A linear response function was established for the range of concentrations 0.5-400 ng/mL (r2 > .999). The practical assay was applied on samples from patients on AMI, genotyped for CYP2C19 and CYP2D6, to understand the influence of metaboliser status and concomitant medication on therapeutic drug monitoring.

Regulatory sciences and translational pharmacogenetics: amitriptyline as a case in point.

Regulatory developments and clinical implementation, or the lack thereof, are primary clinchers, in the enduring endeavors to realize the translational quality of pharmacogenetics. Here, we present the case of amitriptyline, an established drug with pharmacogenetic implications. The integration of pharmacogenetic information in the official product literature and throughout the evaluation of safety concerns is considered. In our opinion, apart from emboldening genomic research in drug development and the valid pursuit towards global harmonization in the field, it is rational to look into the applicability of the data we have today.