Pharmacokinetic-based drug-drug interaction (DDI) data for drugs approved by the U.S. Food and Drug Administration in 2017 (N = 34) were analyzed using the University of Washington Drug Interaction Database. The mechanisms and clinical relevance of these interactions were characterized based on information from new drug application reviews. CYP3A inhibition and induction explained most of the observed drug interactions (new drugs as victims or as perpetrators), and transporters mediated about half of all DDIs, alone or with enzymes. Organic anion transporting polypeptide (OATP)1B1/1B3 played a significant role, mediating more than half of the drug interactions with area under the time-plasma curve (AUC) changes ‡5-fold. As victims, five new drugs were identified as sensitive substrates: abemeciclib, midostaurin, and neratinib for CYP3A and glecaprevir and voxilaprevir for OATP1B1/1B3. As perpetrators, three drugs were considered strong inhibitors: ribociclib for CYP3A, glecaprevir/pibrentasvir for OATP1B1/1B3, and sofosbuvir/velpatasvir/voxilaprevir for OATP1B1/1B3 and breast cancer resistance protein. No strong inducer of enzymes or transporters was identified. DDIs with AUC changes ‡5-fold and almost all DDIs with AUC changes 2-to 5-fold had dose recommendations in their respective drug labels. A small fraction of DDIs with exposure changes <2-fold had a labeling impact, mostly related to drugs with narrow therapeutic indices. As with drugs approved in recent years, all drugs found to be sensitive substrates or strong inhibitors of enzymes or transporters were among oncology or antiviral treatments, suggesting a serious risk of DDIs in these patient populations for whom effective therapy is already complex because of polytherapy. 136 Yu et al. 142 Yu et al.
Vitamin A, via retinoic acid (RA), is a critical micronutrient. Normally, plasma concentrations are tightly regulated. Concentrations of vitamin A metabolites (13cis‐RA, atRA) and relationships between RBP4 and retinoids have never been fully evaluated in adult patients with CKD. We measured retinoid and RBP4 concentrations in plasma and urine from 55 adult patients with CKD and 21 matched healthy subjects. RBP4 and retinol levels were increased approximately twofold in patients with CKD, with a negative correlation between plasma retinol and eGFR (p = 0.006) and plasma RBP4 and eGFR (p = 0.0007). RBP4 renal clearance was higher in patients with CKD than healthy subjects but not associated with eGFR. Circulating concentrations of atRA increased and concentrations of 13cis‐RA decreased in subjects with CKD with no change in RA‐to‐retinol ratio. Increases in circulating retinol, RBP4, and atRA may be due to increased hepatic RBP4 synthesis, retinyl ester hydrolysis, and/or hepatic secretion of RBP4‐retinol.
Introduction
Pharmacogenomic‐guided medication therapy management (PGx‐MTM) can optimize medication therapy for older adults. Pharmacist‐led PGx‐MTM in retirement communities has been infrequently described.
Objectives
We conducted a prospective, single‐arm feasibility study that incorporated PGx‐MTM services into an academic clinical practice at a retirement community. We posited that provision of PGx‐MTM services would be feasible and would enable us to identify one or more drug therapy‐related problems for each participant.
Methods
We screened residents using a predefined list of gene‐drug pairs for which the level of evidence for clinical impact is highest and consented those who were taking one of these medications (qualifying medication). The clinical pharmacist conducted PGx testing using a DNA buccal swab. Tests were analyzed by a commercial laboratory, and a corresponding Personalized Medicine Report generated. The Report included an assessment of gene‐drug pairs not only for qualifying medications, but for all pairs on our predefined list, in the event participants were prescribed these medications in the future (future medications). Results were risk‐categorized as “consider alternatives,” “use with caution,” or “standard precautions” (no change in therapy).The clinical pharmacist reviewed participant‐specific results for all gene‐drug pairs tested, then forwarded results to participants' providers along with recommendations for modifications in drug therapy. We calculated descriptive statistics to characterize participant‐specific demographic and clinical characteristics, medication use, PGx test results, and corresponding recommendations.
Results
Eighteen participants enrolled. We evaluated 23 results of qualifying medications, associated with six genes, 30% (7/23) of which were categorized as “use with caution” (warfarin) or “consider alternatives” (simvastatin, clopidogrel, and paroxetine). One required a change in therapy (simvastatin). When considering future medications (n = 245), the proportion was the same.
Conclusion
Our work demonstrates the feasibility of and suggests the potential for providing PGx‐MTM in retirement communities using preemptive genotyping, offering a new level of care to an often‐overlooked population, and advancing pharmacy practice.
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