The administered dose of a drug modulates whether patients will experience optimal effectiveness, toxicity including death, or no effect at all. Dosing is particularly important for diseases and/or drugs where the drug can decrease severe morbidity or prolong life. Likewise, dosing is important where the drug can cause death or severe morbidity. Since we believe there are many examples where more precise dosing could benefit patients, it is worthwhile to consider how to prioritize drug-disease targets. One key consideration is the quality of information available from which more precise dosing recommendations can be constructed. When a new more precise dosing scheme is created and differs significantly from the approved label, it is important to consider the level of proof necessary to either change the label and/or change clinical practice. The cost and effort needed to provide this proof should also be considered in prioritizing drug-disease precision dosing targets. Although precision dosing is being promoted and has great promise, it is underutilized in many drugs and disease states. Therefore, we believe it is important to consider how more precise dosing is going to be delivered to high priority patients in a timely manner. If better dosing schemes do not change clinical practice resulting in better patient outcomes, then what is the use? This review paper discusses variables to consider when prioritizing precision dosing candidates while highlighting key examples of precision dosing that have been successfully used to improve patient care.

Precision Dosing Priority Criteria: Drug, Disease, and Patient Population Variables.

The implementation system described in this article is a customizable blueprint for delivery of comprehensive medication management (CMM) and other medication optimization services. This system is the result of merging implementation science expertise with lessons learned from the parent study, the “CMM in Primary Care” grant. This system is comprised of a number of components, including implementation steps and strategies (ie, activities, practical resources such as assessments and informational materials, and learning supports). While these components are integral to any implementation effort, this project describes their unique operationalization for delivery of CMM in a primary care context. Application of this system is illustrated through an example focused on improving the delivery of CMM by pharmacist‐led teams in primary care settings.

An implementation system for medication optimization: Operationalizing comprehensive medication management delivery in primary care

Although several pharmacogenetic (PGx) predispositions affecting drug efficacy and safety are well established, drug selection and dosing as well as clinical trials are often performed in a non-pharmacogenetically-stratified manner, ultimately burdening healthcare systems. Pre-emptive PGx testing offers a solution which is often performed using microarrays or targeted gene panels, testing for common/known PGx variants. However, as an added value, whole-genome sequencing (WGS) could detect not only disease-causing but also pharmacogenetically-relevant variants in a single assay. Here, we present our WGS-based pipeline that extends the genetic testing of Mendelian diseases with PGx profiling, enabling the detection of rare/novel PGx variants as well. From our in-house WGS (PCR-free 60× PE150) data of 547 individuals we extracted PGx variants with drug-dosing recommendations of the Dutch Pharmacogenetics Working Group (DPWG). Furthermore, we explored the landscape of DPWG pharmacogenes in gnomAD and our in-house cohort as well as compared bioinformatic tools for WGS-based structural variant detection in CYP2D6. We show that although common/known PGx variants comprise the vast majority of detected DPWG pharmacogene alleles, for better precision medicine, PGx testing should move towards WGS-based approaches. Indeed, WGS-based PGx profiling is not only feasible and future-oriented but also the most comprehensive all-in-one approach without generating significant additional costs.

https://www.mdpi.com/1422-0067/21/7/2308/pdf

Added Value of Clinical Sequencing: WGS-Based Profiling of Pharmacogenes.

Cardiovascular disease is the leading cause of death globally. While pharmacological advancements have improved the morbidity and mortality associated with cardiovascular disease, non-adherence to prescribed treatment remains a significant barrier to improved patient outcomes. A variety of strategies to improve medication adherence have been tested in clinical trials, and include the following categories: improving patient education, implementing medication reminders, testing cognitive behavioral interventions, reducing medication costs, utilizing healthcare team members, and streamlining medication dosing regimens. In this review, we describe specific trials within each of these categories and highlight the impact of each on medication adherence. We also examine ongoing trials and future lines of inquiry for improving medication adherence in patients with cardiovascular diseases.

https://www.bmj.com/content/bmj/374/bmj.n1493.full.pdf

Medication adherence in cardiovascular medicine

Medicinal cannabis use has increased exponentially with widespread legalization around the world. Cannabis-based products are being used for numerous health conditions, often in conjunction with prescribed medications. The risk of clinically significant drug-drug interactions (DDIs) increases in this setting of polypharmacy, prompting concern among health care providers. Serious adverse events can result from DDIs, specifically those affecting CYP-mediated drug metabolism. Both cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), major constituents of cannabis, potently inhibit CYPs. Cannabis-based products contain an array of cannabinoids, many of which have limited data available regarding potential DDIs. This study assessed the inhibitory potential of 12 cannabinoids against CYP-mediated drug metabolism to predict the likelihood of clinically significant DDIs between cannabis-based therapies and conventional medications. Supersomes™ were used to screen the inhibitory potential of cannabinoids in vitro. Twelve cannabinoids were evaluated at the predominant drug-metabolizing isoforms: CYP3A4, CYP2D6, CYP2C9, CYP1A2, CYP2B6, and CYP2C19. The cannabinoids exhibited varied effects and potencies across the CYP isoforms. CYP2C9-mediated metabolism was inhibited by nearly all the cannabinoids with estimated Ki values of 0.2–3.2 μM. Most of the cannabinoids inhibited CYP2C19, whereas CYP2D6, CYP3A4, and CYP2B6 were either not affected or only partially inhibited by the cannabinoids. Effects of the cannabinoids on CYP2D6, CYP1A2, CYP2B6, and CYP3A4 metabolism were limited so in vivo DDIs mediated by these isoforms would not be predicted. CYP2C9-mediated metabolism was inhibited by cannabinoids at clinically relevant concentrations. In vivo DDI studies may be justified for CYP2C9 substrates with a narrow therapeutic index.

Cannabinoid Interactions with Cytochrome P450 Drug Metabolism: a Full-Spectrum Characterization

Background: Public attention and recent US Congressional activity has intensified focus on escalating medication prices. However, the actual cost of medication use extends beyond the up-front cost of purchasing medicines. It also encompasses the additional medical costs of morbidity and mortality resulting from nonoptimized medication regimens, including medication nonadherence. Objectives: Applying the most current nationally representative data sources, our goal was to estimate the cost of prescription drug–related morbidity and mortality in the United States. Methods: Total costs of nonoptimized prescription drug use and average pathway costs for a patient who experienced a treatment failure (TF), a new medical problem (NMP), or a TF and NMP were modeled in Microsoft Excel (Microsoft Corporation, Redmond, WA) and TreeAge Pro Healthcare, v2014 (TreeAge Software, Inc, Williamstown, MA), respectively. Results: The estimated annual cost of prescription drug–related morbidity and mortality resulting from no...

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Terry McInnis

Papers

Cost of Prescription Drug-Related Morbidity and Mortality.