Pharmacogenetics of Statin-Induced Myopathy: A Focused Review of the Clinical Translation of Pharmacokinetic Genetic Variants.

Statins are the most commonly prescribed drugs in the United States and are extremely effective in reducing major cardiovascular events in the millions of Americans with hyperlipidemia. However, many patients (up to 25%) cannot tolerate or discontinue statin therapy due to statin-induced myopathy (SIM). Patients will continue to experience SIM at unacceptably high rates or experience unnecessary cardiovascular events (as a result of discontinuing or decreasing their statin therapy) until strategies for predicting or mitigating SIM are identified. A promising strategy for predicting or mitigating SIM is pharmacogenetic testing, particularly of pharmacokinetic genetic variants as SIM is related to statin exposure. Data is emerging on the association between pharmacokinetic genetic variants and SIM. A current, critical evaluation of the literature on pharmacokinetic genetic variants and SIM for potential translation to clinical practice is lacking. This review focuses specifically on pharmacokinetic genetic variants and their association with SIM clinical outcomes. We also discuss future directions, specific to the research on pharmacokinetic genetic variants, which could speed the translation into clinical practice. For simvastatin, we did not find sufficient evidence to support the clinical translation of pharmacokinetic genetic variants other than SLCO1B1. However, SLCO1B1 may also be clinically relevant for pravastatin- and pitavastatin-induced myopathy, but additional studies assessing SIM clinical outcome are needed. CYP2D6*4 may be clinically relevant for atorvastatin-induced myopathy, but mechanistic studies are needed. Future research efforts need to incorporate statin-specific analyses, multi-variant analyses, and a standard definition of SIM. As the use of statins is extremely common and SIM continues to occur in a significant number of patients, future research investments in pharmacokinetic genetic variants have the potential to make a profound impact on public health.

Relative bioavailability of tolvaptan administered via nasogastric tube and tolvaptan tablets swallowed intact.

PURPOSE: The bioavailability of a crushed tolvaptan tablet suspended in water and administered by nasogastric (NG) tube was compared to the bioavailability from the tablet administered whole. METHODS: In a randomized crossover study, 28 healthy adults received a single 15-mg dose of tolvaptan on two occasions (one dose given as an intact tablet swallowed whole and the other as a crushed tablet in suspension given by NG tube), with a washout interval of ≥7 days. During each administration period, blood samples were collected at 15 time points over 36 hours. A validated liquid chromatography-tandem mass spectrometry assay was used to obtain plasma tolvaptan concentrations. Plasma tolvaptan time-concentration data were analyzed using noncompartmental methods, and pharmacokinetic data including maximum concentration (Cmax), time to Cmax (tmax), area under the concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUCt), and AUC extrapolated to infinity (AUC∞) resulting from oral and NG tube tolvaptan delivery were compared via repeated-measures, mixed-effects analysis of variance. Due to differences in total drug exposure seen, an in vitro experiment was conducted on three dose levels to quantify drug sequestration. RESULTS: The ratios of geometric mean Cmax, AUCt, and AUC∞ values (expressed as a percentage) with NG tube versus oral tolvaptan administration were 88.9%, 74.3%, and 74.2%, respectively; the latter two values were not within the specified bioequivalence tolerance limits (80-125%). In vitro analysis showed that approximately 11% of all tolvaptan doses evaluated was sequestered by the NG tube. CONCLUSION: In healthy adults, a single 15-mg dose of tolvaptan administered as a crushed tablet suspended in water by NG tube resulted in AUCt and AUC∞ values that were approximately 25% lower than those observed after oral administration of a 15-mg tolvaptan tablet swallowed intact.

Genetic tailoring of pharmacotherapy in heart failure: optimize the old, while we wait for something new.

BACKGROUND: The combination of angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic receptor blockers remains the essential component of heart failure (HF) pharmacotherapy. However, individual patient responses to these pharmacotherapies vary widely. The variability in response cannot be explained entirely by clinical characteristics, and genetic variation may play a role. The purpose of this review is to examine our current state of understanding of beta-blocker and ACE inhibitor pharmacogenetics in HF. METHODS AND RESULTS: Beta-blocker and ACE inhibitor pharmacogenetic studies performed in patients with HF were identified from the Pubmed database from 1966 to July 2011. Thirty beta-blocker and 10 ACE inhibitor pharmacogenetic studies in patients with HF were identified. The ACE deletion variant was associated with greater survival benefit from ACE inhibitors and beta-blockers compared with the ACE insertion. Ser49 in the beta-1 adrenergic receptor, the insertion in the alpha-2C adrenergic receptor, and Gln41 in G-protein-coupled receptor kinase 5 are associated with greater survival benefit from beta-blockers, compared with Gly49, the deletion, and Leu41, respectively. However, many of these associations have not been validated. CONCLUSIONS: The HF pharmacogenetic literature is still in its very early stages, but there are promising candidate genetic variants that may identify which HF patients are most likely to benefit from beta-blockers and ACE inhibitors and patients that may require additional therapies.

Pharmacogenetics in chronic heart failure: new developments and current challenges.

The individual patient responses to chronic heart failure (HF) pharmacotherapies are highly variable. This variability cannot be entirely explained by clinical characteristics, and genetic variation may play a role. Therefore, this review will summarize the background pharmacogenetic literature for major HF pharmacotherapy classes (ie, ß-blockers, angiotensin-converting enzyme inhibitors, digoxin, and loop diuretics), evaluate recent advances in the HF pharmacogenetic literature in the context of previous findings, and discuss the challenges and conclusions for HF pharmacogenetic data and its clinical application.

Quantifying the HIV-1 integrase inhibitor raltegravir in female genital tract secretions using high-performance liquid chromatography with ultraviolet detection.

Understanding the pharmacokinetics of drugs in peripheral body compartments, such as the genital tract, is particularly important in the infectious diseases arena. However, extracting drugs from small volumes of viscous, proteinacious substances like cervicovaginal fluid is particularly challenging. The goal of this study was to develop a method to quantify raltegravir, an HIV-1 integrase inhibitor, in the female genital tract. The method included sample preparation with perchloric acid followed by solid-phase extraction, separation with reverse-phase high-performance liquid chromatography, and detection with an ultraviolet wavelength of 218nm. The method was linear from 0.05 to 10.0mg/L, with minimal endogenous interference. The method was accurate (1.2-11.0% deviation) and precise (1.1-12.6% CV) for both within and between-day analyses. The ability to detect raltegravir in the female genital tract is essential for future investigations of raltegravir as an agent for prevention of HIV acquisition, and this method will be used for clinical studies further evaluating pharmacokinetic-pharmacodynamic relationships in this body compartment.