We provide an overview of recent advances in the therapy of hypertriglyceridemia, focusing on several new therapies with potential for treating of familial chylomicronemia, other forms of ...hypertriglyceridemia, and for triglyceride-lowering in patients with other lipid disorders.
Newer triglyceride-lowering modalities under evaluation include gene therapy for lipoprotein lipase deficiency (alipogene tiparvovec), and antisense oligonucleotides against mRNA for apolipoproteins B (mipomersen) and C3 (volanesorsen, ISIS 304801). Other potential therapies include small molecule inhibitors of microsomal triglyceride transfer protein (lomitapide) and diacylglycerol acyltransferase-1 (pradigastat), and a monoclonal antibody against angiopoietin-like protein 3 (REGN1500). There is also renewed interest in omega-3 fatty acids, and in developing potent and selective agonists of peroxisome proliferator-activated receptors.
Several promising triglyceride-lowering therapies are at various stages of development; a few are even available in some markets. Although existing data suggest good biochemical efficacy, data on long-term clinical outcomes are still limited. For some therapies, cost will be an important consideration, and use will likely be restricted to orphan indications, for example very severe cases of hypertriglyceridemia as seen in familial chylomicronemia syndrome, although some therapies could theoretically be more broadly used one day for cardiovascular disease prevention.
Abstract Background Direct-acting oral anticoagulants (DOACs) are widely prescribed for stroke prevention in patients with atrial fibrillation. An important advantage of DOACs is that routine ...monitoring of anticoagulation response is not necessary. Nevertheless, due to their mechanism of action, DOAC anticoagulation effect can be inferred based on observed plasma concentration. However, there is paucity of data relating to observed interpatient variation in DOAC plasma concentrations in the post-market clinical setting. Methods We determined rivaroxaban and apixaban plasma concentrations in atrial fibrillation patients during routine clinic visits. Results Among 243 patients (rivaroxaban, n=94; apixaban, n=149) enrolled in this study, 60- and 50-fold interpatient variation in plasma concentration was observed for rivaroxaban and apixaban respectively. Approximately 12% of rivaroxaban and 13% of apixaban patients exceeded the 95th percentile for predicted maximum plasma concentration observed in clinical trials. Conclusions In this routine care setting, rivaroxaban and apixaban plasma concentrations tended to be more variable than those observed in clinical trials. Identification of additional clinical and molecular determinants that more fully predict patients at risk for excessively high or low DOAC concentrations may enable a more precise DOAC dosing regimen for the individual patient.
OBJECTIVES
Lower than recommended doses of direct‐acting oral anticoagulants are often prescribed to older adults with nonvalvular atrial fibrillation (NVAF). Our goal was to determine the ...consequences of lower than recommended dosing on plasma apixaban concentrations during the clinical care of older adults with NVAF.
DESIGN
Convenience sample of patients receiving anticoagulation during 2017.
SETTING
Academic medical center.
PARTICIPANTS
Stable adults older than 65 years with NVAF receiving apixaban on a chronic basis.
MEASUREMENTS
Patient age, weight, creatinine, co‐medications, and apixaban concentrations.
RESULTS
A total of 110 older adults with NVAF (mean age = 80.4 y; range = 66‐100 y with 45% women) were studied. Overall, 48 patients received recommended dosing of 5 mg twice/day, and 42 received lower than recommended dosing. One patient in each category had concentrations below the expected 5% to 95% range at time of peak concentrations. Differences in proportion of apixaban concentrations within or outside expected ranges were not significant between patients receiving lower than recommended doses and those dosed as recommended at 5 mg twice/day (P = .35). However, in patients dosed as recommended with 5 mg twice/day, four had concentrations above the 5% to 95% range for peak levels expected at 3 to 4 hours after dosing; in two, this occurred around the midpoint of the dosing interval. Twenty patients received 2.5 mg twice/day as recommended. One‐third had apixaban concentrations higher than expected peak concentrations compared with the clinical trials, and more than two‐thirds had levels above the reported median for peak concentrations.
CONCLUSIONS
Apixaban concentrations in older adults with NVAF seen clinically were higher than expected based on clinical trial data. The findings raise questions about the optimal dosing of apixaban in older adults with NVAF encountered outside of clinical trials and suggest a role for the monitoring of apixaban concentrations during care of patients that differ from those in randomized trials or when considering dosing outside of published guidelines. J Am Geriatr Soc 67:1902–1906, 2019
See related editorial by Alexander and Alexander
Rosuvastatin is commonly prescribed for the treatment of hypercholesterolemia and hepatic transporter‐mediated accumulation in the liver enhances its efficacy. Current guidelines indicate no ...preference for fed or fasted rosuvastatin administration. We investigated the association between food intake and rosuvastatin disposition in healthy subjects and low‐density lipoprotein cholesterol (LDL‐C)‐lowering effects among patients taking rosuvastatin. We demonstrate that administration with food resulted in a near 40% reduction of rosuvastatin exposure in healthy Asian (n = 12) and Caucasian (n = 11) subjects. Higher rosuvastatin concentrations in Asian subjects also correlated with higher allele frequency of ABCG2 c.421C>A. In mice, a greater rosuvastatin liver:plasma ratio was noted when administered with food. Among rosuvastatin patients (n = 156), there was no difference in dose needed to reach target LDL‐C, measured LDL‐C, or lathosterol concentrations, when administered in a fed or fasting state. Therefore, taking rosuvastatin with food could reduce systemic concentrations, and subsequent myopathy risk, without compromising LDL‐C‐lowering benefit.
Cardiovascular disease is a major cause of death, and hypercholesterolemia is a major risk factor. Statins, with simvastatin among the most widely used, have ample evidence demonstrating prevention ...of cardiovascular events and mortality. Ezetimibe is effective at improving serum lipids in combination with statins or alone, but its role has been controversial.
Here, we provide an overview of the pharmacokinetics and pharmacodynamics of each component of the combination, as well as pharmacogenetic contributors. Regarding clinical efficacy, our focus will be on the post-marketing clinical trials of ezetimibe-simvastatin combination therapy. We broach the controversy around the role of ezetimibe, particularly in light of the results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).
Ezetimibe in combination with simvastatin or other statins provides an excellent means of incremental lipid-lowering effect, although the clinical benefit has been uncertain. IMPROVE-IT is the first to demonstrate incremental cardiovascular risk reduction with the addition of ezetimibe to simvastatin. What the literature lacks is evidence around the common use of ezetimibe as monotherapy or add-on therapy to lower doses of statins in patients who fail to achieve adequate lipid lowering or do not tolerate high-dose statins.
Tamoxifen is a prodrug, requiring cytochrome P450 enzyme-mediated metabolism to form the active metabolite endoxifen. We identified a case of drug-drug interaction involving tamoxifen and phenytoin, ...associated with a markedly lower endoxifen level than predicted. The patient is a 49-year-old woman, genotyped as a cytochrome P450 2D6 (CYP2D6) extensive metabolizer, chronically taking phenytoin for a seizure disorder. The plasma endoxifen level 2 months after starting tamoxifen was 4.72 nmol/l, the lowest level we have seen in our clinic among patients with CYP2D6 extensive metabolizer genotypes (n=195). To our knowledge, this is the first report documenting the extent of induction in terms of both tamoxifen and endoxifen levels during concomitant phenytoin therapy, and this effect would likely result in loss of therapeutic benefit from tamoxifen. Phenytoin should therefore not be used concurrently with tamoxifen for extended periods of time unless a therapeutic drug (endoxifen) monitoring strategy is utilized.
Doctor My Eyes: A Statin-Cataract Connection? Gryn, Steven E., MD, FRCPC; Hegele, Robert A., MD, FRCPC
Canadian journal of cardiology,
12/2014, Letnik:
30, Številka:
12
Journal Article
Due to high basal interindividual variation in cytochrome P450 3A (CYP3A) activity and susceptibility to drug interactions, there has been interest in the application of efficient probe drug ...phenotyping strategies, as well as endogenous biomarkers for assessment of in vivo CYP3A activity. The biomarkers 4β‐hydroxycholesterol (4βHC) and 6β‐hydroxycortisol (6βHCL) are sensitive to CYP3A induction and inhibition. However, their utility for the assessment of constitutive CYP3A activity remains uncertain. We investigated whether endogenous plasma biomarkers (4βHC and 6βHCL) are associated with basal CYP3A metabolic activity in healthy subjects assessed by a convenient single‐time‐point oral midazolam (MDZ) phenotyping strategy. Plasma 4βHC and 6βHCL metabolic ratios (MRs) were analysed in 51 healthy adult participants. CYP3A activity was determined after administration of an oral MDZ microdose (100 μg). Simple linear and multiple linear regression analyses were performed to assess relationships between MDZ oral clearance, biomarkers and subject covariates. Among study subjects, basal MDZ oral clearance, 4βHC and 6βHCL MRs ranged 6.5‐, 10‐ and 13‐fold, respectively. Participant age and alcohol consumption were negatively associated with MDZ oral clearance (p = 0.03 and p = 0.045, respectively), while weight and female sex were associated with lower plasma 4βHC MR (p = 0.0003 and p = 0.032, respectively). Neither 4βHC nor 6βHCL MRs were associated with MDZ oral clearance. Plasma 4βHC and 6βHCL MRs do not relate to MDZ single‐time‐point metabolic phenotype in the assessment of constitutive CYP3A activity among healthy individuals.
Abstract only
Adverse drug reactions (ADRs) due to warfarin are an important cause of emergency department visits, and also occur frequently among hospitalized patients. We now know common genetic ...variations in
CYP2C9
‐mediated metabolism of warfarin, as well as its target
VKORC1
, account for much of the dosing variation. Accordingly, we hypothesized that application of a pharmacogenomics‐guided warfarin dosing algorithm that our group developed, known as WRAPID, may be clinically useful in guiding warfarin initiation and dosing for hospitalized patients. We initiated a personalized medicine‐based inpatient consult service with a goal of providing WRAPID‐based warfarin dosing recommendations. We now have data on a series of patients who were initiated on warfarin as inpatients who subsequently developed a supratherapeutic international normalized ratio (INR). When assessed by our service, most were shown to possess genotypes associated with marked sensitivity to warfarin, including one patient with the rare
CYP2C9
*3/*3 genotype, as well as several with
CYP2C9
*2/*2 and/or
VKORC1
‐1639 A/A genotype. Based on our WRAPID‐guided dosing, warfarin dose was accurately predicted to be as low as 0.5 mg. Accordingly, we believe genomics‐guided warfarin dosing is useful for identifying hospitalized patients at risk for ADRs, thereby reducing length of stay and preventing readmissions. Funding: AMOSO Drug Innovation Fund.
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