Clinical assessment of momelotinib drug-drug interactions via CYP3A metabolism and transporters.

Momelotinib-approved for treatment of myelofibrosis in adults with anemia-and its major active metabolite, M21, were assessed as drug-drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple-dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single-dose rifampin), and a strong CYP3A4 inducer (multiple-dose rifampin). Momelotinib DDI perpetrator potential (multiple-dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), time to reach Cmax, and half-life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single-dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple-dose rifampin compared with single-dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple-dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1'-hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short-term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

Development of a highly sensitive and green first-derivative synchronous fluorescence spectroscopic method for the simultaneous quantification of telmisartan and rosuvastatin: Greenness metric assessment and application to a pharmacokinetic study in rats.

Hypertension and hyperlipidemia frequently coexist and are correlated with elevated cardiovascular adverse outcomes. Fixed dose combination tablets containing antihypertensive and antihyperlipidemic drugs have the potential to improve patient compliance. Telmisartan and rosuvastatin fixed dose combination tablet has been recently formulated. This study provided the first fluorescence spectroscopic method for simultaneously quantifying telmisartan and rosuvastatin in tablet dosage form and plasma. The native fluorescence spectra of telmisartan and rosuvastatin completely overlapped, making direct measurement unachievable. However, through the implementation of synchronous fluorescence measurements of telmisartan and rosuvastatin at a Δλ = 60, distinct narrow bands were observed at 358 nm and 375 nm, respectively. Regrettably, the challenge of overlapping remained unresolved. Nevertheless, by converting these synchronous spectra into first-order spectra, the problem of overlapping was completely resolved. This conversion also allowed for the selective quantification of telmisartan and rosuvastatin at 374 nm and 358 nm, respectively. The validity of this method was confirmed in accordance with ICH guidelines, yielding satisfactory results in terms of the validation characteristics. The method demonstrated linear relationships between the response and the studied drugs concentrations in working range of 50-1000 ng/mL for telmisartan and 100-2000 ng/mL for rosuvastatin. The described methodology was applied for the pharmacokinetic study of telmisartan and rosuvastatin in rat plasma after a single oral dose of 4 mg/kg telmisartan and 50 mg/kg rosuvastatin. Pharmacokinetic analyses revealed a moderate drug-drug interaction between the two drugs, which was not considered to be clinically significant. Moreover, the described method was assessed in terms of sensitivity and environmental sustainability against three previously documented methods. The comparison effectively underscores the supremacy of the proposed technique over the documented techniques.

In-lab synthesized turn-off fluorescence sensor for estimation of Gemigliptin and Rosuvastatin polypill appraised by Spider diagram, AGREE and whiteness metrics.

Gemigliptin-Rosuvastatin single-pill combination is a promising therapeutic tool in the effective control of hyperglycemia and hypercholesterolemia. Organic sensors with high quantum yields have profoundly significant applications in the pharmaceutical industry, such as routine quality control of marketed formulations. Herein, the fluorescence sensor, 2-Morpholino-4,6-dimethyl nicotinonitrile 3, (λex; 226 nm, λem; 406 nm), was synthesized with a fluorescence quantum yield of 56.86% and fully characterized in our laboratory. This sensor showed high efficiency for the determination of Gemigliptin (GEM) and Rosuvastatin (RSV) traces through their stoichiometric interactions and simultaneously fractionated by selective solvation. The interaction between the stated analytes and sensor 3 was a quenching effect. Various experimental parameters and the turn-off mechanism were addressed. The adopted approach fulfilled the ICH validation criteria and showed linear satisfactory ranges, 0.2-2 and 0.1-1 µg/mL for GEM and RSV, respectively with nano-limits of detection less than 30 ng/mL for both analytes. The synthesized sensor has been successfully applied for GEM and RSV co-assessment in their synthetic polypill with excellent % recoveries of 98.83 ± 0.86 and 100.19 ± 0.64, respectively. No statistically significant difference between the results of the proposed and reported spectrophotometric methods in terms of the F- and t-tests. Ecological and whiteness appraisals of the proposed study were conducted via three novel approaches: the Greenness Index via Spider Diagram, the Analytical Greenness Metric, and the Red-Green-Blue 12 model. The aforementioned metrics proved the superiority of the adopted approach over the previously published one regarding eco-friendliness and sustainability. Our devised fluorimetric turn-off sensing method showed high sensitivity, selectivity, feasibility, and rapidity with minimal cost and environmental burden over other sophisticated techniques, making it reliable in quality control labs.

[Economic evaluation of a fixed-dose combination (acetylsalicylic acid and rosuvastatin) in the cardiovascular context]. / Valutazione farmacoeconomica di una combinazione a dose fissa (acido acetilsalicilico e rosuvastatina) in ambito cardiovascolare.

BACKGROUND: Cardiovascular diseases pose a significant challenge to the society and healthcare systems, with serious implications in terms of mortality and healthcare expenditure. The treatment of cardiovascular diseases, based on acetylsalicylic acid combined with statins in multi-pill regimens, is characterized by a lower adherence rate among patients compared to the single-pill combination. A potential solution lies in single-pill formulations, drugs that combine two or more active ingredients at a fixed dosage within the same dosage unit. METHODS: In order to assess the potential pharmacoeconomic impact of single-pill treatment, a budget impact model (BIM) was developed, considering the combination of 100 mg acetylsalicylic acid and 5 mg, 10 mg, or 20 mg rosuvastatin. RESULTS: The use of the single pill, according to the selected scenario, could result in savings in Italy compared to the use of multi-pill at 100%, ranging from € 951 201 in the case of using both single and multi-pill at 50%, to € 1 902 402 in the case of using the single pill exclusively. Sensitivity analysis confirmed the robustness of the results. CONCLUSIONS: The developed BIM allows observing the potential savings that single-pill treatment could generate, linked both to an increase in adherence rates and the consequent improvement in clinical outcomes for patients, as well as the lower cost of medications. The use of single pills represents a promising solution to enhance patient adherence and reduce costs in the management of cardiovascular diseases in Italy.

Impact assessment of metabolite instability in the development and validation of LC-MS/MS bioanalytical assays for measurement of rosuvastatin in human plasma and urine samples.

During bioanalytical assay development and validation, maintaining the stability of the parent drug and metabolites of interest is critical. While stability of the parent drug has been thoroughly investigated, the stability of unanalyzed metabolites is often overlooked. When an unstable metabolite is known or suspected to interfere with measurement of the parent drug or other metabolites of interest through back-conversion or other routes, additional tests with these unstable metabolites should be conducted. Here, the development and validation of two assays for quantification of rosuvastatin, one in human plasma and one in human urine, was reported. To this end, additional sets of quality control samples were added during assay validation to ensure the reliability of the assays. Acid treatment of samples is shown to be necessary for rosuvastatin quantification. In this regard, stability issues caused by the metabolite, rosuvastatin lactone, may have been overlooked if assay development and validation had only considered the parent drug, rosuvastatin. These assays represent a case study for how to develop and validate assays with unstable metabolites. Taken together, unstable metabolites should be included in all applicable stability tests.

Exploring the Evolution of Statin Pricing in Australia: Observations of Price Disclosure Effects on Pharmaceutical Benefits Scheme Expenditure.

OBJECTIVES: The high cardiovascular disease burden globally and in Australia necessitates attention on statin expenditure, the primary pharmacological intervention for cardiovascular disease risk factors. The Pharmaceutical Benefits Scheme (PBS) subsidies approved statins for Australians. Managing PBS government expenditure occurs through price control strategies of statutory price decreases upon first generic entry and price disclosure. This study investigates the impact price control measures had on statin price evolution and government expenditure between 2010 and 2022. METHODS: Prescription and pricing data were obtained from Services Australia Medicare Statistics, and price reduction strategies from the PBS. Summary statistics compared and described statin price, prescription, number of brands, market share, and government expenditure to atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin price control timelines. RESULTS: Statin prices exposed to price control measures decreased irrespective of dosage and correlated with reductions in government expenditure, with a comparison of 2010 and 2022 showing annual statin expenditure declined by AU$833.5 million (83.25%) whereas prescriptions reduced by 3.0 million (15.7%). Effects of price disclosure on atorvastatin and rosuvastatin market share suggest industry-prompted price reductions may arise from market share loss, whereas reasons external to pricing prompted rosuvastatin to gain market share. CONCLUSIONS: Limited publications on contemporary effects of statin price control measures exist. This investigation found these measures reduced government expenditure for statins by AU$949.1 million, with the price reduction correlating with price control measures. In addition to affirming price control mechanisms remain effective in contemporary times, this investigation provides data for key insights into the Australian statin industry.

Evaluation of rosuvastatin-induced QT prolongation risk using real-world data, in vitro cardiomyocyte studies, and mortality assessment.

Drug-induced QT prolongation is attributed to several mechanisms, including hERG channel blockage. However, the risks, mechanisms, and the effects of rosuvastatin-induced QT prolongation remain unclear. Therefore, this study assessed the risk of rosuvastatin-induced QT prolongation using (1) real-world data with two different settings, namely case-control and retrospective cohort study designs; (2) laboratory experiments using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM); (3) nationwide claim data for mortality risk evaluation. Real-world data showed an association between QT prolongation and the use of rosuvastatin (OR [95% CI], 1.30 [1.21-1.39]) but not for atorvastatin (OR [95% CI], 0.98 [0.89-1.07]). Rosuvastatin also affected the sodium and calcium channel activities of cardiomyocytes in vitro. However, rosuvastatin exposure was not associated with a high risk of all-cause mortality (HR [95% CI], 0.95 [0.89-1.01]). Overall, these results suggest that rosuvastatin use increased the risk of QT prolongation in real-world settings, significantly affecting the action potential of hiPSC-CMs in laboratory settings. Long-term rosuvastatin treatment was not associated with mortality. In conclusion, while our study links rosuvastatin use to potential QT prolongation and possible influence on the action potential of hiPSC-CMs, long-term use does not show increased mortality, necessitating further research for conclusive real-world applications.

The frequency of rs2231142 in ABCG2 among Native Hawaiian and Pacific Islander subgroups: implications for personalized rosuvastatin dosing.

Statins are among the most commonly prescribed medications worldwide. Rosuvastatin is a moderate- to high-intensity statin depending on the prescribed dose. Statin-associated muscle symptoms are the main side effects, contributing to low adherence to statins. The missense variant rs2231142 in ABCG2 affects the functionality of the ABCG2 transporter, altering the pharmacokinetics and pharmacodynamics of rosuvastatin. This special report aims to accentuate the importance of considering the ABCG2 genotype upon prescribing rosuvastatin in high cardiovascular disease risk subgroups, specifically Native Hawaiian and Pacific Islander populations. Based on the reported frequencies of rs2231142 in ABCG2, it may be justifiable to initiate low-dose rosuvastatin in Samoans relative to Marshallese or Native Hawaiians. Interpopulation differences in pharmacogenetic allele frequencies underscore the need to disaggregate broad population categories to achieve health equity in treatment outcomes.

Rosuvastatin is a medication that is used to decrease levels of bad cholesterol in the blood. One of the side effects of rosuvastatin is muscle aches, which can cause patients to stop taking their medication. ABCG2 is a gene responsible for encoding ABCG2, an important transporter that plays a role in how the body interacts with many medications, including rosuvastatin. Genetic variations in ABCG2 result in a functional or nonfunctional transporter. This special report aims to focus on the importance of considering genetic variations in ABCG2 among different population subgroups, in particular Native Hawaiians, Samoans and Marshallese. The ABCG2 genotype could inform clinicians about the most effective rosuvastatin dose to prescribe. This approach highlights the importance of individualized patient characteristics above and beyond race and ethnicity.

Assessment of Anti-Xa activity in patients receiving concomitant apixaban with strong p-glycoprotein inhibitors and statins.

WHAT IS KNOWN AND OBJECTIVES: Although the apixaban Food and Drug Administration (FDA) package insert recommends dose reduction in patients administered dual strong inhibitors of p-glycoprotein (P-gp) and cytochrome P-450 (CYP) 3A4, there are limited published data regarding potential drug-drug interactions between apixaban (Eliquis) and common p-glycoprotein (P-gp) and CYP3A4 inhibitors co-administered with statins. The aim of this study was to investigate the degree of elevation relative to apixaban serum peak and trough concentration after the co-administration of amiodarone, diltiazem and statins (atorvastatin, rosuvastatin and simvastatin). METHODS: Patients prescribed apixaban 5mg twice daily for at least one week were identified from the anticoagulation clinic database and contacted for potential enrolment. A total of 117 volunteers were enrolled with eight excluded due to discontinued use, resulting in 109 volunteers (44 females and 65 males delineated into age groups 40-64 and ≥65 years old) completing the observational study. Fifty-five volunteers were administered apixaban without the P-gp inhibitors amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin and simvastatin). Fifty-four volunteers were administered apixaban with either amiodarone or diltiazem, with or without statins (atorvastatin, rosuvastatin or simvastatin). Peak and trough concentrations were assessed for each patient utilizing an apixaban anti-Xa assay. RESULTS: Of the combinations studied, the mean apixaban trough concentration upon co-administration of amiodarone without a statin was elevated compared to apixaban alone (experimental 156.83 +/- 79.59 ng/ml vs. control 104.09 +/- 44.56 ng/ml; p = 0.04). The co-administration of diltiazem and rosuvastatin, and the administration of amiodarone without a statin led to greater than 1.5-fold increase in apixaban concentrations (peak experimental 315.19 +/- 157.53 ng/ml vs control 207.6 +/- 83.38 ng/ml; p = 0.08 and trough experimental 182.03 +/- 95.93 ng/ml vs control 112.32 +/- 37.78 ng/ml; p = 0.17) suggesting the need to assess dose adjustment for patients per the FDA package insert. In addition, the aggregated mean peak (p = 0.0056) and trough (p = 0.0089) elevation of CYP3A4 experimental groups (atorvastatin and simvastatin) co-administered apixaban and diltiazem were statistically significant compared with the aggregated non-CYP3A4 control groups (no statin and rosuvastatin). WHAT IS NEW AND CONCLUSION: Herein, we report novel data regarding peak and trough apixaban concentrations after concomitant administration of P-gp and CYP3A4 inhibitors (amiodarone or diltiazem) co-administered with statins (atorvastatin, rosuvastatin or simvastatin). Providers should consider utilizing the apixaban anti-Xa assay or comparative heparin anti-Xa assay to determine if patients require dose reduction to decrease adverse events in high-risk patients prescribed apixaban and concomitant p-glycoprotein and CYP3A4 inhibitors amiodarone or diltiazem with and without a CYP3A4 or non-3A4 statin.

Assessment of the Effect of Filgotinib on the Pharmacokinetics of Atorvastatin, Pravastatin, and Rosuvastatin in Healthy Adult Participants.

Filgotinib, an oral Janus kinase-1 preferential inhibitor, is approved in Europe and Japan for adults with rheumatoid arthritis. Patients with rheumatoid arthritis are at higher risk of cardiovascular morbidity/mortality; thus, it is important to understand potential drug-drug interactions of filgotinib with lipid-lowering agents. This open-label, randomized, 2-way crossover study evaluated the pharmacokinetics of atorvastatin, pravastatin, and rosuvastatin with and without filgotinib coadministration. Healthy participants (N = 27) received single doses of atorvastatin (40 mg) and of a pravastatin (40 mg)/rosuvastatin (10 mg) cocktail-alone or with filgotinib (200 mg once daily for 11 days)-on 2 different occasions with washout in between. Serial pharmacokinetic blood samples were collected, and safety was assessed. Pharmacokinetic parameters were evaluated using 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratio of the test treatment (statin coadministration with filgotinib) vs statin alone, with prespecified lack-of-interaction bounds of 0.70 to 1.43. Coadministration of filgotinib did not affect atorvastatin area under the plasma concentration-time curve extrapolated to infinity (AUCinf ; [GLSM ratios (90% CI): 0.91 (0.84-0.99)]), but maximum concentration [Cmax ] was slightly lower [0.82 (0.69-0.99)]. The exposure of 2-hydroxy-atorvastatin was unaffected (GLSM ratios [90% CI], 0.98 [0.81-1.19] for Cmax ; 1.11 [1.02-1.22] for AUCinf ). Pravastatin AUCinf was also unaffected (GLSM ratios, 1.22 [1.05-1.41], but Cmax was slightly higher 1.25 [1.01-1.54]). Rosuvastatin exposure was moderately higher with filgotinib coadministration-GLSM ratios (90% CI), 1.68 (1.43-1.97) for Cmax ; 1.42 (1.30-1.57) for AUCinf -but this was not considered clinically relevant. These results indicate that filgotinib has no clinically meaningful effect on exposure of atorvastatin, pravastatin, or rosuvastatin.

Assessment of Transporter-Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients With Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome.

As a first-in-class, selective, potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation. An in vitro study showed that enasidenib at clinically relevant concentrations has effects on multiple drug metabolic enzymes and transporters, including inhibition of P-glycoprotein, breast cancer resistance protein, organic anion transporter (OAT) P1B1, and OATP1B3 transporters. Therefore, a drug-drug interaction study was conducted to assess the impact of enasidenib at steady state on the pharmacokinetics of several probe compounds in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome, including the probes herein described in this article, digoxin and rosuvastatin. Results from 8 patients (all Asian) with a mean age of 67.1 years showed that following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), digoxin's (0.25 mg) area under the plasma concentration-time curve from time 0 to 30 days was 1.2-fold (90% confidence interval, 0.9-1.6), compared with digoxin alone. Following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), rosuvastatin's (10 mg) area under the plasma concentration-time curve from time 0 to infinity was 3.4-fold (90% confidence interval, 2.6-4.5) compared with rosuvastatin alone. These results should serve as the basis for dose recommendations for drugs that are substrates of P-glycoprotein, breast cancer resistance protein, OATP1B1, and OATP1B3 transporters, when used concomitantly with enasidenib.

Biomarker-Informed Model-Based Risk Assessment of Organic Anion Transporting Polypeptide 1B Mediated Drug-Drug Interactions.

Quantitative prediction of drug-drug interactions (DDIs) involving organic anion transporting polypeptide (OATP)1B1/1B3 inhibition is limited by uncertainty in the translatability of experimentally determined in vitro inhibition potency (half-maximal inhibitory concentration (IC50 )). This study used an OATP1B endogenous biomarker-informed physiologically-based pharmacokinetic (PBPK) modeling approach to predict the effect of inhibitor drugs on the pharmacokinetics (PKs) of OATP1B substrates. Initial static analysis with about 42 inhibitor drugs, using in vitro IC50 values and unbound liver inlet concentrations (Iin,max,u ), suggested in vivo OATP1B inhibition risk for drugs with R-value (1+ Iin,max,u /IC50 ) above 1.5. A full-PBPK model accounting for transporter-mediated hepatic disposition was developed for coproporphyrin I (CP-I), an endogenous OATP1B biomarker. For several inhibitors (cyclosporine, diltiazem, fenebrutinib, GDC-0810, itraconazole, probenecid, and rifampicin at 3 different doses), PBPK models were developed and verified against available CP-I plasma exposure data to obtain in vivo OATP1B inhibition potency-which tend to be lower than the experimentally measured in vitro IC50 by about 2-fold (probenecid and rifampicin) to 37-fold (GDC-0810). Models verified with CP-I data are subsequently used to predict DDIs with OATP1B probe drugs, rosuvastatin and pitavastatin. The predicted and observed area under the plasma concentration-time curve ratios are within 20% error in 55% cases, and within 30% error in 89% cases. Collectively, this comprehensive study illustrates the adequacy and utility of endogenous biomarker-informed PBPK modeling in mechanistic understanding and quantitative predictions of OATP1B-mediated DDIs in drug development.

Rosuvastatin calcium-based novel nanocubic vesicles capped with silver nanoparticles-loaded hydrogel for wound healing management: optimization employing Box-Behnken design: in vitro and in vivo assessment.

Chronic wounds are a serious problem that could cause severe morbidity and even death. The ability of statins including rosuvastatin calcium (RVS) to enhance wound healing was well reported. However, RVS is poorly soluble and has low bioavailability. Thus, this study aimed to prepare and evaluate RVS-loaded nanocubics to enhance its skin performance. In addition, silver nanoparticles (AgNPs) exhibited potent antimicrobial activity, thus, the optimum RVS-loaded nanocubics was capped with AgNPs to evaluate its effect in wound management. Box-Behnken design was adopted to prepare RVS nanocubics. The design investigated the effect of lecithin, poloxamer 407 concentrations and hydration time on vesicle size, zeta potential (ZP), entrapment efficiency (EE%) and in vitro drug release%. Optimum formulation capped with AgNPs was incorporated into a gel base and examined for wound healing efficiency using different pharmacological tests in rats. Nanocubics have shown a mean diameter between 167.2 ± 7.8 and 408 ± 18.4 nm, ZP values ranging from -20.9 ± 1.9 to -53.5 ± 4 mV, EE% equivocated between 31.6 ± 1.4 and 94.4 ± 8.6 and drug release after 12 h between 17.9 ± 1.9 and 68.0 ± 4.0%. The histopathological studies and serum tumour necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß) levels confirmed the greater efficacy of RVS nanocubics capped with AgNPs gel in wound healing when compared with gentamicin ointment. RVS-loaded nanocubic vesicles and AgNPs-loaded hydrogel could be considered as a promising platform to enhance the wound healing and tissue repair processes.

Identification of drugs associated with reduced severity of COVID-19 - a case-control study in a large population.

Background: Until coronavirus disease 2019 (COVID-19) drugs specifically developed to treat COVID-19 become more widely accessible, it is crucial to identify whether existing medications have a protective effect against severe disease. Toward this objective, we conducted a large population study in Clalit Health Services (CHS), the largest healthcare provider in Israel, insuring over 4.7 million members. Methods: Two case-control matched cohorts were assembled to assess which medications, acquired in the last month, decreased the risk of COVID-19 hospitalization. Case patients were adults aged 18 to 95 hospitalized for COVID-19. In the first cohort, five control patients, from the general population, were matched to each case (n=6202); in the second cohort, two non-hospitalized SARS-CoV-2 positive control patients were matched to each case (n=6919). The outcome measures for a medication were: odds ratio (OR) for hospitalization, 95% confidence interval (CI), and the p-value, using Fisher's exact test. False discovery rate was used to adjust for multiple testing. Results: Medications associated with most significantly reduced odds for COVID-19 hospitalization include: ubiquinone (OR=0.185, 95% CI [0.058 to 0.458], p<0.001), ezetimibe (OR=0.488, 95% CI [0.377 to 0.622], p<0.001), rosuvastatin (OR=0.673, 95% CI [0.596 to 0.758], p<0.001), flecainide (OR=0.301, 95% CI [0.118 to 0.641], p<0.001), and vitamin D (OR=0.869, 95% CI [0.792 to 0.954], p<0.003). Remarkably, acquisition of artificial tears, eye care wipes, and several ophthalmological products were also associated with decreased risk for hospitalization. Conclusions: Ubiquinone, ezetimibe, and rosuvastatin, all related to the cholesterol synthesis pathway were associated with reduced hospitalization risk. These findings point to a promising protective effect which should be further investigated in controlled, prospective studies. Funding: This research was supported in part by the Intramural Research Program of the National Institutes of Health, NCI.

Assessment of therapeutic effects of statin on cardiac sympathetic nerve activity after reperfusion therapy in patients with first ST-segment elevation myocardial infarction and normal low-density lipoprotein cholesterol.

BACKGROUND: Statin treatment reduces enhanced cardiac sympathetic nerve activity (CSNA) in patients with heart disease, and reduces adverse cardiac events in patients with coronary artery disease. METHODS: We retrospectively evaluated the first ST-segment elevation myocardial infarction (STEMI) patients and low-density lipoprotein cholesterol < 120 mg/dL in our database who underwent 123I-metaiodobenzylguanidine (MIBG) scintigraphy 3 weeks after admission. Sixty STEMI patients after primary coronary angioplasty were selected, and used propensity score matching to compare patients treated with strong statin (n = 30), and those who did not (n = 30). Moreover, echocardiographic left ventricular (LV) parameters were determined, and plasma procollagen type III amino terminal peptide (PIIINP) was also measured before and 3 weeks after treatment. RESULTS: Following primary angioplasty, age, gender, risk factors, culprit coronary artery, peak serum creatine phosphokinase concentration, and recanalization time were similar in the two groups. However, the statin group showed significantly lower delayed total defect score and washout rate evaluated by 123I-MIBG scintigraphy (22.4 ± 8.1 vs. 29.6 ± 10.5; P < 0.01, and 30.4 ± 8.9% vs. 40.1 ± 11.4%; P < 0.005, respectively) and higher delayed heart/mediastinum count ratio (2.17 ± 0.38 vs. 1.96 ± 0.30, P < 0.05) compared with the non-statin group. Moreover, the degree of change in LV parameters and PIIINP was more favorable in the statin group than in the non-statin group. CONCLUSIONS: Administration of statin improves CSNA after reperfusion therapy in patients with first STEMI.

Static Model-Based Assessment of OATP1B1-Mediated Drug Interactions with Preincubation-Dependent Inhibitors Based on Inactivation and Recovery Kinetics.

Quantitative assessment of drug-drug interactions (DDIs) via organic anion transporting polypeptide (OATP) 1B1 is one of the key issues in drug development. Although OATP1B1 inhibition exhibits unique characteristics, including preincubation dependence for some inhibitors, a limited approach has been attempted based on the static model that considers such preincubation dependence in the prediction of DDIs via OATP1B1. The present study aimed to establish the prediction of DDIs via OATP1B1 using preincubation-dependent inhibitors based on the static model and incorporating both inactivation and recovery of OATP1B1 activity. Cyclosporine A was selected as a preincubation-dependent inhibitor, as well as five substrates that include probes and pharmaceuticals. The inhibition ratio (R value) calculated on the basis of a conventional static model, considering inhibition of OATP1B1 and contribution ratio of OATP1B1 to the overall hepatic uptake, was much lower than the reported AUC ratio, even when IC50 values were estimated after preincubation conditions. Conversely, the R value that was estimated by considering inactivation and recovery parameters was closer to the AUC ratio. The R value that was calculated assuming the complete contribution of OATP1B1 was much higher than the AUC ratio, avoiding false-negative prediction. The R value estimated by considering inactivation and recovery for another combination of a preincubation-dependent inhibitor, asunaprevir, and substrate drug, rosuvastatin, was also closer to the AUC ratio. Thus, R values calculated based on such OATP1B1 kinetics would be potential alternative indexes for the quantitative prediction of OATP1B1-mediated DDIs using preincubation-dependent inhibitors, although this prediction is affected by estimation of the contribution ratio of substrates. SIGNIFICANCE STATEMENT: Static model-based quantitative prediction of organic anion transporting polypeptide 1B1-mediated drug-drug interactions induced by preincubation-dependent inhibitors was newly proposed to avoid false-negative prediction.

Cost-Effectiveness Analysis of Ezetimibe as the Add-on Treatment to Moderate-Dose Rosuvastatin versus High-Dose Rosuvastatin in the Secondary Prevention of Cardiovascular Diseases in China: A Markov Model Analysis.

BACKGROUND: For patients with inadequate control of cholesterol using moderate-dose statins in the secondary prevention of cardiovascular diseases (CVD), either doubling the dose of statins or adding ezetimibe should be considered. The cost-effectiveness of them is unknown in the Chinese context. The aim of this study is to compare the cost and effectiveness of the two regimens, and estimate the incremental cost-effectiveness ratio (ICER). METHODS: A Markov model of five health statuses were used to estimate long-term costs and quality-adjusted life-years (QALYs) of the two treatment regimens from the healthcare perspective. The effectiveness data used to calculate the transition probability was based on a previously published randomized trial. The utility data was gathered from literature and the costs were gathered from the electronic medical record system of West China Hospital in Chinese Yuan (CNY) in 2017 price. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted. RESULTS: The ICER for ezetimibe plus moderate-dose rosuvastatin was 47,102.99 CNY per QALY for 20 years simulation, which did not reach the threshold of per capita gross domestic product (GDP) of 59,660 CNY per QALY in 2017 in China. Non-CVD-related mortality and CVD-related mortality contributed most to the ICER. CONCLUSION: Adding ezetimibe to the moderate-dose statin in secondary prevention for CVD is cost-effective, compared with the high-dose statin in the Chinese context whose low-density lipoprotein cholesterol (LDL-c) was not inadequately controlled by moderate-dose statin alone.

Assessment of Transporter Polymorphisms as a Factor in a BCRP Drug Interaction Study With Lanabecestat.

Lanabecestat is a human ß-site amyloid precursor protein-cleaving enzyme 1 inhibitor in development to slow disease progression in patients with early Alzheimer's disease. The study evaluated the breast cancer resistance protein (BCRP) inhibition potential of lanabecestat on the pharmacokinetics (PK) of rosuvastatin, a probe for BCRP activity, in healthy white subjects who were not carriers of SLCO1B1 (c.521T>C), not homozygotes for ABCG2 (c.421C>A or c.34G>A), and not heterozygotes of ABCG2 (c.421C>A and c.34G>A). The safety of lanabecestat + rosuvastatin, the effects of rosuvastatin on the PK of lanabecestat, and the effects of multiple genetic polymorphisms on rosuvastatin exposure were assessed. Geometric mean ratios of the maximum observed rosuvastatin concentration (Cmax ), area under the rosuvastatin concentration-versus-time curve (AUC) from time 0 to infinity, and time of maximum observed drug concentration (tmax ) when rosuvastatin was administered alone and with lanabecestat were contained within 0.8-1.25, as were lanabecestat AUC at steady state and tmax at steady state when lanabecestat was administered alone or with rosuvastatin. Lanabecestat Cmax at steady state increased 8% in the presence of rosuvastatin. Except for an approximately 80% increase of rosuvastatin AUC (P < .05) in the heterozygotes of ABCG2 c.421C>A relative to the CC genotype, there were no statistically significant associations between rosuvastatin exposure and polymorphisms assessed. Lanabecestat + rosuvastatin was associated with few treatment-emergent adverse events, all of which resolved and were mild. Lanabecestat does not meaningfully impact BCRP activity; therefore, restriction of concomitant administration with BCRP substrates, such as rosuvastatin, may be unnecessary.

Generic atorvastatin and rosuvastatin in the South Korean market: time of introduction in relation to manufacturer characteristics.

Background: The competition for and market dynamics of generic medicines can be understood by analyzing manufacturers' behavior. In this study, we analyzed the various types of generic atorvastatin and rosuvastatin that were introduced onto the South Korean market from 2002 to 2018 and their corresponding manufacturers. Methods: Based on publicly available data, we selected drugs containing atorvastatin and rosuvastatin as active ingredients for the analysis. We calculated the time between the date of marketing approval for the first generic and that of the remaining generics. Then, we categorized manufacturers that marketed generics into first movers and latecomers. Results: We confirmed that many manufacturers have marketed generic drugs in South Korea and that manufacturers can be categorized as first movers and latecomers. Interestingly, latecomers account for a large portion of the manufacturers of generics, and they have entered the market steadily, even after the market matured with a number of manufacturers. Additionally, the characteristics of the manufacturers were closely related to manufacturers' behaviors in the market. Conclusions: The order-of-entry effect, which is commonly observed in other markets, is marginal in the South Korean market, and this phenomenon is mainly explained by the rare price competition among generic manufacturers.

Association of Region and Hospital and Patient Characteristics With Use of High-Intensity Statins After Myocardial Infarction Among Medicare Beneficiaries.

Importance: High-intensity statin use after myocardial infarction (MI) varies by patient characteristics, but little is known about differences in use by hospital or region. Objective: To explore the relative strength of associations of region and hospital and patient characteristics with high-intensity statin use after MI. Design, Setting, and Participants: This retrospective cohort analysis used Medicare administrative claims and enrollment data to evaluate fee-for-service Medicare beneficiaries 66 years or older who were hospitalized for MI from January 1, 2011, through June 30, 2015, with a statin prescription claim within 30 days of discharge. Data were analyzed from January 4, 2017, through May 12, 2019. Exposures: Beneficiary characteristics were abstracted from Medicare data. Hospital characteristics were obtained from the 2014 American Hospital Association Survey and Hospital Compare quality metrics. Nine regions were defined according to the US Census. Main Outcomes and Measures: Intensity of the first statin claim after discharge characterized as high (atorvastatin calcium, 40-80 mg, or rosuvastatin calcium, 20-40 mg/d) vs low to moderate (all other statin types and doses). Trends in high-intensity statins were examined from 2011 through 2015. Associations of region and beneficiary and hospital characteristics with high-intensity statin use from January 1, 2014, to June 15, 2015, were examined using Poisson distribution mixed models. Results: Among the 139 643 fee-for-service beneficiaries included (69 968 men [50.1%] and 69 675 women [49.9%]; mean [SD] age, 76.7 [7.5] years), high-intensity statin use overall increased from 23.4% in 2011 to 55.6% in 2015, but treatment gaps persisted across regions. In models considering region and beneficiary and hospital characteristics, region was the strongest correlate of high-intensity statin use, with 66% higher use in New England than in the West South Central region (risk ratio [RR], 1.66; 95% CI, 1.47-1.87). Hospital size of at least 500 beds (RR, 1.15; 95% CI, 1.07-1.23), medical school affiliation (RR, 1.11; 95% CI, 1.05-1.17), male sex (RR, 1.10; 95% CI, 1.07-1.13), and patient receipt of a stent (RR, 1.35; 95% CI, 1.31-1.39) were associated with greater high-intensity statin use. For-profit hospital ownership, patient age older than 75 years, prior coronary disease, and other comorbidities were associated with lower use. Conclusions and Relevance: This study's findings suggest that geographic region is the strongest correlate of high-intensity statin use after MI, leading to large treatment disparities.