Concomitant Use Of Simvastatin Research Articles

Simvastatin, but Not Atorvastatin, Is Associated with Higher Peak Rivaroxaban Serum Levels and Bleeding: an Asian Cohort Study from Singapore.

This study attempts to identify predictors associated with bleeding and stroke and systemic embolism (SSE) in Singaporean Asians taking rivaroxaban and apixaban. A total of 134 Singaporean patients on either rivaroxaban or apixaban for non-valvular atrial fibrillation were included for this study. Baseline characteristics were recorded at recruitment while bleeding and SSE events were recorded during a 1-year follow-up. Peak and trough drug plasma concentrations were collected based on the dosing interval and pharmacokinetics of the drugs and quantified using high performance liquid chromatography. Characteristics of patients with or without bleeds were compared using relevant statistical tests. Multivariable regression that included covariates with p < 0.1 from an initial univariable regression was performed to analyse predictors that resulted in higher risk of bleeding in patients. Median creatinine clearance (CrCl) was significantly lower in patients on rivaroxaban who experienced bleeds as compared to patients who did not experience bleeds (61.5 vs 70.8 mL/min, p = 0.047), while concomitant simvastatin use was found to be independently associated with a sixfold increased risk of bleeding (adjusted OR = 6.14 (95% CI: 1.18-31.97), p = 0.031) for rivaroxaban after controlling for body mass index, CrCl and having experienced a previous SSE. Our findings suggest that concomitant use of simvastatin with rivaroxaban may be associated with bleeding events in an Asian cohort. Further studies using physiologically based pharmacokinetic modelling are required to investigate the drug-drug interactions between these drugs.

A case of complete atrioventricular block with extremely high blood concentration of azelnidipine

BackgroundAzelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported.Case presentationIn the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient’s physician that the patient’s serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient’s serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment.ConclusionsAzelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.

Low-dose photodynamic therapy-induced increase in the metastatic potential of pancreatic tumor cells and its blockade by simvastatin

Pancreatic tumor are a deadly malignancy with high aggressiveness, and photodynamic therapy (PDT) is a prospective remedy. Nevertheless, the cells in the peripheral tissues of large tumors are often subjected to low-dose illumination and tend to survive after sublethal PDT exposure. Thus, it is of critical importance to determine the metastatic influence of PDT on pancreatic neoplasms. (17R, 18R)-2-(1-Hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt (YLG-1) is a novel chlorine derivative photosensitizer, and we previously demonstrated potent growth inhibition of pancreatic neoplasms by YLG-1-mediated PDT (YLG-1-PDT). In this study, we assessed the metastatic effect of low-dose PDT with YLG-1 on pancreatic tumors and its combination with simvastatin. We found that sublethal YLG-1-PDT promoted MMP-2/9 expression in residual pancreatic tumor cells as well as tumor cell motility/invasion and liver metastasis. Since simvastatin was reported to improve the survival of patients with pancreatic tumors at an early stage and suppress the metastasis of most cancers, we utilized it during YLG-1-PDT and discovered alleviated migration/invasion, metastasis and MMP-2/9 expression. Collectively, our study results raise the concern that PDT could also be a Janus-like treatment owing to its prometastatic potential provoked by a low dosage. Concomitant use of simvastatin during PDT might be an effective method to attenuate such adverse reactions.

Pharmacodynamic and pharmacokinetic interactions between simvastatin and diazepam in rats.

Statins and benzodiazepines are widely used drugs, especially in ischemic heart disease, where exacerbation caused by anxiety can even lead to cardiac death. There have not been any reports of statin drug interaction with anxiolytics so far, but it is possible that these drugs interact with each other. We examined the effect of chronic oral administration of simvastatin on the anxiolytic activity and pharmacokinetics of diazepam in rats. Studies were conducted on male Wistar Han rats treated with simvastatin (2.5, 5, 10, 20mg/kg) for 4-6 weeks, and/or diazepam (2.5, 5, 10mg/kg) administered once on the day of the study. Evaluation of potential pharmacodynamic interaction was based on the behavioral tests: elevated plus maze (EPM) test and the Vogel conflict test (VCT). The assessment of the potential pharmacokinetic interaction was based on measurements of concentrations of diazepam and its metabolites in the blood of animals. Diazepam 5 and 10mg/kg given together with simvastatin 10 and 20mg/kg showed no anxiolytic effect in the EPM test. In the VCT diazepam combinations with simvastatin did not produce any anxiolytic effect either, with an exception of the co-administration of diazepam 10mg/kg and simvastatin 10mg/kg. Simvastatin (20mg/kg) significantly reduced the area under curve (AUC) of diazepam by 51.6% and temazepam by 54.6%. Abolition of diazepam anxiolytic effect during concomitant use of simvastatin is probably caused by diminished bioavailability of diazepam, although pharmacodynamic interaction between these drugs cannot be excluded.

Pharmacokinetic model for the inhibition of simvastatin metabolism by itraconazole.

Concomitant use of simvastatin, a HMG-CoA reductase inhibitor, with a potent CYP3A4 inhibitor, itraconazole, can result in a serious drug-drug interaction induced severe adverse event, rhabdomyolysis. Even though pharmacokinetic data regarding such interaction are available, they cannot be used for quantitative prediction. For this reason, we aimed to develop a pharmacokinetic model for predicting the magnitude of inhibition of simvastatin metabolism by itraconazole. Published data involving pharmacokinetic of simvastatin, itraconazole, and pharmacokinetic interaction between simvastatin and itraconazole were selected from PubMed search. Serum simvastatin concentrations were subsequently extracted and used for model development. Advanced Continuous Simulating Language Extreme (ACSLX) was used for modeling. The drug-drug interaction model between simvastatin and itraconazole was simultaneously modeled using a one compartment parent-metabolite model for simvastatin, and a two-compartment model for itraconazole. The final drug-drug interaction model can adequately describe the actual simvastatin concentrations. Model application can be of advantage for dosing adjustment to avoid serious adverse effects resulted from concomitant use of both drugs.

A pharmacokinetic drug-drug interaction model of simvastatin and verapamil in humans.

Verapamil is a calcium channel blocker commonly used in treatments of hypertension. Verapamil and its active metabolite, norverapamil, are known to be CYP3A4 inhibitors. Co-administration of verapamil with CYP3A4 substrates can alter the pharmacokinetics of the substrates. Simvastatin, a commonly used HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia is extensively metabolized by CYP3A4. Therefore, concomitant use of simvastatin and verapamil can increase simvastatin plasma concentration levels, resulting in a higher risk of rhabdomyolysis, a serious adverse drug reaction. Even though, pharmacokinetic data regarding the interaction between both drugs have been published, their use is limited to semiquantitative applications. Therefore, we aimed to develop a mathematical model describing drug-drug interaction between simvastatin and verapamil in humans. Eligible pharmacokinetic interaction study between simvastatin and verapamil in humans was selected from PubMed database. The concentration-time courses from this study were digitally extracted and used for model development. The drug-drug interaction between simvastatin and verapamil was modeled simultaneously with a two compartment model for verapamil with its active metabolite, norverapamil and a one compartment model for simvastatin with its active form, simvastatin hydroxy acid. The effects of verapamil and norverapamil on pharmacokinetics of simvastatin and its active form, simvastatin hydroxy acid were described by Michaelis-Menten equation. Simulated simvastatin and simvastatin hydroxy acid concentrations obtained from the final model produced a good fit to the dataset from a literature. The final model adequately describes pharmacokinetic interaction between simvastatin and verapamil which can be helpful in prediction of rhabdomyolysis in patients with concurrent use of these drugs.

PS-047 Co-prescription of simvastatin and potent inhibitors of CYP3A4; monitoring system in hospital

BackgroundDrug-drug interactions may increase the risk of adverse events. Understanding the pharmacokinetic and pharmacodynamic properties of drugs and their interaction mechanisms is fundamental to optimising therapeutic results. The benefits of...

Rhabdomyolysis after Concomitant Use of Simvastatin and Voriconazole in an Allogeneic Stem Cell Transplant Patient

Objective: To report a case of rhabdomyolysis after concomitant use of simvastatin and voriconazole. Case Summary: A 65-year-old white male, weight 66 kg, 79 months post allogeneic stem cell transplant for chronic lymphocytic leukemia, was on a stable medication regimen that included voriconazole. He was hospitalized with weakness and elevated creatine kinase a few weeks after initiation of simvastatin for treatment of hyperlipidemia. His symptoms resolved and creatine kinase level returned to within the normal range after fluid administration and discontinuation of simvastatin. Discussion: The use of statins has become a standard in the treatment and prevention of atherosclerotic disease. Most statins are metabolized via the cytochrome P450 enzyme system. For simvastatin, metabolism occurs specifically via the CYP3A4 isoenzyme. Drugs known to inhibit this isoenzyme, such as voriconazole, can increase the risk for toxicities, including rhabdomyolysis, when used concomitantly with simvastatin. This case represents a probable drug-drug interaction, based on the Horn Drug Interaction Probability Scale. Conclusions: Due to the broad use of statins for the treatment and prevention of atherosclerotic disease, as well as the need for azole antifungals in the stem cell transplant population, interactions between these agents are becoming an increasing possibility. Care should be taken to minimize these interactions and, when feasible, a change to an alternative agent may be warranted to avoid adverse effects.

CPC-106 Pharmacokinetic Drug-Drug Interactions Due to Treatment with Amiodarone – a Practical Approach

BackgroundThe drug amiodarone has a complex pharmacokinetic profile and can be a challenge to use due to the high potential for drug-drug interactions.Purpose To identify and submit proposals for handling...

Severe Rhabdomyolysis and Acute Renal Failure Secondary to Concomitant Use of Simvastatin With Rapamycin Plus Tacrolimus in Liver Transplant Patient

Objective To report a severe interaction between simvastatin and rapamycin resulting in rhabdomyolysis and acute renal failure in a liver transplant patient. Background A 56-year-old man with hepatitis C virus cirrhosis (Child B) was diagnosed with hepatocellular carcinoma and underwent liver transplantation in April 2007. He was immunosuppressed with tacrolimus (FK) and mycophenolate mofetil (MMF). Postoperative complications were arterial hypertension and renal insufficiency. In June 2007, liver dysfunction was detected and acute rejection was diagnosed by biopsy. He received three 500-mg boluses of methylprednisolone and FK levels were maintained between 10 and 12 ng/mL. Laboratory values revealed persistent rejection and MMF was stopped with initiation of rapamicin. One month later, hyperlipidemia appeared as a consequence of rapamicin therapy; simvastatin was administered. In August 2007, the patient was readmitted due to severe muscule pain and the inability to ambulate. Laboratory values were: total bilirubin 16 mg/dL, serum creatinine 4.3 mg/dL, and total creatine kinase (CK) 42,124 U/L. With the suspicion of rhabdomyolysis, leading to worsening of his basal renal insufficiency, rapamycin and tacrolimus were stopped. Hemodialysis was initiated owing to renal failure and hyperkalemia. Some hours later, the patient developed ventricular fibrillation and respiratory failure and succumbed. Discussion Calcineurin inhibitors (CNI), corticosteroids, and mammalian target of rapamycin (m-TOR) inhibitors are associated with adverse dyslipidemic effects. To reduce the overall cardiovascular risk in these patients, lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been widely used. CNI and m-TOR inhibitors, as well as most statins, are metabolized by cytochrome P450 (CYP)3A4; thus, pharmacokinetic interactions between these drugs are possible. Previous reports have indicated an increased risk of rhabdomyolysis in the presence of concomitant drugs that inhibit simvastatin metabolism. Conclusions Concomitant administration of statin therapy and drugs that inhibit cytochrome P450 (CYP)3A4 increased the risk of rhabdomyolysis in a patient suffering liver and renal dysfunction.

Rhabdomyolysis caused by co-medication with simvastatin and clarithromycin

Rhabdomyolysis is a rare side-effect of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase-inhibitors. Co-medication with inhibitors of the cytochrome P450 3A4 (CYP34A) pathway may increase this risk. We describe the case of a female patient who developed severe rhabdomyolysis due to concomitant use of simvastatin (20 mg) and clarithromycin. Previous reports on this interaction involved patients on high doses of statins. This case demonstrates that even low-dose therapy of CYP3A4metabolized statins is associated with an increased risk of rhabdomyolysis when combined with CYP3A4 inhibitors. Due to the wide use of statins in stroke medicine, a knowledge of this interaction has significant clinical

Il pericolo ancora sottovalutato delle interazioni tra farmaci. Un caso clinico esemplificativo

Treatment of hypercholesterolemia has been shown to reduce mortality in patients with coronary artery disease. Patients with severe lipid abnormalities may require high-dose statin therapy, at times used in combination with additional agents. The occurrence of rhabdomyolysis is one of the rare side-effects of the cholesterol-lowering agents. During the use of simvastatin, the risk of this side-effect might be increased when macrolides are used concomitantly. The interacting mechanism likely was inhibited cytochrome P450 (CYP) 3A4 metabolism and possibly P-glycoprotein transport of simvastatin as well. We present a patient who developed rhabdomyolysis during the concomitant use of simvastatin and erythromycin. Coprescribing of medications not compatible with statins occurs frequently: to prevent future events, it is crucial that clinicians recognize the interaction risk associated with coprescribing, to assure that the risk of untoward effects is mitigated.

Severe Rhabdomyolysis and Acute Renal Failure Secondary to Concomitant Use of Simvastatin, Amiodarone, and Atazanavir

To report a case of a severe interaction between simvastatin, amiodarone, and atazanavir resulting in rhabdomyolysis and acute renal failure. A 72-year-old white man with underlying human immunodeficiency virus, atrial fibrillation, coronary artery disease, and hyperlipidemia presented with generalized pain, fatigue, and dark orange urine for 3 days. The patient was taking 80 mg simvastatin at bedtime (initiated 27 days earlier); amiodarone at a dose of 400 mg daily for 7 days, then 200 mg daily (initiated 19 days earlier); and 400 mg atazanavir daily (initiated at least 2 years previously). Laboratory evaluation revealed 66,680 U/L creatine kinase, 93 mg/dL blood urea nitrogen, 4.6 mg/dL creatinine, 1579 U/L aspartate aminotransferase, and 738 U/L alanine aminotransferase. Simvastatin, amiodarone, and the patient's human immunodeficiency virus medications were all temporarily discontinued and the patient was given forced alkaline diuresis and started on dialysis. Nine days later the patient's creatine kinase had dropped to 1695 U/L and creatinine was 3.3 mg/dL. The patient was discharged and continued outpatient dialysis for 1 month until his renal function recovered. The risk of rhabdomyolysis is increased in the presence of concomitant drugs that inhibit simvastatin metabolism. Simvastatin is metabolized by CYP3A4. Amiodarone and atazanavir are recognized CYP3A4 inhibitors. Pharmacokinetic differences in statins are an important consideration for assessing the risk of potential drug interactions. In patients requiring the concurrent use of statins and CYP3A4 inhibitors, pravastatin, fluvastatin, and rosuvastatin carry the lowest risk of drug interactions; atorvastatin carries moderate risk, whereas simvastatin and lovastatin have the highest risk and should be avoided in patients taking concomitant CYP3A4 inhibitors.

Adverse events with concomitant use of simvastatin or atorvastatin and thiazolidinediones*

<h2>Abstract</h2> On the basis of adverse events reported to the US Food and Drug Administration, it was observed that atorvastatin-associated adverse event reports were 3.1 times more likely to list rosiglitazone or pioglitazone as a concomitant medication compared with simvastatin-associated adverse event reports.

Adverse events with concomitant use of simvastatin or atorvastatin and thiazolidinediones

On the basis of adverse events reported to the US Food and Drug Administration, it was observed that atorvastatin-associated adverse event reports were 3.1 times more likely to list rosiglitazone or pioglitazone as a concomitant medication compared with simvastatin-associated adverse event reports.

Risk of cataract in patients treated with statins.

Studies in dogs showed that some hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are associated with cataract when administered in excessive doses. Clinical safety data of statins regarding cataract development in humans have been of limited value so far. To determine whether long-term use of statins is associated with an increased risk of cataract. We conducted a case-control analysis using data from the United Kingdom-based General Practice Research Database. The main outcome was a first-time diagnosis of cataract and/or cataract extraction in patients aged 40 to 79 years. Controls were matched to cases on age, sex, practice, calendar time, and duration of medical history in the database. Use of statins, fibrates, or other lipid-lowering drugs was compared with nonuse of any lipid-lowering drug, stratified by exposure duration and dose. We identified 7405 cases and 28 327 controls. Long-term use of statins (eg, > or =30 prescriptions) was not associated with an increased cataract risk (adjusted odds ratio [OR], 0.9; 95% confidence interval [CI], 0.5-1.6), nor was use of fibrates or of other lipid-lowering drugs (adjusted OR, 0.5; 95% CI, 0.3-1.1; and OR, 0.7; 95% CI, 0.1-5.6, respectively). We found evidence that concomitant use of simvastatin and erythromycin, a potent inhibitor of simvastatin metabolism, is associated with an increased cataract risk (adjusted odds ratio, 2.2; 95% confidence interval, 1.2-4.1). Our study provides evidence that long-term use of therapeutic statin doses does not increase the risk of developing cataract. Concomitant use of erythromycin and simvastatin may increase the cataract risk.