cerivastatin and Renal-Insufficiency

The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated in this nonrandomized, non-blinded, 7-day, multiple-dose study.. Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CL(CR) >90 ml/min/1.73 m2, n = 9), or patients with either mild (CL(CR) 61 ml/min/1.73 m2 to < or =90 ml/min/1.73 m2, n = 9), moderate (CL(CR) 30 ml/min/1.73 m2 to < or =60 ml/ min/1.73 m2, n = 8), or severe (CL(CR) <30 ml/min/ 1.73 m2, but not on dialysis, n = 9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin, including the area under the concentration-time curve (AUC)0-24, peak plasma concentration (Cmax), time to reach Cmax (tmax) and elimination half-life (t1/2), were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance (ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events, and laboratory safety indices.. The day-1 AUC in patients with mild renal impairment was similar to that of patients with normal function (19.6 microg/h/l vs 19.2 microg/h/l, respectively). However, the AUC for cerivastatin patients with moderate or severe renal impairment was 40-60% higher (30.8 microg/h/l and 29.0 microg/h/l, respectively). Cmax values for patients with normal, mild, moderate, and severe renal impairment were 3.3, 3.4, 4.6, and 5.2 microg/l, respectively. This modest increase in plasma cerivastatin levels is nearly equivalent to a 0.4-mg daily dose, which has been recently approved in the United States. The mean t1/2 of cerivastatin was less than 4.5 h in all patients, indicating that renal dysfunction did not promote cerivastatin accumulation. This observation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient groups. Furthermore, the mean AUC and Cmax values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function. Adverse events were observed in 37% of the subjects; nearly all were mild and generally of short duration, and most resolved without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were no clinically significant laboratory changes other than those consistent with renal disease.. This study demonstrates that dosage adjustment of the daily 0.3-mg cerivastatin dose in patients with significant renal impairment is likely unnecessary.

Topics: Adult; Aged; Analysis of Variance; Area Under Curve; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyridines; Regression Analysis; Renal Insufficiency

Statins are currently the mainstay of dyslipidemia management for the primary and secondary prevention of cardiovascular disease. Controversial concerns about the safety of the newly marketed statin rosuvastatin have been raised on the basis of premarketing studies and a few postmarketing reports.. We reviewed rosuvastatin-associated adverse events reported to the US Food and Drug Administration over its first year of marketing. On the basis of prescription data obtained from IMS Health, rates of adverse event reports (AERs) per million prescriptions were calculated. Rates of rosuvastatin-associated AERs over its first year of marketing were compared with those seen with atorvastatin, simvastatin, and pravastatin over the concurrent timeframe and during their respective first years of marketing. Comparison was also made to the first year of marketing of cerivastatin. The primary analysis examined the composite end point of AERs of rhabdomyolysis, proteinuria, nephropathy, or renal failure. With either timeframe comparison, rosuvastatin was significantly more likely to be associated with the composite end point of rhabdomyolysis, proteinuria, nephropathy, or renal failure AERs. Reported cases of rhabdomyolysis, proteinuria, or renal failure tended to occur early after the initiation of therapy and at relatively modest doses of rosuvastatin. The increased rate of rosuvastatin-associated AERs relative to other widely used statins was also observed in secondary analyses when other categories of AERs were examined, including adverse events with serious outcomes, liver toxicity, and muscle toxicity without rhabdomyolysis.. The present analysis supports concerns about the relative safety of rosuvastatin at the range of doses used in common clinical practice in the general population.

Topics: Consumer Product Safety; Drug Evaluation; Drug Prescriptions; Fluorobenzenes; Humans; Kidney Diseases; Morbidity; Product Surveillance, Postmarketing; Proteinuria; Pyridines; Pyrimidines; Renal Insufficiency; Retrospective Studies; Rhabdomyolysis; Rosuvastatin Calcium; Sulfonamides

Topics: Drug Industry; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Muscle Weakness; Pyridines; Renal Insufficiency

A worldwide frequently applied HMG-CoA-reductase-inhibitor ("statin") recently has been withdrawn from the market. This obviously has been caused by serious adverse events. The question is whether the package inserts sufficiently inform about the risks. But, although they list up numerous side effects, they lack informations concerning the frequency of them, so the patients when reading the package inserts become confused. Thus they have to rely on their doctors choice regarding the danger outlined in the inserts. In that respect packing inserts could be improved.

Topics: Adverse Drug Reaction Reporting Systems; Anticholesteremic Agents; Austria; Dose-Response Relationship, Drug; Drug Information Services; Drug Labeling; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Patient Education as Topic; Pyridines; Renal Insufficiency; Rhabdomyolysis

Statins are now widely prescribed and without doubt save many lives. However there are rare potentially serious side-effects, including acute renal failure. Patient education and physician vigilence are vital.

Topics: Acute Disease; Aged; Humans; Male; Muscle Weakness; Pyridines; Renal Insufficiency; Rhabdomyolysis

Rhabdomyolysis is an uncommon complication associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. We observed six cases of cerivastatin-associated rhabdomyolysis: two patients developed acute renal failure requiring hemodialysis, and one patient died. Four of the patients had impaired renal function, and five were prescribed drugs with the potential to interact with cerivastatin. Also, five of the six patients presented with symptoms of rhabdomyolysis 3-4 weeks after starting cerivastatin therapy.

Topics: Acute Kidney Injury; Aged; Creatine Kinase; Drug Interactions; Fatal Outcome; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyridines; Renal Dialysis; Renal Insufficiency; Rhabdomyolysis

Gemfibrozil-statin combination therapy is a well-known risk factor for myopathy and rhabdomyolysis. Cerivastatin is a currently available statin with dual elimination; it is therefore expected to cause less drug-drug interaction. This case is the second reported case with severe rhabdomyolysis caused by cerivastatin-gemfibrozil combination. Moreover, in this case, the rhabdomyolysis was more severe and caused severe renal failure and death. The authors discuss how these drugs cause rhabdomyolysis and how rhabdomyolysis can cause renal failure.

Topics: Diabetes Mellitus; Drug Interactions; Drug Therapy, Combination; Electrocardiography; Fatal Outcome; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Myocardial Ischemia; Pyridines; Renal Dialysis; Renal Insufficiency; Rhabdomyolysis

Topics: Aged; Drug Interactions; Drug Therapy, Combination; Female; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Pyridines; Renal Insufficiency; Rhabdomyolysis

The influence of renal impairment on the clearance of the new HMG-CoA reductase inhibitor cerivastatin was evaluated. A single oral dose of 300 microg cerivastatin was given to 18 patients with different degrees of renal impairment and 6 healthy controls. Concentrations of total cerivastatin, its fraction unbound, and the total concentrations of the active metabolites M1 and M23 were measured in plasma. Serum concentrations of unbound cerivastatin were calculated for each individual from the concentration of total cerivastatin and cerivastatin's fraction unbound at t = 2.5 hours. In contradiction to what had been expected, renal impairment significantly influenced the pharmacokinetics of cerivastatin. The best correlation to the AUC and Cmax of unbound cerivastatin was found with serum albumin concentration. Also, serum albumin concentration was the only factor significantly correlated to t 1/2 of cerivastatin. Significant but slighter correlation with the AUC and Cmax of unbound cerivastatin was also observed for creatinine clearance and cerivastatin's fraction unbound, while no correlation was observed with total plasma protein. No significant correlation of creatinine clearance, serum albumin concentration, fu, or total plasma protein concentration with the AUC and Cmax of total cerivastatin or the AUC, Cmax or t 1/2 of M1 and M23 was observed. The authors conclude that low serum albumin concentration rather than low creatinine clearance predicts the pharmacokinetics of cerivastatin in renal impairment.

Topics: Adult; Aged; Area Under Curve; Creatinine; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyridines; Renal Insufficiency; Serum Albumin; Statistics, Nonparametric