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Leon A Simons - One of the best experts on this subject based on the ideXlab platform.

  • additive effect of plant sterol ester margarine and Cerivastatin in lowering low density lipoprotein cholesterol in primary hypercholesterolemia
    American Journal of Cardiology, 2002
    Co-Authors: Leon A Simons
    Abstract:

    Abstract The objective of this study was to evaluate whether plant sterol-ester margarine has an additive or interactive effect on low-density lipoprotein (LDL) cholesterol reduction when ingested in combination with a statin drug. This was a multicenter, randomized, double-blind study with 4 parallel treatment arms in a balanced 2 × 2 factorial design. The 4 daily treatment options were: (1) placebo plus regular margarine 25 g (n = 38); (2) placebo plus sterol-ester margarine 25 g (2 g of plant sterol) (n = 39); (3) Cerivastatin 400 μg plus regular margarine 25 g (n = 38); and (4) Cerivastatin 400 μg plus sterol-ester margarine 25 g (n = 37). The study was conducted in men and women with primary hypercholesterolemia with baseline LDL cholesterol ≥97 mg/dl (mean 206). The primary efficacy parameter was the percent change in LDL cholesterol between baseline and at the end of 4 weeks’ treatment. Cerivastatin (vs placebo) reduced LDL cholesterol by 32% (95% confidence intervals 28% to 36%, p

  • additive effect of plant sterol ester margarine and Cerivastatin in lowering low density lipoprotein cholesterol in primary hypercholesterolemia
    American Journal of Cardiology, 2002
    Co-Authors: Leon A Simons
    Abstract:

    The objective of this study was to evaluate whether plant sterol-ester margarine has an additive or interactive effect on low-density lipoprotein (LDL) cholesterol reduction when ingested in combination with a statin drug. This was a multicenter, randomized, double-blind study with 4 parallel treatment arms in a balanced 2 x 2 factorial design. The 4 daily treatment options were: (1) placebo plus regular margarine 25 g (n = 38); (2) placebo plus sterol-ester margarine 25 g (2 g of plant sterol) (n = 39); (3) Cerivastatin 400 microg plus regular margarine 25 g (n = 38); and (4) Cerivastatin 400 microg plus sterol-ester margarine 25 g (n = 37). The study was conducted in men and women with primary hypercholesterolemia with baseline LDL cholesterol >/=97 mg/dl (mean 206). The primary efficacy parameter was the percent change in LDL cholesterol between baseline and at the end of 4 weeks' treatment. Cerivastatin (vs placebo) reduced LDL cholesterol by 32% (95% confidence intervals 28% to 36%, p <0.0001) and sterol-ester margarine (vs regular margarine) by 8% (95% confidence interval 4% to 12%, p <0.0001). The effect of sterol-ester margarine and Cerivastatin together was additive (39% reduction in LDL cholesterol), but there was no significant interactive effect between sterol-ester margarine and Cerivastatin (p = 0.29). The treatments were generally well tolerated with no major differences in adverse events between groups. In subjects with primary hypercholesterolemia, statin and sterol-ester margarine used together produce a purely additive effect on LDL cholesterol reduction. The addition of sterol-ester margarine to statin therapy offers LDL cholesterol reduction equivalent to doubling the dose of statin.

Evan A Stein - One of the best experts on this subject based on the ideXlab platform.

  • long term efficacy and safety of Cerivastatin 0 8 mg in patients with primary hypercholesterolemia
    Clinical Cardiology, 2001
    Co-Authors: William Insull, Jonathan L Isaacsohn, Peter O Kwiterovich, R Brazg, Carlos A Dujovne, M Shan, Evan A Stein, Ma Patrick, E Shugruecrowley
    Abstract:

    Background: Statins are the agents of choice in reducing elevated plasma low-density lipoprotein cholesterol (LDL-C). Hypothesis: Cerivastatin 0.8 mg has greater long-term efficacy in reducing LDL-C than pravastatin 40 mg in primary hypercholesterolemia. Methods: In this double-blind, parallel-group, 52-week study, patients (n = 1,170) were randomized (4:1:1) to Cerivastatin 0.8 mg, Cerivastatin 0.4 mg, or placebo daily. After 8 weeks, placebo was switched to pravastatin 40 mg. Patients with insufficient LDL-C lowering after 24 weeks were allowed open-labeled resin therapy. Results: Cerivastatin 0.8 mg reduced LDL-C versus Cerivastatin 0.4 mg (40.8 vs. 33.6%, p 10 × the upper limit of normal (ULN) occurred in 1,1.5, and 0% of patients receiving Cerivastatin 0.8 mg, Cerivastatin 0.4 mg, and pravastatin 40 mg, respectively. Repeat hepatic transaminases >3 × ULN occurred in 0.3–0.5,0.5, and 0% of patients, respectively. Conclusion: In long-term use, Cerivastatin 0.8 mg effectively and safely brings the majority of patients to NCEP goal.

  • pharmacodynamics safety tolerability and pharmacokinetics of the 0 8 mg dose of Cerivastatin in patients with primary hypercholesterolemia
    American Journal of Cardiology, 1999
    Co-Authors: Evan A Stein, Jonathan L Isaacsohn, Arthur Mazzu, Randall Stoltz, Mingchung Liu, Cindy Lane, Allen H Heller
    Abstract:

    Abstract Cerivastatin is a third generation hydroxy-methyl-glutaryl-Co-enzyme A (HMG-CoA) reductase inhibitor proven to lower low-density lipoprotein (LDL) cholesterol 28% to 31% in patients with primary hypercholesterolemia when given at 0.3 mg/day. This study evaluates the safety, tolerability, pharmacodynamics, and pharmacokinetics of Cerivastatin 0.8 mg once daily for 4 weeks. In this randomized, double-blind, placebo-controlled parallel group trial conducted at 2 study centers, 41 patients (63% women) with primary hypercholesterolemia were placed on an American Heart Association Step 1 diet for 4 weeks. Single-blind placebo was administered for the final 2 weeks, before randomization. Patients received Cerivastatin 0.8 mg (n = 28) or placebo (n = 13) once each evening for 28 days. Cerivastatin at 0.8 mg daily was well tolerated. No discontinuations occurred during the study. Adverse events were mild and transient. One Cerivastatin-treated patient experienced asymptomatic creatinine kinase, 8× the upper limit of normal (ULN) elevation on the last day of the study, which resolved 6 days after the completion of the study. Cerivastatin 0.8 mg daily significantly reduced LDL cholesterol compared with placebo (−44.0 ± 2.0% vs 2.2 ± 2.8%, p

  • Cerivastatin in primary hyperlipidemia a multicenter analysis of efficacy and safety
    American Journal of Cardiology, 1998
    Co-Authors: Evan A Stein
    Abstract:

    Abstract Cerivastatin, a novel, synthetic, and enantiomerically pure 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been administered, in clinical trials, to >2,700 patients with primary hypercholesterolemia, of whom >1,000 received treatment for periods of up to 1 year. A global, pooled analysis of the efficacy, safety, and tolerability of Cerivastatin was performed on data obtained from all randomized, double-blind studies in which Cerivastatin at doses of 0.025–0.4 mg/day was compared with either placebo or active comparator. All studies had a 10-week, diet-controlled run-in period, the last 6 weeks of which included administration of single-blind placebo. Efficacy analysis of the pooled data at 8 weeks postrandomization showed that in comparison with placebo, Cerivastatin achieved significant dose-dependent reductions in low-density lipoprotein (LDL) cholesterol, the primary efficacy parameter, of 14.2–36.1%. Reductions in LDL cholesterol were accompanied by significant reductions in total cholesterol and triglycerides, together with increases in high-density lipoprotein (HDL) cholesterol. The magnitude of the reduction in plasma triglycerides was strongly related to baseline triglyceride levels. In patients with baseline plasma triglycerides of >250 mg/dL, treatment with 0.4 mg/day Cerivastatin decreased these levels by 37%. Cerivastatin was well tolerated, with the type and incidence of clinical adverse effects comparable to that of placebo and comparator drugs. The incidence of biochemical adverse effects was also similar to that seen with either placebo or comparator drugs and was independent of the dose of Cerivastatin. Less than 1% of patients treated with Cerivastatin at doses of 0.025–0.4 mg/day experienced clinically significant increases in either hepatic transaminases (>3× the upper limit of normal) or creatine phosphokinase (>5× the upper limit of normal). The good tolerability of Cerivastatin was reflected in a low rate of premature withdrawal from treatment, below or comparable to that of placebo-treatment. The pooled efficacy and safety analyses have shown that at doses equal to 1–3% of the doses of other statins, Cerivastatin is a safe, well-tolerated, and highly effective HMG-CoA reductase inhibitor for the treatment of type IIa (triglycerides 250 mg/dL) hypercholesterolemia.

  • extending therapy options in treating lipid disorders a clinical review of Cerivastatin a novel hmg coa reductase inhibitor
    Drugs, 1998
    Co-Authors: Evan A Stein
    Abstract:

    Cerivastatin is a third generation pure enantiomeric HMG-CoA reductase inhibitor. It reduces low density lipoprotein (LDL)-cholesterol by 22 to 44% at doses of 0.1 to 0.8 mg/day The drug has been extensively evaluated for more than 5 years in clinical trials and is currently marketed in a number of countries at doses of 0.1 to 0.3 mg/day. Cerivastatin has been tested in more than 4000 patients during extensive phase II and III studies. About 40% of patients in these trials were women, and many participants were aged between 65 and 75 years. The trial populations had moderate to severe hypercholesterolaemia, with mean baseline LDL-cholesterol levels of approximately 5.2 mmol/L (200 mg/dl). In large phase III trials, Cerivastatin, over the dosage range of 0.1 to 0.4 mg/day, reduced LDL-cholesterol by 22.4 to 36.1% from baseline. As with other HMG-CoA reductase inhibitors, the log-linear dose-response curve of Cerivastatin showed a 6% additional decrease in mean LDL-cholesterol levels for each doubling of the daily dose, with no plateau effect noted at the highest dosage yet tested (0.8 mg/day). High density lipoprotein cholesterol levels increased by 4 to 10% during Cerivastatin therapy. This effect, which was consistent with that of other HMG-CoA reductase inhibitors, was not dose related. As has been found with other statins, the triglyceride-lowering effects of Cerivastatin are dependent on baseline triglyceride levels, with very small reductions occurring in patients with low initial levels [ 2.8 mmol/L (250 mg/dl). Cerivastatin was well tolerated in all studies. Cerivastatin recipients and recipients of other HMG-CoA reductase inhibitors experienced a similar incidence of adverse events (including hepatic transaminase elevations) in comparative studies. Cerivastatin is an effective and safe lipid-lowering agent for most patients with hypercholesterolaemia.

  • Cerivastatin a new potent synthetic hmg co a reductase inhibitor effect of 0 2 mg daily in subjects with primary hypercholesterolemia
    Journal of Cardiovascular Pharmacology and Therapeutics, 1997
    Co-Authors: Evan A Stein, D Sprecher, K S Allenby, R L Tosiello, E Whalen, Steven Ripa
    Abstract:

    Background: Reduction of serum cholesterol, most notably low-density lipoprotein choles terol is associated with reductions in cardiovascular morbidity and mortality. Statins have been shown to effectively reduce low-density lipoprotein cholesterol via inhibition of the hydroxymethyl-coenzyme A (HMG-CoA) reductase. Cerivastatin is the most potent HMG- CoA reductase inhibitor currently under study in the United States.Methods and Results: A parallel group, randomized, placebo-controlled, double-blind, mul ticenter study was conducted to compare the efficacy and safety of three different dosing reg imens of 0.2 mg/day of Cerivastatin, a new HMG-CoA reductase inhibitor, in patients with hypercholesterolemia. After a 10-week diet-placebo lead-in period, 319 patients with low- density lipoprotein cholesterol >160 mg/dL were randomized to 4 weeks of treatment with one of the following regimens: Cerivastatin 0.1 mg twice daily, Cerivastatin 0.2 mg once daily with the evening meal, Cerivastatin 0.2 mg once daily ...

B Widgren - One of the best experts on this subject based on the ideXlab platform.

  • Cerivastatin gender effect sub analyses of results from a multinational randomised double blind study
    Current Medical Research and Opinion, 2000
    Co-Authors: Leiv Ose, O Luurila, Johan G Eriksson, Anders G Olsson, Hans Lithell, B Widgren
    Abstract:

    SummaryWe previously reported the results of a multicentre, randomised, double-blind, parallelgroup study comparing the efficacy and safety of Cerivastatin 0.4 mg/day and Cerivastatin0.2 mg/day in patients with primary hypercholesterolaemia. Exploratory analysis in this study suggested a gender difference in the 0.4 mg group: mean low-density lipoprotein cholesterol (LDL-C) decreased by 44.4 ± 8.9% in women, compared with a mean decrease of 37.0 ± 0.9% in men (p 40%, compared with 38.0% (n = 76) of men taking the same dose. In the Cerivastatin 0.2 mg PP population, 34% (n = 17) of women had an LDL-C decrease of > 40%, compared with 19% (n = 18) of men. Mean LDL-C/HDL-C ratio decreased by 43% from baseline to the end of the study in the Cerivastatin 0.4 mg PP group: –41.3% in males vs. –48.3% in females. ...

  • efficacy and safety of Cerivastatin 0 2 mg and 0 4 mg in patients with primary hypercholesterolaemia a multinational randomised double blind study
    Current Medical Research and Opinion, 1999
    Co-Authors: Leiv Ose, O Luurila, Johan G Eriksson, Anders G Olsson, Hans Lithell, B Widgren
    Abstract:

    SummaryElevated serum cholesterol level is a key risk factor for cardiovascular morbidity and mortality. Cerivastatin is a highly effective lipid-lowering agent currently licensed at doses of 0.1, 0.2, 0.3 and 0.4 mg.This was a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of Cerivastatin OAmglday with that of Cerivastatin 0.2 mg/day in patients with primary hypercholesterolemia. There was a six-week placebo run-in phase followed by a 24-week active treatment phase. A total of 494 patients were randomised to receive Cerivastatin 0.4mg (n = 332) or 0.2mg (n = 162). Per-protocol (PP) analysis revealed that mean low-density lipoprotein cholesterol (LDL-C) level decreased by 38.4 ± 0.7% from baseline in the 0.4 mg group, compared with a decrease of 31.5 ± 0.9% in the 0.2mg group (p < 0.0001). There was a significant gender difference in the 0.4 mg group: LDL-C decreased by 44.4 ± 8.9% in women, compared with a decrease of 37.0 ± 0.9% in men (p < 0.046). In the P...

Leiv Ose - One of the best experts on this subject based on the ideXlab platform.

  • Cerivastatin gender effect sub analyses of results from a multinational randomised double blind study
    Current Medical Research and Opinion, 2000
    Co-Authors: Leiv Ose, O Luurila, Johan G Eriksson, Anders G Olsson, Hans Lithell, B Widgren
    Abstract:

    SummaryWe previously reported the results of a multicentre, randomised, double-blind, parallelgroup study comparing the efficacy and safety of Cerivastatin 0.4 mg/day and Cerivastatin0.2 mg/day in patients with primary hypercholesterolaemia. Exploratory analysis in this study suggested a gender difference in the 0.4 mg group: mean low-density lipoprotein cholesterol (LDL-C) decreased by 44.4 ± 8.9% in women, compared with a mean decrease of 37.0 ± 0.9% in men (p 40%, compared with 38.0% (n = 76) of men taking the same dose. In the Cerivastatin 0.2 mg PP population, 34% (n = 17) of women had an LDL-C decrease of > 40%, compared with 19% (n = 18) of men. Mean LDL-C/HDL-C ratio decreased by 43% from baseline to the end of the study in the Cerivastatin 0.4 mg PP group: –41.3% in males vs. –48.3% in females. ...

  • efficacy and safety of Cerivastatin 0 2 mg and 0 4 mg in patients with primary hypercholesterolaemia a multinational randomised double blind study
    Current Medical Research and Opinion, 1999
    Co-Authors: Leiv Ose, O Luurila, Johan G Eriksson, Anders G Olsson, Hans Lithell, B Widgren
    Abstract:

    SummaryElevated serum cholesterol level is a key risk factor for cardiovascular morbidity and mortality. Cerivastatin is a highly effective lipid-lowering agent currently licensed at doses of 0.1, 0.2, 0.3 and 0.4 mg.This was a multicentre, randomised, double-blind, parallel-group study comparing the efficacy and safety of Cerivastatin OAmglday with that of Cerivastatin 0.2 mg/day in patients with primary hypercholesterolemia. There was a six-week placebo run-in phase followed by a 24-week active treatment phase. A total of 494 patients were randomised to receive Cerivastatin 0.4mg (n = 332) or 0.2mg (n = 162). Per-protocol (PP) analysis revealed that mean low-density lipoprotein cholesterol (LDL-C) level decreased by 38.4 ± 0.7% from baseline in the 0.4 mg group, compared with a decrease of 31.5 ± 0.9% in the 0.2mg group (p < 0.0001). There was a significant gender difference in the 0.4 mg group: LDL-C decreased by 44.4 ± 8.9% in women, compared with a decrease of 37.0 ± 0.9% in men (p < 0.046). In the P...

  • clinical efficacy and safety of Cerivastatin summary of pivotal phase iib iii studies
    American Journal of Cardiology, 1998
    Co-Authors: Jean Davignon, William Insull, Donald B Hunninghake, M Hanefeld, Noriaki Nakaya, Leiv Ose
    Abstract:

    Abstract Cerivastatin is a new, third-generation 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (“statin”), which is administered to hypercholesterolemic patients at doses equivalent to 1–3% of the doses of other statins. This report reviews the pivotal Phase IIb/III clinical trials in which the efficacy and safety of Cerivastatin was compared with placebo and active comparator statins (lovastatin, simvastatin, and pravastatin) after both short- and long-term administration. Overall, the studies showed that at doses of 0.025–0.4 mg/day, Cerivastatin produced dose-dependent reductions in low-density lipoprotein (LDL) cholesterol and total cholesterol, which were significantly greater than placebo. The greatest reductions were achieved with 0.4 mg/day Cerivastatin. On this dose, >40% of patients achieved reductions in LDL cholesterol >40% and in a further 9% of patients, LDL cholesterol was decreased by >50%. At higher doses, Cerivastatin also demonstrated potent triglyceride-lowering effects in a subgroup of patients with raised plasma triglycerides. Reductions in atherogenic lipids and lipoproteins were accompanied by significant increases in high-density lipoprotein (HDL) cholesterol, apolipoprotein A-I, and antiatherogenic lipoprotein A-I. Long-term administration of Cerivastatin for periods of up to 2 years was associated with persistent reductions in LDL cholesterol, total cholesterol, triglycerides, and apolipoprotein B as well as increases in HDL cholesterol similar to those observed after initial administration. Long-term Cerivastatin treatment was also well tolerated. There was no significant difference between the incidence of adverse effects with Cerivastatin and comparator statins or between Cerivastatin and other statins with respect to clinically significant increases in either hepatic enzymes or creatine phosphokinase. In conclusion, these studies indicate that Cerivastatin is a safe and effective long-term treatment for patients with primary hypercholesterolemia and also suggest that higher doses should be investigated.

Susan R. Heckbert - One of the best experts on this subject based on the ideXlab platform.

  • OATP1B1-related drug-drug and drug-gene interactions as potential risk factors for Cerivastatin-induced rhabdomyolysis
    2020
    Co-Authors: Bani Tamraz, Kristin D. Marciante, Rheem A. Totah, Hisayo Fukushima, Rudiger Kaspera, Alan R Wolfe, James S Floyd, Catherine Chu, Susan R. Heckbert
    Abstract:

    Objective Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking Cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of Cerivastatin. Methods This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on Cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of Cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1. Results The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P < 0.001) in Cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of Cerivastatin. Conclusion Reduced function of OATP1B1 related to genetic variation and drug-drug interactions likely contributed to Cerivastatin-induced rhabdomyolysis. Although Cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1

  • oatp1b1 related drug drug and drug gene interactions as potential risk factors for Cerivastatin induced rhabdomyolysis
    Pharmacogenetics and Genomics, 2013
    Co-Authors: Bani Tamraz, Kristin D. Marciante, Susan R. Heckbert, Rheem A. Totah, Hisayo Fukushima, Rudiger Kaspera, Alan R Wolfe, James S Floyd, Catherine Chu, Bruce M Psaty
    Abstract:

    Objective Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking Cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of Cerivastatin.

  • a screening study of drug drug interactions in Cerivastatin users an adverse effect of clopidogrel
    Clinical Pharmacology & Therapeutics, 2012
    Co-Authors: James S Floyd, Kristin D. Marciante, Susan R. Heckbert, Thomas Lumley, Bani Tamraz, Rudiger Kaspera, Noel S Weiss, Kerri L Wiggins, Puiyan Kwok
    Abstract:

    An analysis of a case–control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug–drug interactions. Medication use in cases of rhabdomyolysis using Cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998–2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1–143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving Cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2–infinity). Several medications were tested in vitro for their potential to cause drug–drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of Cerivastatin metabolism. Clopidogrel and its metabolites also inhibited Cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug–drug interactions with other medications metabolized by CYP2C8. Clinical Pharmacology & Therapeutics (2012); 91 5, 896–904. doi:10.1038/clpt.2011.295

  • Cerivastatin, genetic variants, and the risk of rhabdomyolysis.
    Pharmacogenetics and genomics, 2011
    Co-Authors: Kristin D. Marciante, Jon P. Durda, Susan R. Heckbert, Thomas Lumley, Ken Rice, Barbara Mcknight, Rheem A. Totah, Bani Tamraz, Deanna L. Kroetz, Hisayo Fukushima
    Abstract:

    Objective The withdrawal of Cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response--rhabdomyolysis in a small proportion of users-- points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for Cerivastatin-associated rhabdomyolysis.

  • Cerivastatin in vitro metabolism by cyp2c8 variants found in patients experiencing rhabdomyolysis
    Pharmacogenetics and Genomics, 2010
    Co-Authors: Rudiger Kaspera, Kristin D. Marciante, Susan R. Heckbert, Bani Tamraz, Suresh Babu Naraharisetti, Tariku Sahele, Matthew J Cheesman, Puiyan Kwok, Bruce M Psaty, Rheem A. Totah
    Abstract:

    OBJECTIVES: Cerivastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor withdrawn from the market because of serious adverse effects, is metabolized primarily by CYP2C8. The occurrence of associated myotoxicity and rhabdomyolysis were attributed to altered Cerivastatin pharmacokinetics on account of gemfibrozil-inhibition or genetic variations in CYP2C8 and drug transporters involved in Cerivastatin clearance. However, the effect of CYP2C8 genetic variation on Cerivastatin metabolism has not been fully elucidated. METHODS: In this study, patients (n=126) with confirmed cases of rhabdomyolysis after Cerivastatin administration had their CYP2C8 gene resequenced and the metabolism of Cerivastatin by the discovered CYP2C8 variants was assessed in proteins expressed in Escherichia coli. RESULTS: In this unique patient population, 12 novel single nucleotide polymorphisms were discovered of which six were exclusively found in patients not using gemfibrozil. Three rare exonic variants resulted in amino acid substitutions and a frame shift deletion (V472fsL494 generating a defective mostly heme-free CYP2C8 protein). A particular promoter located deletion (-635-634delTA) was tightly linked to CYP2C8*3. Heterologously expressed CYP2C8.3 and CYP2C8.4 displayed an increase in Cerivastatin metabolic clearance of up to six-fold compared with the wild-type enzyme. Similarly, an independent sample of microsomes from human livers carrying the CYP2C8*3 and CYP2C8*4 alleles exhibited a 2-fold to 14-fold increase in normalized Cerivastatin intrinsic clearance, compared with microsomes from livers carrying only the wild type allele. CONCLUSION: Gain or loss of catalytic function found in the CYP2C8 gene could certainly alter Cerivastatin pharmacokinetics and may influence, at least in part, susceptibility to the development of myotoxicity.