Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors.
Three-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are first-line treatments for hypercholesterolemia. Although exceedingly well tolerated, treatment with statins incurs a small risk of myopathy or potentially fatal rhabdomyolysis, particularly when coadministered with medications that increase their systemic exposure. Studies compared the multiple-dose pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with 4 inhibitors of cytochrome P450-3A4 isoenzymes in healthy subjects. Compared with pravastatin alone, coadministration of verapamil, mibefradil, or itraconazole with pravastatin was associated with no significant changes in pravastatin pharmacokinetics. However, concomitant verapamil increased the simvastatin area under the concentration:time curve (AUC) approximately fourfold, the maximum serum concentration (C(max)) fivefold, and the active metabolite simvastatin acid AUC and C(max) approximately four- and threefold, respectively (all comparisons p <0.001). Similar (greater than fourfold) important increases in these parameters and a >60% increase in the serum half-life (p = 0.03) of atorvastatin were observed when coadministered with mibefradil. The half-life of atorvastatin also increased by approximately 60% (p = 0.052) when coadministered with itraconazole, which elicited a 2.4-fold increase in the C(max) of atorvastatin and a 47% increase in the AUC (p <0.001 for C(max) and AUC). Clarithromycin significantly (p <0.001) increased the AUC (and C(max)) of all 3 statins, most markedly simvastatin ( approximately 10-fold increase in AUC) and simvastatin acid (12-fold), followed by atorvastatin (greater than fourfold) and then pravastatin (almost twofold). Pravastatin has a neutral drug interaction profile relative to cytochrome P450-3A4 inhibitors, but these substrates markedly increase systemic exposure to simvastatin and atorvastatin.
Jacobson
Terry A
TA
Office of Health Promotion and Disease Prevention, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30303, USA. tjaco02@emory.edu
D000293:Adolescent; D000328:Adult; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D003402:Creatine Kinase / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D017964:Itraconazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D020748:Mibefradil / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D017035:Pravastatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics; D019821:Simvastatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics
D000924:Anticholesteremic Agents; D000981:Antiprotozoal Agents; D015415:Biomarkers; D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011500:Protein Synthesis Inhibitors; D011758:Pyrroles; D020748:Mibefradil; D017964:Itraconazole; D003577:Cytochrome P-450 Enzyme System; D000069059:Atorvastatin; D019821:Simvastatin; D014700:Verapamil; D003402:Creatine Kinase; D017291:Clarithromycin; D017035:Pravastatin