Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin.
BACKGROUND
3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are metabolized by distinct pathways that may alter the extent of drug-drug interactions. Cerivastatin is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8. Atorvastatin is metabolized solely by CYP3A4, and pravastatin metabolism is not well defined. Coadministration of higher doses of these statins with CYP3A4 inhibitors has the potential for eliciting adverse drug-drug interactions.


OBJECTIVE
To determine the comparative effect of itraconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of cerivastatin, atorvastatin, and pravastatin.


METHODS
In this single-site, randomized, three-way crossover, open-labeled study, healthy subjects (n = 18) received single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without and with itraconazole 200 mg. Pharmacokinetic parameters [AUC(0-infinity), AUC(0-tn), peak concentration (Cmax), time to reach Cmax (tmax), and half-life (t1/2)] were determined for parent statins and major metabolites.


RESULTS
Concomitant cerivastatin/itraconazole treatment produced small elevations in the cerivastatin AUC(0-infinity), Cmax, and t1/2 (27%, 25%, and 19%, respectively; P < .05 versus cerivastatin alone). Itraconazole coadministration produced similar changes in pravastatin pharmacokinetics [AUC elevated 51% (P < .05 versus pravastatin alone), 24% (Cmax), and 23% (t1/2), respectively]. However, itraconazole dramatically increased atorvastatin AUC (150%), Cmax (38%), and t1/2 (30%) (P < .05). The elevation in atorvastatin AUC was significantly greater than that of cerivastatin (P < .005) or pravastatin (P < .005).


CONCLUSIONS
Itraconazole markedly elevated atorvastatin plasma levels (2.5-fold) after 20 mg dosing, suggesting that concomitant itraconazole/atorvastatin therapy be carefully considered. Itraconazole produced modest elevations in the plasma levels of cerivastatin 0.8 mg or pravastatin 40 mg (1.3-fold and 1.5-fold, respectively), indicating that combination treatment with itraconazole with cerivastatin or pravastatin may be preferable.
Mazzu
A L
AL
Bayer Corporation Pharmaceutical Division, Department of Clinical Pharmacology, West Haven, Conn 06516, USA. arthur.mazzu.b@bayer.com
Lasseter
K C
KC
Shamblen
E C
EC
Agarwal
V
V
Lettieri
J
J
Sundaresen
P
P
D000328:Adult; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D000069059:Atorvastatin; D018592:Cross-Over Studies; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D017035:Pravastatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values; D013997:Time Factors
D000924:Anticholesteremic Agents; D000935:Antifungal Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D017964:Itraconazole; D000069059:Atorvastatin; C086276:cerivastatin; D017035:Pravastatin