title: Steady-state pharmacokinetic interactions of darunavir/ritonavir with lipid-lowering agent rosuvastatin.
abstract: HIV-1 protease inhibitors often cause dyslipidemia, necessitating the use of lipid-lowering agents such as rosuvastatin. However, when given concomitantly, these therapeutic agents often exhibit adverse drug interactions. In this study (phase I open-label trial, n = 12 HIV-1 seronegative participants), the authors assessed the drug interactions between darunavir/ritonavir given in combination with rosuvastatin. Participants were randomized to receive rosuvastatin (10 mg/day) or darunavir/ritonavir (600/100 mg twice daily) alone for 7 days in a crossover design followed by combination therapy for 7 days with intervening 7-day washout periods. Intensive blood sampling for pharmacokinetics and fasting lipids was performed on days 7, 21, and 35. The geometric mean AUC(0-24 h) of rosuvastatin increased from 109 to 161 ng·h/mL (P < .005) and C(max) increased 6.7 to 16.3 ng/mL (P < .001) when coadministered with darunavir/ritonavir. In the presence of darunavir/ritonavir and rosuvastatin, total cholesterol and triglyceride levels increased by 10% (P = .007) and 56% (P = .011), whereas the high-density lipoprotein cholesterol levels decreased by 13% (P = .006) relative to rosuvastatin administration alone. There were no significant adverse events attributable to the coadministration of these drugs. Rosuvastatin levels increase in the presence of darunavir/ritonavir coadministration, whereas the lipid-lowering benefits are blunted. The clinical significance of these changes requires further investigation.
authors.affiliation: James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio 45267-0004, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Samineni
authors.forename: Pankaj B
authors.initials: PB
authors.lastname: Desai
authors.forename: Larry
authors.initials: L
authors.lastname: Sallans
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Fichtenbaum
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D018592:Cross-Over Studies; D000069454:Darunavir; D004338:Drug Combinations; D004347:Drug Interactions; D005464:Fluorobenzenes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D019438:Ritonavir / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
chemical_list: D002784:Cholesterol; D008076:Cholesterol, HDL; D000069454:Darunavir; D004338:Drug Combinations; D005464:Fluorobenzenes; D017320:HIV Protease Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D019438:Ritonavir; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; D014280:Triglycerides