Background: Rosuvastatin (RSV) is a potent statin with a lower potential for drug interactions. However, recent data have revealed unexpected increases in RSV concentrations with lopinavir/ritonavir. The objective is to study the pharmacokinetic interaction of RSV with atazanavir/ritonavir (ATV/RTV) or fosamprenavir/ritonavir (FPV/RTV).
Methods: In a prospective pharmacokinetic drug interaction study, six HIV-seronegative, healthy adult volunteers received single 10-mg doses of RSV at baseline and after 6 days of ATV/RTV and FPV/RTV, with 6-day washout periods. Plasma concentrations of RSV and its metabolites, N-desmethyl-RSV and RSV-lactone, were measured by using a internally validated tandem mass spectrometric (LC-MS/MS) method over 24 hours.
Results: Compared to baseline, the area under the plasma concentration-time curve (AUC0-24h) and maximum plasma concentration (Cmax) of RSV increased by 213% and 600%, respectively, and the time to reach Cmax was shorter (1.75 h vs. 2.91 h) when given with ATV/RTV (P < 0.05). However, coadministration with FPV/RTV did not significantly affect the pharmacokinetics of RSV. The AUC0-24h of N-desmethyl-RSV was not significantly affected by either combinations, but that of RSV-lactone increased (P < 0.05) by 61% and 76% after coadministration with ATV/RTV and FPV/RTV, respectively.
Conclusion: ATV/RTV significantly increases the plasma concentrations of rosuvastatin, most likely by increasing rosuvastatin's oral bioavailability. Dose limitations of RSV with ATV/RTV may be needed.
From the *School of Pharmacy, Texas Tech University Health Sciences Center, Dallas, TX; †Veterans Affairs North Texas Health Care System, Dallas, TX; ‡University of Texas Southwestern Medical Center, Dallas, TX; §Pediatric Pharmacology Research and Development Center, Children's Medical Center, Dallas, TX; and ¶School of Pharmacy, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, TX.
Received for publication February 28, 2008; accepted April 9, 2008.
Supported by the Dallas VA Research Corporation, Dallas, Texas and AstraZeneca LP (drug-level analysis only).
Dr. Hall's involvement in this study was supported by Grant Number KL2RR024983, titled, “North and Central Texas Clinical and Translational Science Initiative” (Milton Packer, M.D., PI) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or NIH.
Reprints: Anthony J. Busti, PharmD, Texas Tech University Health Sciences Center, School of Pharmacy, Dallas Fort Worth Regional Campus, 4500 S. Lancaster Rd., Dallas, TX 75216 (e-mail: firstname.lastname@example.org).