Steady-state pharmacokinetic interactions of darunavir/ritonavir with lipid-lowering agent rosuvastatin.
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Study Design
In a randomized, phase I, 3-period, open-label, controlled drug interaction study, 12 participants were divided into two study arms. Study participants were HIV-seronegative men and nonpregnant women.
Participants in arm 1 were given rosuvastatin 10 mg daily in the morning for 7 days. After a 7-day washout period, participants were administered darunavir/ritonavir 600/100 mg twice daily for 7 days. After a 7-day washout period, rosuvastatin and darunavir/ritonavir were coadministered for 7 days. The participants underwent PK sampling on day 7, 21, and 35. Blood samples were collected for rosuvastatin analysis before dosing and at 0, 1, 2, 4, 8, 12, 24, 48, and 72 hours after the dose was administered.
Participants randomized to arm 2 followed the following sequence: darunavir/ritonavir alone, rosuvastatin alone, and darunavir/ritonavir along with rosuvastatin with pharmacokinetic sampling and washout similar to arm 1. All study medications were administered with food throughout the study.
Participants’ fasting total cholesterol, triglycerides, HDL-C, and LDL-C were measured at baseline and on study days 7, 21, 35, and 45.
Study Results
During co-administration in the study, all 12 participants experienced an increase in rosuvastatin Cmax and AUC in the presence of darunavir/ritonavir. For Rosuvastatin, the GMR for Cmax was 2.4 (P < .001; 90% CI, 1.6 to 3.6), and the GMR for AUC was 1.5 (P = .03; 90% CI, 1.0 to 2.1).
There were no significant changes of darunavir or ritonavir pharmacokinetics in the presence of rosuvastatin.
It was observed that total cholesterol and triglyceride levels increased by 10% and 56% and HDL levels decreased by 13% during co-administration when compared to rosuvastatin alone. There were no significant adverse effects reported due to the combination of these medications.
Study Conclusions
Caution should be exercised if rosuvastatin must be administered with darunavir/ritonavir. Titrate the rosuvastatin dose carefully and use the lowest rosuvastatin dose necessary, while implementing careful monitoring of adverse events (including abnormal liver function tests, muscle pain, and rhabdomyolysis, etc). Although specific guidelines do not exist in the United States, the Canadian prescribing information recommends restricting the maxium dose of rosuvastatin to no more than 20mg/day in cominbation with darunavir/ritonavir.
References
Samineni D, Desai PB, Sallans L, Fichtenbaum CJ. Steady-state pharmacokinetic interactions of darunavir/ritonavir with lipid-lowering agent rosuvastatin. Journal Of Clinical Pharmacokinetics. 2012; : 922-931.
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