Pharmacokinetic Drug-Drug Interaction Study Between Raltegravir and Atorvastatin 20 mg in Healthy Volunteers.

BACKGROUND

Dyslipidemia is highly prevalent among patients with HIV infection and contributes to an increased risk of cardiovascular disease. We investigated the influence of a frequently used statin, atorvastatin, on the pharmacokinetics of the HIV-integrase inhibitor raltegravir and vice versa.

METHODS

Open-label, crossover 3-period phase I trial in 24 healthy volunteers. Subjects took raltegravir 400 mg two times a day for 7 days, atorvastatin 20 mg once a day for 7 days, and the combination of atorvastatin 20 mg once a day + raltegravir 400 mg two times a day for 7 days with 2-week washout periods in between. Intensive steady-state 12- and 24-hour pharmacokinetic blood sampling was performed. Geometric mean ratios of the test treatment (combination raltegravir + atorvastatin) versus the reference treatment (raltegravir or atorvastatin alone) and 90% confidence intervals were calculated for the area under the plasma concentration-time curve (AUC). Fasting lipid profiles were obtained to assess short-term lipid-lowering effect of atorvastatin with or without concomitant raltegravir use.

RESULTS

Twenty-four healthy volunteers (11 males) were enrolled. All but 1 subject completed the trial, and no serious adverse events were reported. Geometric mean ratios (90% confidence interval) were 1.01 (0.68-1.51) for raltegravir AUC(0-12h) and 1.00 (0.90-1.11) for atorvastatin AUC(0-24h). The AUC(0-24h) metabolite-to-parent ratio for atorvastatin lactone, ortho-hydroxy, and para-hydroxy atorvastatin did not change during concomitant raltegravir use. The effect of atorvastatin on low-density lipoprotein cholesterol was not significantly different when combined with raltegravir versus atorvastatin alone (P = 0.638).

CONCLUSIONS

Atorvastatin 20 mg has no clinically relevant effect on the pharmacokinetics of raltegravir and vice versa. The combination was well tolerated and can be administered without dose adjustments.