Pharmacokinetic Drug–Drug Interaction Study Between Raltegravir and Atorvastatin 20 mg in Healthy Volunteers.
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Study Design
This was an open-label, cross-over, three-period phase I trial in 24 healthy volunteers. Subjects took raltegravir 400 mg BID for 7 days, atorvastatin 20 mg QD for 7 days, and the combination of atorvastatin 20 mg QD + raltegravir 400 mg BID for 7 days with 2-week washout periods in between. Treatment sequence was allocated at random. Intensive steady-state 12- and 24-hour pharmacokinetic (PK) blood sampling was performed on day 7 of each treatment period. PK parameters (AUClast, Cmax, Clast) were determined by non-compartmental analysis for raltegravir and the sum of atorvastatin and its active metabolites (atorvastatin-equivalents). Geometric mean ratios (GMR) of the test treatment [combination raltegravir + atorvastatin] versus the reference treatment [raltegravir or atorvastatin alone] and 90% confidence intervals (CI) were calculated after log-transformation of within-subject ratios. Fasting lipid profiles were obtained on day 1 and day 7 of each treatment period to assess short-term effect on serum lowdensity lipoprotein (LDL) cholesterol. To compare the change in LDL cholesterol after atorvastatin with and without raltegravir a paired t-test was performed.
Study Results
Twenty-four healthy volunteers, of which 11 males, were enrolled (23 Caucasian, 1 mixed race). One subject did not complete the treatment period with raltegravir alone due to reasons not related to the study. Median (range) age and BMI were 31 (18-55) years and 20.9 (18.3-28.9) kg/m2, respectively. No serious adverse events were reported. GMR (90% CI) of raltegravir PK parameters were: 1.01 (0.68-1.51) for AUC0-12h; 1.14 (0.70-1.86) for Cmax; 0.96 (0.69-1.32) for C12h. GMR (90% CI) of atorvastatin-equivalents PK parameters were: 0.98 (0.91-1.06) for AUC0-24h; 1.02 (0.83-1.26) for Cmax; 0.97 (0.87-1.10) for C24h. Mean (95% CI) change in LDL cholesterol (day7 - day1) was -1.12 (-1.37;-0.87) mmol/L for atorvastatin alone compared to -1.29 (-1.50;-1.08) mmol/L for atorvastatin when combined with raltegravir (p=0.19).
Study Conclusions
***Before beginning raltegravir, patients should be asked by their healthcare provider if they have a history of rhabdomyolysis, myopathy or increased creatine kinase or if they are taking medications known to cause these conditions such as statins, fenofibrate, gemfibrozil or zidovudine.
Patients should be instructed to immediately report to their healthcare provider any unexplained muscle pain, tenderness, or weakness while taking raltegravir.
References
Blonk M, van Beek M, Colbers A, Schouwenberg B, Burger D. Pharmacokinetic drug–drug interaction study between raltegravir and atorvastatin 20 mg in healthy volunteers. Jaids: Journal Of Acquired Immunodeficiency Syndrome. 2015; 1: 44-51.
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