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Impact of Pravastatin on Raltegravir Levels in Healthy Volunteers
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11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
Pravastatin lowered raltegravir minimum concentrations 41% in healthy volunteers [1], but academic researchers in the Netherlands, Germany, and Portugal do not believe this finding should affect efficacy of raltegravir, which correlates with area under the curve (AUC), not with minimum concentration [2,3].
Although pravastatin is the first-choice statin in people with HIV, it may interact with raltegravir because both drugs are metabolized by glucuronidation. To discern potential interactions between the drugs, Matthijs van Luin at Radboud University Nijmegen and colleagues at other centers studied the drugs in a randomized, three-period, crossover trial involving 24 healthy volunteers.
Study participants took raltegravir (400 mg twice daily) and pravastatin (40 mg daily) alone and together in three 4-day periods separated by 10-day washouts in which they took no drugs. The investigators measured plasma levels of the drugs in 12 samples collected on day 4 of each treatment period. They also measured fasting lipid values with pravastatin alone and pravastatin plus raltegravir.
All 24 volunteers completed the trial with no serious side effects. The investigators saw no creatinine kinase elevations or cases of myopathy, which are possible when pravastatin levels are high.
Raltegravir had no impact on any measured value of pravastatin. Nor did raltegravir affect pravastatin's ability to lower low-density lipoprotein cholesterol over 4 days of dosing.
Pravastatin raised the 12-hour AUC of raltegravir 13% (geometric mean ratio [GMR] of raltegravir+pravastatin/raltegravir alone 1.13, 90% confidence interval [CI] 0.77 to 1.65), and the statin raised raltegravir's maximum concentration 31% (GMR 1.31, 90% CI 0.81 to 2.13). But taking pravastatin with raltegravir lowered raltegravir's minimum concentration 41% (GMR 0.59, 90% CI 0.39 to 0.88).
The investigators rated the 31% rise in raltegravir maximum concentration as modest and "not likely to cause any safety concerns." They argued that the 41% raltegravir minimum concentration with pravastatin should not affect efficacy, because earlier studies indicate that AUC--not Cmin--is the raltegravir level related to efficacy [2,3]. And AUC rose 13% with pravastatin.
References
1. Van Luin M, Colbers A, Van Ewijk-Beneken Kolmer EWJ, et al. Drug-drug interactions between raltegravir and pravastatin in healthy volunteers. 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Abstract 29.
2. Wenning L, Nguyen B, Teppler H, et al. Pharmacokinetic/pharmacodynamic analyses for raltegravir in phase II and III studies in treatment experienced HIV-infected patients. 9th International Workshop on Clinical Pharmacology of HIV Therapy. April 7-9, 2008. New Orleans. Abstract O21.
3. McSharry J, Weng Q, Kulaway R, Drusano G. Dose range and dose fractionation studies for raltegravir pharmacodynamics in an in vitro hollow fiber infection model system. 10th International Workshop on Clinical Pharmacology of HIV Therapy. April 15-17, 2009. Amsterdam. Abstract O_09.
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