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Pravastatin Levels 81% Higher With Darunavir/Ritonavir
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8th International Workshop on Pharmacology of HIV Therapy
April 16-18, 2007, Budapest
Mark Mascolini
Giving darunavir/ritonavir with pravastatin hoisted levels of the statin 81%, a finding that surprised Tibotec researchers, according to the company's Vanitha Sekar, who detailed results of a study in 14 healthy volunteers [1]. On the basis of these data, Tibotec advises starting pravastatin at the lowest possible dose--then raising that dose gradually with careful monitoring--when this anticholesterol agent must be given with darunavir/ritonavir.
Earlier work found that nelfinavir and ritonavir-boosted saquinavir approximately halve levels of pravastatin, while lopinavir/ritonavir has no clinically meaningful impact on this statin. To see how darunavir/ritonavir might affect pravastatin, Tibotec researchers randomized 14 volunteers to one of two dosing schemes: (1) a single 40-mg dose of pravastatin, 5 or more days with no drug, then 600/100 mg of darunavir/ritonavir twice daily for 7 days with a single 40-mg dose of pravastatin on day 7; (2) this sequence reversed with a no-drug phase of 15 days or more between the two treatment periods.
Darunavir/ritonavir jacked up the maximum concentration (Cmax) of pravastatin 63% on average, while raising the area under the concentration-time curve (AUC) 81% (Table). Time to pravastatin Cmax (Tmax) got 50% longer with darunavir.
Sekar underlined the high person-to-person variability in levels of pravastatin, even when given alone (indicated by the numbers after +/- in the table). Individual ratios of pravastatin levels alone versus with darunavir/ritonavir ranged from 0.57 to 6.79 for AUC and from 0.44 to 10.44 for Cmax. Four volunteers had much higher pravastatin levels with the PIs than without them, while another 9 had small or no changes in pravastatin concentrations with darunavir/ritonavir. One person had 50% lower pravastatin levels with versus without darunavir/ritonavir.
What explains these striking person-to-person swings in pravastatin levels? Sekar noted that a polypeptide labeled OATP1B1 carries pravastatin into liver cells. Certain gene shifts--or single-nucleotide polymorphisms (SNPs)--in OATP1B1 slow pravastatin uptake in the liver. Because some people have these SNPs and others don't, pravastatin levels can be low in some people and high in others. On top of that, ritonavir suppresses activity of OATP1B1 and so probably furthers person-to-person differences in pravastatin levels. Sekar and colleagues are designing another study to investigate this potential mechanism.
Reference
1. Sekar VJ, Spinosa-Guzman S, Marien K, et al. Pharmacokinetic drug-drug interaction between the new HIV protease inhibitor darunavir (TMC114) and the lipid-lowering agent pravastatin. 8th International Workshop on Pharmacology of HIV Therapy. April 16-18, 2007. Budapest. Abstract 55.
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