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Critical Interactions Between Darunavir (TMC114), Lopinavir, Viagra, and Oral Contraceptives
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46th ICAAC, September 27-30, 2006, San Francisco
Mark Mascolini
September 27, 2006
Three separate studies demonstrated important interactions between the protease inhibitor (PI) darunavir (TMC114) and (1) lopinavir/ritonavir, (2) sildenafil (Viagra), and (3) the oral contraceptive Ortho-Novum, which contains ethinyl estradiol and norethindrone.
Despite doubling the darunavir dose from 600 to 1200 mg twice daily, researchers could not keep levels of this new PI high enough when given with 400/100 mg of lopinavir/ritonavir or 533/133 mg of the boosted PI [1]. The Tibotec investigators concluded that darunavir should not be prescribed with lopinavir/ritonavir.
This study in 33 HIV-infected volunteers recorded a slightly raised lopinavir/ritonavir area under the concentration-time curve (AUC), minimum concentration, and predose concentration with either 400/100 or 533/133 mg of lopinavir/ritonavir twice daily and either 1200 mg of darunavir twice daily or 1200/100 mg of darunavir/ritonavir twice daily.
Despite the doubled dose of darunavir, the PI's AUC, maximum concentration, minimum concentration, and predose concentration were all considerably lower with lopinavir/ritonavir than without the boosted PI. Darunavir's AUC at a dose of 1200 mg twice daily plus lopinavir/ritonavir was about 40% of the AUC with darunavir/ritonavir at 600/100 mg twice daily without lopinavir.
The sildenafil study enrolled 16 healthy HIV-uninfected men who took 100 mg of sildenafil on day 1, then 400/100 mg of darunavir/ritonavir twice daily for 8 days, with a single 25-mg sildenafil dose on day 7 [2]. Despite the quartered sildenafil dose given with darunavir/ritonavir, sildenafil AUC was equivalent to the AUC of full-dose sildenafil given without the PIs. Sildenafil's maximum concentration was 38% lower with the 25 mg dose plus the PIs than with 100 mg without the PIs. The Tibotec researchers expect that results would be similar if 25 mg of sildenafil were given with the licensed darunavir/ritonavir dose of 600/100 mg twice daily.
The Tibotec team proposes that 25 mg of sildenafil over 48 hours can be recommended as a starting dose when sildenafil is taken with darunavir/ritonavir. They suggest that results of this study can be used to shape dosage recommendations for other CYP3A substrate PDE-5 inhibitors given with darunavir/ritonavir, including verdenafil (single dose not to exceed 2.5 mg in 72 hours) and tadalafil (single dose not to exceed 10 mg in 72 hours).
The oral contraceptive study involved 19 HIV-infected women, 8 of whom did not complete the study [3]. Five stopped because of side effects, 1 withdrew consent, and 2 stopped coming back for study visits. The study design called for women to stop treatment if they had a grade 2 cutaneous problem; 3 had drug eruptions, 1 had papular rash, and 1 had a hypersensitivity reaction.
Levels of both ethinyl estradiol and norethindrone fell when women took Ortho-Novum with 600/100 mg of darunavir/ritonavir twice daily. Average minimum concentration, maximum concentration, and AUC of norethindrone dropped by 30%, 10%, and 14% with the PIs. Ortho-Novum did not greatly affect concentrations of darunavir/ritonavir.
The Tibotec researchers recommend alternative or additional contraceptive measures when women take estrogen-based contraceptives similar to Ortho-Novum with darunavir/ritonavir.
References
1. Sekar V, Lefebvre E, Spinosa-Guzman, et al. Pharmacokinetic interaction between the protease inhibitors TMC114 and lopinavir/ritonavir. 46th ICAAC. September 27-30, 2006, San Francisco. Abstract A-367.
2. Sekar V, Lefebvre E, De Marez T, et al. Pharmacokinetic interaction between TMC114, a new protease inhibitor, and sildenafil. 46th ICAAC. September 27-30, 2006, San Francisco. Abstract A-369.
3. Sekar V, Lefebvre E, Spinosa-Guzman, et al. Pharmacokinetic interaction between ethinyl estradiol, norethindrone and TMC114, a new protease inhibitor. 46th ICAAC. September 27-30, 2006, San Francisco. Abstract A-368.
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