549 TMC114, A Next Generation HIV Protease Inhibitor: Pharmacokinetics and Safety Following Oral Administration of Multiple Doses With and Without Low Doses of Ritonavir in Healthy Volunteers R. Hoetelmans*1, I. Van der Sandt2, M. De Pauw1, K. Struble3, M. Peeters1, R. Van der Geest1 1Tibotec, Mechelen, Belgium; 2Kinesis, Breda, The Netherlands; and 3Tibotec-Virco, Durham, NC
Background: TMC114 is a next generation protease inhibitor (PI) with potent in vitro antiviral activity against wild-type and PI-resistant HIV-1. The objective of the study was to evaluate the pharmacokinetics (PK) and safety/tolerability of TMC114 with and without low doses of ritonavir (RTV) in healthy volunteers.
Methods: Two (2) randomized, multiple-dose escalating Phase I trials in a total of 76 healthy volunteers receiving TMC114 as a PEG-containing oral solution, with or without low doses of RTV for 14 days. In the first placebo-controlled double blind trial (n = 6 active, n = 3 placebo/panel), TMC114 was administered at dosages of 400 mg BID, 800 mg BID, 800 mg TID, and 1,200 mg TID. In a second open trial (n = 8/panel), TMC114/RTV was administered at dosages of 200/100 mg QD, 400/100 mg QD, 300/100 mg BID, 600/200 mg QD, and 1,200/200 mg QD.
Results: TMC114 was rapidly absorbed with a time to Cmax within 3 hrs. Steady-state concentrations were reached within 3 days. In the unboosted trial, mean Cmin, Cmax, and Css,av at day 14 ranged from 14 ng/ml, 2,168 ng/ml, and 270 ng/ml for the lowest dosage to 142 ng/ml, 8,040 ng/ml, and 1,395 ng/ml for the highest dosage. In the RTV-boosted trial, Cmin, Cmax, and Css,av at day 14 ranged from 480 ng/ml, 1,569 ng/ml, and 725 ng/ml for the lowest dosage to 1,486 ng/ml, 5,453 ng/ml, and 2,460 ng/ml for the highest dosage. The most commonly reported Aes were GI, skin, and CNS disorders. For TMC114 alone, the incidence of Aes were diarrhea 78%, nausea 14%, vomiting 17%, headache 22%, and skin disorder 41%. For TMC114/RTV, the incidence of Aes were diarrhea 30%, nausea 7.5%, headache 15%, and skin disorder 5%. GI effects are largely attributed to the PEG-containing solution. There was an apparent reduction in the frequency of Aes reported in subjects who received TMC114/RTV compared to TMC114 alone. Lab abnormalities: TMC114: 11% grade 2 CHOL vs TMC114/RTV: 7.5% grade 2 CHOL, 2.5% grade 3 CHOL.
Conclusion: In healthy volunteers, the co-administration of TMC114, a next generation PI, with low doses of RTV resulted in improved PK, despite lower doses of TMC114, and a more favorable safety/tolerability profile compared to TMC114 alone.
