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Levels of Novel HIV Attachment Inhibitor With or Without Ritonavir
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12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami
Mark Mascolini
At various doses with or without ritonavir, the HIV attachment inhibitor BMS-663068 yielded adequate concentrations of BMS-626529, the active form of the drug, in single and multiple ascending-dose studies involving HIV-negative volunteers [1]. No serious complications or clinically relevant side effects or lab abnormalities could be attributed to the new drug.
In an open-label multiple-dose trial in HIV-positive people reported earlier this year, viral loads fell by a median of 1.69 log copies/mL after 8 days of BMS-663068 alone or with a ritonavir boost [2]. Median CD4 counts rose in all five treatment groups, but CD4 results varied widely in this small study. A phase 2b trial of BMS-663068 plus other antiretrovirals in treatment-experienced people is planned for 2011.
BMS-663068 binds to the gp120 protein on HIV and so blocks its attachment to CD4 cells. Median protein binding-adjusted 90% effective concentration is 9.6 ng/mL. Work to date indicates that once- or twice-daily dosing is feasible.
The single and multiple ascending-dose studies were double-blind, placebo-controlled trials that enrolled healthy 18- to 45-year-olds without HIV and with a body mass index of 18 to 30 kg/m(2). The single-dose study involved 88 people, while 40 enrolled in the multiple-dose study. Doses ranged from 20 to 1200 mg of BMS-663068 in an immediate-release or extended-release formulation with or without ritonavir.
Of the 88 volunteers in the ascending single-dose study, 66 were men, 22 were women, and 47 (53%) were Caucasian. Age averaged 30 years and ranged from 18 to 45. Weight ranged from 59.2 to 100.7 kg and body mass index from 19.1 to 29.9 kg/m(2).
BMS-663068 plasma concentrations were generally below the 1-ng/mL limit of quantitation, a result indicating rapid conversion to the active drug, BMS-626529, which had an approximate 1-hour time to maximum concentration. Maximum concentration (Cmax) and area under the concentration-time curve (AUC) increased more than dose-proportionally from 20 to 1000 mg. Ritonavir raised BMS-626529 AUC about 1.8-fold. Less than 4% of BMS-626529 was recovered in urine.
No one stopped treatment because of adverse events. Viral meningitis, the only serious adverse event, was judged not related to study drugs. Nausea and headache were the most frequent side effects, and both became more frequent at higher doses.
The 10-day multiple ascending dose study had 8 patients in each of five panels, 6 randomized to BMS-663068 and 2 to placebo. The five doses were (1) 100 mg immediate-release BMS-663068 every 8 hours, (2) 200 mg of immediate-release BMS-663068 every 8 hours, (3) 600 mg of extended-release BMS-663068 plus 100 mg of ritonavir every 12 hours, (4) 1200 mg of extended-release BMS-663068 every 12 hours, and (5) 1200 mg of extended-release BMS-663068 plus 100 mg of ritonavir every 12 hours.
Median BMS-626529 time to maximum concentration in the multiple ascending-dose study ranged from 1.5 to 2.0 hours with the immediate-release formulation and from 4 to 5 hours with the extended-release formulation. Average BMS-626529 plasma terminal half-life on day 10 ranged from 3.2 to 4.5 hours with the immediate-release formulation and from 7 to 14 hours with the extended-release formulation, with or without ritonavir.
As in the multiple-dose study, BMS-663068 metabolized rapidly to the active drug, BMS-626529, after multiple immediate-release or extended-release doses. Volunteers generally reached steady-state levels of BMS-626529 on day 2 or 3.
One person taking 600 mg of extended-release BMS-663068 plus ritonavir dropped out because of rash. Pruritus (itching), nausea, headache, flatulence (gas), and rash proved the most common complaints in the multiple-dose study. In the monotherapy trial of BMS-663068 in people with HIV, rash affected 8 of 50 (16%) [2]. In the ascending-dose studies, researchers recorded no clinically relevant effects on electrocardiograms, lab values, vital signs, or physical exams.
References
1. Nettles R, Chien C, Elefant E, et al. Single and multiple dose pharmacokinetics and safety in non-HIV-infected healthy subjects dosed with BMS-663068, an oral HIV attachment inhibitor. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract O_04.
2. Nettles R, Schurmann D, Zhu L, et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068: a potentially first-in-class HIV attachment inhibitor. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 49. http://www.natap.org/2011/CROI/croi_06.htm.
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