Pharmacokinetics and pharmacodynamics of TBR-652, a novel CCR5 antagonist, in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients.

TBR-652 is a novel CCR5 antagonist with potent in vitro anti-HIV activity. The objective of this study was to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of TBR-652 in HIV-1-infected, antiretroviral treatment-experienced, CCR5 antagonist-naïve patients. A double-blind, placebo-controlled, randomized, dose-escalating study of TBR-652 monotherapy given once daily orally for 10 days was performed, followed by a 40-day follow-up period. Approximately 10 patients/dose level received 25, 50, 75, 100, and 150 mg TBR-652 or placebo (4:1). Blood was collected at different intervals for PK and HIV-1 RNA assessments. PK analysis of TBR-652 was performed using noncompartmental methods. PK/PD was modeled using a maximum inhibitory effect model (E(max)) and 50% inhibitory concentrations (IC50). TBR-652 was well absorbed in the systemic circulation. TBR-652 concentration levels declined slowly, with mean elimination half-lives ranging from 22.5 to 47.62 h across dose levels. TBR-652 treatment resulted in potent, dose-dependent decreases in viral load, with statistically significant decreases in nadir HIV-1 RNA compared to baseline for all dose levels. Suppression of HIV-1 RNA persisted over the 40-day follow-up period. A steep exposure-effect relationship was observed, with an E(max) of -1.43 log10 copies/ml and IC50 of 13.1 ng/ml. TBR-652 was generally safe and well tolerated at all dose levels studied. Short-term monotherapy treatments of TBR-652 in HIV-1-infected patients resulted in promising PK and PD results, with a clear exposure-response relationship at the current dose levels studied. Data from this study support further development of TBR-652 in HIV-infected patients.

Safety, efficacy, and pharmacokinetics of TBR-652, a CCR5/CCR2 antagonist, in HIV-1-infected, treatment-experienced, CCR5 antagonist-naive subjects.

OBJECTIVES: To determine the antiviral activity, pharmacokinetics, pharmacodynamics, safety, and tolerability of several dose levels of oral TBR-652 monotherapy in HIV-1-infected, antiretroviral experienced, CCR5 antagonist-naive subjects. DESIGN: Double-blind placebo-controlled study in the United States and Argentina. METHODS: Subjects were randomized in a ratio of 4:1 per dose level to TBR-652 (25, 50, 75, 100, or 150 mg) or placebo, taken once daily for 10 days. Changes from baseline in HIV-1 RNA and CD4 cell counts were measured through day 40 and for monocyte chemotactic protein-1 (MCP-1), high-sensitivity C-reactive protein (hs-CRP), and IL-6 at day 10. Pharmacokinetic data were analyzed using noncompartmental statistics. Laboratory and clinical adverse events (AEs) and electrocardiogram changes were recorded. RESULTS: Maximum median reductions in HIV-1 RNA values for the 25, 50, 75, and 150 mg doses were -0.7, -1.6, -1.8, and -1.7 log10 copies per milliliter, respectively. All changes were significant. Median time to nadir was 10-11 days. Suppression persisted well into the posttreatment period. Mean MCP-1 increased significantly by day 10 in the 50-mg and 150-mg dose groups. Effects on CD4 cell counts, hs-CRP, and IL-6 levels were negligible. TBR-652 was generally safe and well tolerated, with no withdrawals due to AEs. CONCLUSIONS: TBR-652 caused significant reductions in HIV-1 RNA at all doses. Significant increases in MCP-1 levels suggested a strong CCR2 blockade. TBR-652 was generally well tolerated with no dose-limiting AEs. Pharmacodynamics indicate that TBR-652 warrants further investigation as an unboosted once-daily oral CCR5 antagonist with potentially important CCR2-mediated anti-inflammatory effects.

Safety and pharmacokinetics of GSK364735, a human immunodeficiency virus type 1 integrase inhibitor, following single and repeated administration in healthy adult subjects.

GSK364735 is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor with potent in vitro antiviral activity. This study was a double-blind, randomized, placebo-controlled, dose escalation, phase I study to assess single- and repeated-dose safety, tolerability, pharmacokinetics (PK), and food effect of GSK364735 in healthy subjects. In part A, three alternating cohorts of 10 subjects (8 receiving the active drug and 2 receiving a placebo) received single doses of 50 to 400 mg while fasting or 200 mg and 400 mg coadministered with food. In part B, five cohorts received repeated doses of 100 to 600 mg daily coadministered with food for 8 days. Safety was assessed throughout the study. Serial blood samples were analyzed for GSK364735 plasma concentrations using a validated high-performance liquid chromatography-tandem mass spectrometry assay. PK parameters were estimated using noncompartmental methods. Seventy-nine (30 in part A and 49 in part B) subjects were enrolled and received GSK364735 or placebo. GSK364735 was readily absorbed following oral dose administration, with the maximum concentration achieved between 0.75 to 5.0 h postdose. GSK364735 exposure increased less than dose proportionally, demonstrated wide variability, and appeared to reach a plateau at 100- to 200-mg doses. Food increased GSK364735 exposure by 28 to 91%. GSK364735 was safe and well tolerated after single- and repeated-dose administration. No serious or severe adverse events (AEs) or AEs leading to withdrawal and few drug-related AEs were reported. Despite solubility-limited absorption, GSK364735 exceeded therapeutic trough concentrations for the majority of doses studied. The PK and safety profile supported the continued investigation of GSK364735 in HIV-infected subjects.