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Pharmacokinetics (PK), safety, and tolerability of single doses of the chemokine C-C receptor 5 (CCR5) antagonist TBR-652 in healthy volunteers
Abstract Content:
Background: Promising treatment for HIV-1 infection is blockade of CCR5, used by HIV-1 to enter target cells. TBR-652 is a potent CCR5 antagonist with a 0.25nmol/L EC90 against HIV-1 clinical isolates in human PBMC and a plasma half-life (t1/2) of 31-40 hours after oral dosing, which supports once-daily dosing.
Methods: This was a double-blind, randomized, placebo-controlled study of two formulations of oral TBR-652 in fasted, healthy volunteers 18-55 years old. Two cohorts of 12 subjects received 1x10mg, 1x25mg, and 4x25mg or 1x100mg, 4x100mg, and 8x100mg TBR-652 sequentially, with a 7- or 10-day washout, respectively, between doses. PK and safety data were summarized descriptively. Analysis of variance was used to determine dose proportionality and intersubject variability.
Results: TBR-652 absorption was similar across most groups (median tmax 3-4 hours). Elimination showed linear kinetics (mean t1/2 about 35 hours). Cmax and AUC0-inf were dose proportional in cohort 1, but not in cohort 2. Mean bioavailability (AUC0-inf/dose) was 25.8-31.7 in cohort 1. Cmax was greater than 3 times higher after 100mg in cohort 1 compared to cohort 2, which was attributed to the different formulations. Cohort 2 PK had greater intersubject variability, with mean bioavailability 8.58-14.1. Of 25 and 12 treatment-emergent adverse events (AEs) in cohorts 1 and 2, respectively, 19 and 6 were thought possibly related to study drug, 92% and 100% were mild in intensity. Headache, diarrhea, abdominal pain, and nausea were the most common AEs and occurred more frequently in cohort 1. Five subjects discontinued dosing early. No subjects were withdrawn for an AE, and there were no unexpected, severe, or life-threatening AEs.
Conclusions: TBR-652 was rapidly absorbed and demonstrated good oral bioavailability. TBR-652 was generally well-tolerated and safe across all doses tested. This trial supports further exploration of TBR-652 for potential use in HIV-infected patients.
Methods: This was a double-blind, randomized, placebo-controlled study of two formulations of oral TBR-652 in fasted, healthy volunteers 18-55 years old. Two cohorts of 12 subjects received 1x10mg, 1x25mg, and 4x25mg or 1x100mg, 4x100mg, and 8x100mg TBR-652 sequentially, with a 7- or 10-day washout, respectively, between doses. PK and safety data were summarized descriptively. Analysis of variance was used to determine dose proportionality and intersubject variability.
Results: TBR-652 absorption was similar across most groups (median tmax 3-4 hours). Elimination showed linear kinetics (mean t1/2 about 35 hours). Cmax and AUC0-inf were dose proportional in cohort 1, but not in cohort 2. Mean bioavailability (AUC0-inf/dose) was 25.8-31.7 in cohort 1. Cmax was greater than 3 times higher after 100mg in cohort 1 compared to cohort 2, which was attributed to the different formulations. Cohort 2 PK had greater intersubject variability, with mean bioavailability 8.58-14.1. Of 25 and 12 treatment-emergent adverse events (AEs) in cohorts 1 and 2, respectively, 19 and 6 were thought possibly related to study drug, 92% and 100% were mild in intensity. Headache, diarrhea, abdominal pain, and nausea were the most common AEs and occurred more frequently in cohort 1. Five subjects discontinued dosing early. No subjects were withdrawn for an AE, and there were no unexpected, severe, or life-threatening AEs.
Conclusions: TBR-652 was rapidly absorbed and demonstrated good oral bioavailability. TBR-652 was generally well-tolerated and safe across all doses tested. This trial supports further exploration of TBR-652 for potential use in HIV-infected patients.