Demographic characteristics of patients are summarized by treatment group in . A total of 87% of the population was male, and 96.3% of the patients were enrolled in the United States. The two patients from Argentina were both enrolled in the 100-mg dose group (cohort 4). The mean overall age was 38.9 years. The predominant races were Caucasian (56%) and African-American (26%). Mean BMI was greatest in the 50-mg QD group (30.51 kg/m2), which also had a higher mean body weight than the other treatment groups. The other groups had mean BMI values that ranged from 23.52 to 26.50 kg/m2 and were similar to the overall mean of 25.65 kg/m2. Mean plasma concentration-time profiles of TBR-652 following multiple oral administrations of 25, 50, 75, 100, and 150 mg QD are presented on semi-log scale in . TBR-652 was well absorbed following repeated dosing, and all plasma concentrations of TBR-652 were above the LLOQ of the assay. Mean plasma concentrations of TBR-652 declined in a multiexponential manner. Descriptive statistics of PK parameters of TBR-652 are presented in . One subject (no. 2007) randomly assigned to cohort 2 (50 mg/day of TBR-652) mistakenly received 25 mg TBR-652 during the study. As a result, PK and PD data for this subject were assessed as part of cohort 1 (25 mg/day of TBR-652; n = 9). Mean oral clearance (CL/F) values for TBR-652 at the 50-, 75-, and 100-mg QD dose levels were relatively constant, with mean values of 49.26, 42.17, and 48.06 liters/h, respectively. Mean CL/F values at the 25- and 150-mg QD dose levels (i.e., 81.31 and 22.95 liters/h, respectively) appeared to be markedly different from those observed at the 50- and 100-mg QD dose levels. Two patients enrolled at the clinical site in Argentina displayed TBR-652 systemic exposure more than 2-fold higher than those observed in other subjects in cohort 4 (100 mg QD). This difference may suggest the presence of a food effect on the PK of TBR-652 since patients at the clinical site in Argentina received meals with a fat content higher than that of meals administered in the U.S. clinics. Mean terminal elimination half-lives of TBR-652 across the 25- to 150-mg QD dose levels ranged from 22.50 to 47.62 h. Dose-adjusted exposure parameters of TBR-652 (AUC0–24 and Cmax) were calculated to assess the dose range over which PK parameters increased in a dose-proportional manner. Dose-adjusted AUC0–24 values for the 25-, 50-, 75-, 100-, and 150-mg QD dose levels were 15.3, 24.9, 25.5, 26.6, and 48.5, respectively. Dose-adjusted Cmax for the 25-, 50-, 75-, 100-, and 150-mg QD dose levels were 1.40, 2.05, 2.09, 1.97, and 3.39, respectively. Overall, the above results suggest that AUC0–24 and Cmax of TBR-652 increased in a dose-proportional manner from 50 to 100 mg QD. The AUC0–24 and Cmax of TBR-652 for the 150-mg dose appeared to increase in a more-than-proportional manner compared to those for other dose levels. Time to steady state was evaluated using a Helmert contrast approach. Steady-state concentrations of TBR-652 were observed on day 8 for all dose levels since mean concentration levels were not statistically significantly different from those observed on days 9 and 10. These results suggest that PK parameters of TBR-652 calculated on day 10 in HIV-infected patients were assessed under steady-state conditions.
Demographic characteristics of HIV-1 patients
Mean (+SD) plasma concentration-time profiles of TBR-652 on day 10.
Summary of pharmacokinetic parametersa of TBR-652 on day 10
Median change in HIV-1 RNA levels over the 10-day study and during the study or during follow-up through day 40 are presented in . Descriptive statistics of HIV-1 RNA levels are also presented in .
Median change in HIV-1 RNA levels from baseline over time.
One subject (no. 5002) assigned to cohort 5 (150 mg/day of TBR-652) was found to have a tropism shift from CCR5 to CXCR4 coreceptor at baseline and should not have been eligible for the study. There were no shifts in viral tropism among the other patients, who provided usable samples for testing at study termination. Ad hoc
retesting of patient 5002's baseline sample was performed at another laboratory (BC Centre for Excellence in HIV/AIDS, Vancouver, Canada) using the geno2pheno algorithm to infer tropism from triplicate population sequencing of the V3 loop (6
). Results confirmed that the patient had a preponderance of CXCR4-tropic virus at entry, which made this patient ineligible for the study. As a result, this patient was omitted from antiviral efficacy analyses. TBR-652 showed strong antiviral activity after 10 days of once-daily dosing. The median changes in HIV-1 RNA from baseline on day 11 for the placebo and 25-, 50-, 75-, 100-, and 150-mg dose levels were +0.1, −0.5, −1.3, −1.6, −1.2, and −1.5 log10
copies/ml, respectively. The mean HIV-1 RNA reductions from baseline achieved statistical significance by day 4 for all doses and by day 7 reached P
values of <0.002 for the 25-mg QD dose and <0.001 for the 50-, 75-, 100-, and 150-mg QD dose levels. This level of significance persisted through day 15 for the 50- to 150-mg QD dosing groups. HIV-1 RNA reductions were still significant on day 24 in the 150-mg dose group (P
= 0.03). Median nadir HIV-1 RNA values in the 25-, 50-, 75-, 100-, and 150-mg dose groups were −0.7, −1.6, −1.8, −1.4, and −1.7 log10
A simple Emax model was used to describe the relationship between PK and PD of TBR-652 based on the minimization of the AIC. Results obtained from the simple Emax model are presented in . The Emax and IC50 of TBR-652 were −1.43 log10 copies/ml and 13.1 ng/ml, respectively. Standard errors (SE) of Emax and IC50 parameters of TBR-652 were 0.138 log10 copies/ml and 6.53 ng/ml, respectively. Based on the PK/PD model, the average steady-state concentration levels of TBR-652 for the 25-, 50-, 75-, 100-, and 150-mg doses are expected to result in 54.5%, 79.6%, 85.7%, 89.3%, and 95.8% of the maximum inhibitory effect (Emax) of TBR-652, respectively. The above results suggest that TBR-652 doses of 75, 100, and 150 mg QD are expected to result in robust antiviral activity, with PD effects greater than 80% of the maximum inhibition (Imax) of TBR-652 in HIV-1-infected patients.
Correlation between average concentrations of TBR-652 and Δlog HIV-1 RNA on day 11.
The relationship between the exposure of TBR-652 and MCP-1 plasma concentrations was described using a simple Emax model. Results obtained with the Emax model for MCP-1 are presented in . The Emax and IC50 of TBR-652 were 2.63 log10 and 29.8 ng/ml, respectively. SE of Emax and IC50 parameters of TBR-652 were 0.233 log10 pg/ml and 9.45 ng/ml, respectively. Based on the PK/PD model, MCP-1 concentrations increase rapidly with higher dose levels and reach a plateau at exposure levels of TBR-652 associated with the 150-mg dose level. The above results suggest a strong CCR2 blockade at the higher dose levels of TBR-652. Additional studies will be required to assess the longer-term effect of TBR-652 on MCP-1.
Correlation between average concentrations of TBR-652 and Δlog MCP-1 concentrations (pg/ml).
Adverse events were reported in a total of 34 patients, 30 of whom received TBR-652 treatments. Of these 34 patients, 20 patients on TBR-652 treatment had adverse events considered possibly or probably related to the drug. A total of 40% of patients on placebo reported at least one adverse event; the greatest number of patients reporting an adverse event were in the 150-mg dose group (100%), but the least number were in the 75-mg dose group (22%). Overall, adverse events were generally mild, and there were no indications of a relationship with TBR-652 dose. The most frequent adverse events were gastrointestinal (63%) and general disorders (37%). Nearly all patients with AEs were considered to have a grade 1 or 2 event except one patient each on placebo and the 75-mg dose who had grade 3 adverse events. The latter was an abscess that was judged nonserious and unrelated to study drug and resolved without sequelae. There were no grade 4 AEs, no serious AEs (SAEs), no deaths, and no study discontinuations because of an AE.