Background: 873140 is a spirodiketopiperazine CCR5 antagonist that binds specifically to human CCR5 and demonstrates potent in vitro and in vivo anti-HIV activity. In vitro studies suggest prolonged CCR5 receptor occupancy by 873140 with an offset half-life of > 100 hours. Previous in vivo studies have shown that 873140 selectively inhibits monoclonal antibody binding to CCR5 and exhibits substantial (> 97%) CCR5 receptor occupancy in blood during repeated oral administration of 873140. Furthermore, 873140 shows sustained viral suppression for 24 to 48 hours after therapy discontinuation. The objective of the current study was to assess the duration of CCR5 receptor occupancy in HIV⁺ and HIV^– subjects following repeat-dose administration of 873140.

Methods:  Flow cytometric analysis was used to determine duration of in vivo blood CCR5 receptor occupancy in 8 HIV^– and 31 HIV⁺ subjects administered various doses of 873140 for 7 or 10 days, respectively. In vivo CCR5 receptor occupancy was analyzed at baseline, last day of dosing, and over 7 to 14 days following multiple dose administration. The half-life (t1/2) for receptor occupancy decline, a measure of the duration of CCR5 receptor occupancy, was estimated by fitting a first-order exponential model to the resulting receptor occupancy versus time data.

Results:  Median CD4⁺ cell CCR5 receptor occupancy following 7 days of 600 mg twice daily 873140 dosing in 8 HIV^– subjects was 98%. Post-treatment analysis on days 8, 9, 11, and 13 suggested t1/2 receptor occupancy on CD4⁺ cells was 127 hours post-last dose. HIV⁺ subjects received 200 mg once daily, 200 mg twice daily, 400 mg once daily, or 600 mg twice daily over 10 days. Median CD4⁺ cell CCR5 receptor occupancy on day 10 was > 95% across doses. A cross-dose combined post-treatment analysis at days 11, 12, 15, 17, 19, and 24 estimated a t1/2 receptor occupancy on CD4⁺ cells at 122 hours post last dose. Higher doses tended to result in longer duration of occupancy (t1/2 receptor occupancy of 69 hours [95% CI 53 to 97 hours] for 200 mg once daily vs 152 hours [95% CI 107 to 264 hours] for 600 mg twice daily). The t1/2 receptor occupancy decline was comparable between total lymphocytes and CD4⁺ cells for both HIV^– and HIV⁺ subjects.

Conclusions:  Studies using CCR5-specific monoclonal antibodies demonstrate substantial and prolonged in vivo blood CCR5 receptor occupancy by 873140. At sample times post final dose, when plasma drug levels were undetectable, significant CCR5 receptor occupancy (> 50%) was observed for approximately 5 days. The prolonged CCR5 receptor occupancy suggests a potential mechanism for the sustained antiretroviral effect seen following 873140 administration in HIV⁺ subjects. Taken together, the data support further evaluation of 873140 in HIV-infected individuals.

Keywords: 873140; CCR5; pharmacodynamics