Background:  AMD11070 (070) is a specific and reversible CXCR4 antagonist undergoing phase IIa studies. Activity has been demonstrated in the first-dose cohort in an ongoing proof-of-activity study. The aim of this analysis was to assess the plasma pharmacokinetics of 070 when administered twice daily to HIV-infected patients and investigate its relationship with virological response.

Methods:  A single-arm, open-label, dose-escalating study was conducted in HIV-infected patients carrying X4-tropic virus (determined by a luciferase activity of ≥2000 relative light units (rlu) on the monogram HIV co-receptor tropism assay. We administered to 8 patients 070 200 mg twice daily and to 2 100 mg twice daily for 10 days. Sampling for plasma 070 concentration determinations were performed at multiple time points following the morning and afternoon doses on the last day of administration (day 10). Samples were also obtained immediately prior to the morning dose on days 1 to 10 for trough level analysis. Pharmacokinetics analysis was performed using a non-compartmental extravascular input model provided by WinNonlin V.4.0.1.

Results:  When 070 was administered 100 and 200 mg twice daily, the average times to reach C_max were 180±60 minutes and 108.8±23 minutes (median = 105 minutes), respectively. Mean AUC_0-24hr were 1123.5±145.0 ng×h/mL and 6471.8±1511.2 (median = 5650.2 ng×h/mL); and mean C_max were 346.5±26.5 ng/mL and 1271.2.1±234.2 ng/mL (median = 1350.0 ng/mL), respectively. AUC_0-24 coefficient of variation was 66.0%. The 100 to 200 mg AUC_0-24hr ratio was 5.7, suggesting a greater than proportional increase in exposure. For the 200-mg dose group, the median C_12hr on day 10 was 84.1 ng/mL (mean ± SEM = 97.8±24.3 ng/mL), which was close to the protein-adjusted in vitro EC₉₀ (~100 ng/mL) of 070. Half-life was 5.5±0.7 h (n = 5 on 200 mg twice daily). Trough levels analysis suggested that steady-state was not achieved in all patients after 10 days of twice-daily dosing. At the 100 and 200 mg twice-daily dose levels, no significant relationship was observed between AUC_0-24hr or C_12hr and X4 log rlu reduction at day 10.

Conclusions:  AMD11070 is orally bioavailable and exhibits evidence of accumulation following repeated administration. Pharmacokinetic data suggested that the 070 pharmacokinetic parameters in HIV-infected patients are comparable to those in healthy volunteers. At doses studied to date, no relationship was observed between 070 pharmacokinetic parameters and virological response. Future dose-escalating studies will continue to assess the pharmacokinetic/pharmacodynamic relationship of this novel ART compound.