Pharmacokinetics of 852A, an imidazoquinoline Toll‐like receptor 7‐specific agonist, following intravenous, subcutaneous, and oral administrations in humans

LI Harrison, C Astry, S Kumar… - The Journal of Clinical …, 2007 - Wiley Online Library
LI Harrison, C Astry, S Kumar, C Yunis
The Journal of Clinical Pharmacology, 2007Wiley Online Library
852A is an imidazoquinoline Toll‐like receptor 7 agonist undergoing evaluation for the
systemic treatment of cancer. 852A was administered to 6 healthy subjects as 3 rising
subcutaneous doses (0.5 to 1.0 to 2.0 mg), to 6 subjects as 3 oral doses (10.0 to 20.0 to 15.0
mg, the third dose being a de‐escalation), and to 6 subjects as a 2.0‐mg dose by the
subcutaneous, intravenous, and oral routes in crossover fashion. The subcutaneous and
intravenous doses were well tolerated. One subject withdrew following the 20.0‐mg oral …
852A is an imidazoquinoline Toll‐like receptor 7 agonist undergoing evaluation for the systemic treatment of cancer. 852A was administered to 6 healthy subjects as 3 rising subcutaneous doses (0.5 to 1.0 to 2.0 mg), to 6 subjects as 3 oral doses (10.0 to 20.0 to 15.0 mg, the third dose being a de‐escalation), and to 6 subjects as a 2.0‐mg dose by the subcutaneous, intravenous, and oral routes in crossover fashion. The subcutaneous and intravenous doses were well tolerated. One subject withdrew following the 20.0‐mg oral dose because of hypotension. The 2.0‐mg subcutaneous dose had 80.5% ± 12.8% (mean ± SD) bioavailability and gave serum concentrations comparable to intravenous administration by 30 minutes. Linear kinetics and an interferon‐α dose response were observed for the 3 subcutaneous doses. Serum concentrations following the 2.0‐mg oral dose were always lower than those following the same intravenous dose, and the oral route had a bioavailability of 26.5% ± 7.84%. Concentrations appeared to increase with oral dose; however, large variabilities in both the rate and extent of absorption were seen between individuals. Approximately 40% of an absorbed dose was excreted unchanged in the urine. Overall, the study suggests that subcutaneous administration may be an acceptable method to deliver 852A for systemic applications.
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