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Pharmacokinetics of 852A, an Imidazoquinoline Toll-Like Receptor 7-Specific Agonist, Following Intravenous, Subcutaneous, and Oral Administrations in Humans

From the Department of Pharmacokinetics/Drug Metabolism (Dr Harrison) and the Department of Medical Operations (Dr Astry and former employees Drs Kumar and Yunis), 3M Pharmaceuticals, St Paul, Minnesota.

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- 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.

Key Words: Pharmacokinetics • 852A • imidazoquinoline • bioavailability • Toll-like receptor 7 agonist

Address for correspondence: Lester I. Harrison, PhD, 3M Center Bldg 270-3S-05, St Paul, MN 55144; e-mail: liharrison{at}mmm.com.

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