Pharmacokinetics of 852A, an imidazoquinoline Toll-like receptor 7-specific agonist, following intravenous, subcutaneous, and oral administrations in humans.
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-alpha 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.
Department of Pharmacokinetics/Drug Metabolism, 3M Pharmaceuticals, Center Bldg 270-3S-05, St Paul, MN 55144, USA. liharrison@mmm.com
Lester I
LI
Harrison
Calvin
C
Astry
Sandeep
S
Kumar
Carla
C
Yunis
D000293:Adolescent; D000328:Adult; D000368:Aged; D001682:Biological Availability; D015331:Cohort Studies; D018592:Cross-Over Studies; D004333:Drug Administration Routes; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051199:Toll-Like Receptor 7 / Q000819:agonists*
C523097:N-(4-(4-amino-2-ethyl-1H-imidazo(4,5c)quinolin-1-yl)butyl)methanesulfonamide; D011804:Quinolines; D013449:Sulfonamides; D051199:Toll-Like Receptor 7