The pharmacokinetics and absorption of recombinant human relaxin in nonpregnant rabbits and rhesus monkeys after intravenous and intravaginal administration.

Recombinant human relaxin (rhRlx) is being developed as a potential cervical ripening agent to be applied intravaginally or intracervically prior to parturition. The pharmacokinetics and absorption of rhRlx were determined in nonpregnant female rabbits and rhesus monkeys after intravenous bolus (iv) and intravaginal administration of 0.1 mg/kg; additionally, rabbits were dosed with 0.5 mg/kg intravaginally. In rabbits (n = 6), mean (±SD) peak concentrations following iv bolus administration were 1554 ± 296 ng/mL. The weight-normalized clearance (CL/W) was 5.9 ± 0.4 mL/min/kg, initial volume of distribution (V1/W) was 57 ± 9 mL/kg, and volume of distribution at steady state (VSS/W), assuming central compartment elimination, was 240 ± 20 mL/kg. Vss/W could be as large as 2000 ± 400 mL/kg without this assumption. The estimated amounts of rhRlx absorbed in rabbits following intravaginal administration of 0.1 and 0.5 mg/kg (n = 5/dose) were 3.1 ± 1.4 and 0.7 ± 0.3%, respectively; peak concentrations were 600 ± 297 and 1066 ± 584 pg/mL, respectively. In rhesus monkeys (n = 5) after iv administration, peak concentrations were 971 ± 277 ng/mL; CL/W was 4.1 ± 0.6 mL/ min/kg, V1/W was 78 ± 25 mL/kg, and Vss/W, assuming central compartment elimination, was 690 ± 220 mL/kg. The upper limit for Vss/W was 1600 ± 200 mL/kg when no assumptions were made regarding site (compartment) of elimination. After intravaginal administration (n = 6), two monkeys had undetectable rhRlx concentrations throughout the 48-hr sampling interval; one monkey had only one sample containing measurable rhRlx (51 pg/mL) at 24 hr; and three monkeys absorbed <2% of the 0.1 mg/kg dose. Peak concentrations in these three animals ranged from 64 to 1475 pg/mL. The absorption of rhRlx was low and variable in both species, and similar results have been observed in women.