title: Pharmacokinetics and pharmacodynamics of recombinant human interleukin-12 in male rhesus monkeys.
abstract: The pharmacokinetics and pharmacodynamics of recombinant human interleukin-12 (rHuIL-12) were investigated in male rhesus monkeys. The monkeys received a 40-min i.v. infusion of 42.5 micrograms/kg of recombinant human interleukin-12 on day 1 followed by a s.c. injection of the same dose on day 5. Serum samples were collected at appropriate time points and assayed for interleukin (IL-12) by an IL-12 capture bioassay, interferon (IFN-gamma) by an IFN-gamma enzyme-linked immunosorbent assay, and neopterin by a neopterin radioimmunoassay. After i.v. infusion, the systemic clearance rate of this protein was very slow (average, 3 ml/hr/kg). The volume of distribution at steady state ranged from 59 to 90 ml/kg. After the s.c. dose, the mean Cmax was 61 ng/ml and the mean Tmax was 18 hr. The absolute bioavailability was moderate (20-30%) after s.c. injection. By compartmental analysis, by using a two-compartment model the T 1/2 lambda 1 ranged from 0.2 to 5 hr and the T 1/2 lambda 2 ranged from 13 to 19 hr. When determining the percentage of the area of the serum concentration-time curve, per phase, > 85% of the protein was found in the lambda 2 phase. We selected IFN-gamma as one of the pharmacodynamic markers to study because it is produced by T-lymphocytes and natural killer cells in response to IL-12. In addition, once IFN-gamma is produced, it primes macrophages for tumor killing that in turn secrete neopterin. We show that within 24 to 48 hr after the i.v. dose, IFN-gamma concentrations are elevated in these monkeys (average, 300 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Nadeau
authors.forename: C
authors.initials: C
authors.lastname: Ostrowski
authors.forename: G
authors.initials: G
authors.lastname: Ni-Wu
authors.forename: D J
authors.initials: DJ
authors.lastname: Liberato
mesh_terms: D000818:Animals; D006801:Humans; D018664:Interleukin-12 / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D011994:Recombinant Proteins; D018664:Interleukin-12