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)
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|