Plasma and lymph pharmacokinetics of recombinant human interleukin-2 and polyethylene glycol-modified interleukin-2 in pigs

Modification of recombinant human interleukin-2 (IL-2) with polyethylene gl ycol (PEG-IL-2) decreases clearance and might favor absorption into the lym phatics, due to its increased molecular weight. In the present study, we co mpared the plasma and lymph concentrations of IL-2 and PEG-IL-2 in Yorkshir e pigs. The IL-2 regimens were i.v. bolus (0.1-1.6 x 10(6) I.U., MIU/kg), 1 5-min i.v. infusion (0.1 MIU/kg), or s.c. bolus (0.1-3.0 MIU/kg). The PEG-I L-2 doses were 15-min i.v. infusion (0.01 MIU/kg) or s.c. bolus (0.01-0.10 MIU/kg). Lymph and plasma data were analyzed using noncompartmental methods and NONMEM. Bioavailability of IL-2 was route- and dose-dependent. Bioavai lability of i.v. bolus doses of greater than or equal to 0.16 MIU/kg was co mplete but only 39% at 0.1 MIU/kg. For the infusion and s.c. doses, bioavai lability was 28 and 42%, respectively. Noncompartmental and NONMEM estimate s of clearance and volume of distribution at steady state agreed: 300 ml/h/ kg and 570 ml/kg, respectively, for IL-2. The ratio of the area under the c urve in lymph and plasma increased from 0.67 to 3.4 when comparing i.v. and s.c. routes, and the s.c. delivery advantage (ratio of dose-normalized rat io of the area under the curve in lymph after s.c. and i.v. administration) was 6.6 to 16. For PEG-IL-2, bioavailability was 100%, clearance was 5.9 m l/h/kg, and volume of distribution at steady state was 370 ml/kg. The ratio of the area under the curve in lymph and plasma increased from 0.33 (i.v.) to 1.2 (s.c.), and the s.c. delivery advantage was 3.8. Subcutaneous dosin g would be favored over i.v. dosing, and IL-2 would be favored over PEG-IL- 2 to maximize lymph and minimize plasma exposure. Because IL-2 efficacy may be related to lymph concentrations, dosing regimens can now be designed to test this hypothesis.