Abstract
Modification of recombinant human interleukin-2 (IL-2) with polyethylene glycol (PEG-IL-2) decreases clearance and might favor absorption into the lymphatics, due to its increased molecular weight. In the present study, we compared the plasma and lymph concentrations of IL-2 and PEG-IL-2 in Yorkshire pigs. The IL-2 regimens were i.v. bolus (0.1–1.6 × 106 I.U., MIU/kg), 15-min i.v. infusion (0.1 MIU/kg), or s.c. bolus (0.1–3.0 MIU/kg). The PEG-IL-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. Bioavailability of i.v. bolus doses of ≥0.16 MIU/kg was complete but only 39% at 0.1 MIU/kg. For the infusion and s.c. doses, bioavailability was 28 and 42%, respectively. Noncompartmental and NONMEM estimates 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 curve 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 ratio 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 ml/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 dosing 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.
Footnotes
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Send reprint requests to: Sharon A. Chen, Microcide Pharmaceuticals, Inc., 850 Maude Ave., Mountain View, CA 94043. E-mail:schen{at}microcide.com
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↵1 This work was previously presented at the 1996 Annual Meeting of the American Association of Pharmaceutical Scientists [Chen SA, Sawchuk RJ, Brundage RC, Horvath C, Mendenhall HV and Braeckman RA (1996) Plasma and lymph pharmacokinetics of recombinant interleukin-2 (IL-2) and polyethylene glycol modified IL-2 (PEG IL-2) in female pigs.Pharm Res13:S-397].
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↵2 Present address: Microcide Pharmaceuticals, Inc., 850 Maude Ave., Mountain View, CA 94043.
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↵3 Present address: LeukoSite, Inc., 215 First St., Cambridge, MA 02142.
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↵4 Present address: Ceptyr, 22215 26th Ave. SE, Bothell, WA 98021.
- Abbreviations:
- IL-2
- interleukin-2
- MIU
- ×106I.U
- PEG-IL-2
- polyethylene glycol-modified IL-2
- PEG
- polyethylene glycol
- CL and CL/F
- clearance and apparent clearance
- Vss and Vss/F
- volume of distribution at steady state and apparent volume of distribution at steady state
- MRT
- mean residence time
- ka
- kacentral, and kalymph, absorption rate constant and absorption rate constant into the central and lymph compartments, respectively
- F and Fbol
- Finf, Fi.v., and Fs.c., bioavailability and bioavailability after dosing by bolus and infusion and after i.v. and s.c. administration, respectively
- FL
- fraction of the s.c. dose that initially is absorbed via the lymphatic system
- lo
- med, and hi, low, middle, and high dose ranges
- AUC
- AUCinf, AUCP, AUCL, AUCLi.v., and AUCLs.c., area under the curve and after dosing by infusion, area under the plasma curve and lymph curves, and area under the lymph curve after i.v. and s.c. administration, respectively
- DsAL
- distribution advantage
- DvAL
- delivery advantage
- ELISA
- enzyme-linked immunosorbent assay
- Received August 11, 1999.
- Accepted November 15, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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