Pharmacokinetics of recombinant human interleukin 3 administered subcutaneously and by continuous intravenous infusion in patients after chemotherapy for ovarian cancer.
Twenty chemotherapy-naive patients with ovarian carcinoma received 1, 5, 10, or 15 micrograms/kg/day (five patients per dose step) of recombinant human interleukin 3 (rhIL-3) over 7 days after carboplatin/cyclophosphamide in Cycles 1 and 3. Patients received rhIL-3 by continuous i.v. infusion or once daily s.c. injection in Cycle 1 and the alternate route in Cycle 3. Plasma rhIL-3 samples were obtained once daily on Days 1 to 6 and serially over a 24-h period on Day 7 for pharmacokinetic assessment of s.c. and i.v. administered rhIL-3 in 16 and 17 patients, respectively. Concentrations were assayed by a time-resolved fluorescence sandwich immunoassay. Pharmacokinetic parameters were derived by noncompartmental methods. Mean steady-state concentrations during continuous i.v. infusion ranged from 117 pg/ml (1 microgram/kg/day) to 2217 pg/ml (15 micrograms/kg/day) and were linearly related to dose (r = 0.87, P < 0.001). When dose normalized, the mean steady-state concentrations were comparable at all doses. The total-body clearance was approximately 4 to 5 ml/min/kg. Elimination half-life (t1/2 i.v.) could be assessed for the 5- to 15-micrograms/kg/day dose levels and was 53, 41, and 26 min for the 5-, 10-, and 15-micrograms dose levels, respectively (not significant between dose levels). Following s.c. injection, the maximum rhIL-3 plasma concentration ranged from 206 pg/ml (1 microgram/kg/day) to 6930 pg/ml (15 micrograms/kg/day). Both the maximum measured plasma concentration (r = 0.89, P < 0.0001) and the area under the plasma concentration/time curve (r = 0.93, P < 0.0001) were related to dose. Dose-normalized values were comparable over the entire dose range. Elimination t1/2s.c. was 4.8 h at the 1-microgram dose level and roughly half this time for the 5- to 15-micrograms/kg/day dose levels. The systemic clearance of approximately 5 to 6 ml/min/kg was comparable at all dose levels. Based on trough levels of the 7-day s.c. course, no rhIL-3 accumulation occurred. Bioavailability of s.c. administered rhIL-3 was nearly 100%. No correlation between creatinine clearance and pharmacokinetic parameters of rhIL-3 could be demonstrated. Since there was also no difference in hematological efficacy between the two routes of rhIL-3 administration, we conclude that the s.c. route of administration appears to have no disadvantages over the i.v. route and may facilitate its clinical application.
Biesma
B
B
Department of Internal Medicine, University Hospital, Groningen, The Netherlands.
Pokorny
R
R
Kovarik
J M
JM
Duffy
F A
FA
Willemse
P H
PH
Mulder
N H
NH
de Vries
E G
EG
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001682:Biological Availability; D001772:Blood Cell Count / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007377:Interleukin-3 / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011994:Recombinant Proteins / Q000493:pharmacokinetics
D007377:Interleukin-3; D011994:Recombinant Proteins; D003520:Cyclophosphamide; D016190:Carboplatin