Pharmacokinetic modeling of recombinant interleukin-2 in patients with human immunodeficiency virus infection.
A novel model was developed to characterize the time-varying clearance of recombinant interleukin-2 (IL-2). Sixty-eight patients with human immunodeficiency virus infection received 83 cycles of IL-2 either by continuous infusion or by subcutaneous injection for 5 days. IL-2 concentrations after intravenous infusions peaked at 24 hours and then declined by 55% to 78% during the remainder of the infusion. Soluble IL-2 receptors increased greater than 10-fold before gradually returning to baseline. Subcutaneous administration showed a dose-dependent decrease in area under the concentration-time curve (AUC) between days 1 and 5. A model was developed in 9 patients who had IL-2 concentrations and soluble IL-2 receptors determined by ELISA. Concentrations were fitted by an indirect stimulatory pharmacodynamic model. An additional 59 patients with only IL-2 concentrations were fitted to a simplified empiric model. Both models provided an overall r2 of 0.99 for the plot of observed versus fitted concentrations. The time-dependent increase in IL-2 clearance, likely receptor-mediated, was well described with use of an indirect-effects pharmacokinetic-pharmacodynamic model.
Piscitelli
S C
SC
Department of Pharmacy, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. spisc@nih.gov
Forrest
A
A
Vogel
S
S
Chaitt
D
D
Metcalf
J
J
Stevens
R
R
Baseler
M
M
Davey
R T
RT
Kovacs
J A
JA
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013997:Time Factors
D007376:Interleukin-2; D015375:Receptors, Interleukin-2