Pharmacokinetic parameters and biodistribution of soluble cytokine receptors.
The potential use of soluble cytokine receptors as therapeutics in disease states when excessive or prolonged cytokine expression leads to pathogenesis is just beginning (Van Brunt, 1989). The inhibitory effects of soluble receptors have been found to be highly potent and specific for their respective cytokines (Maliszewski and Fanslow, 1990; Maliszewski et al., 1990). Recent in vivo data have shown that exogenously administered soluble receptors can function as cytokine antagonists and suppress autoimmune inflammatory responses (Jacobs et al., 1991a), allograft rejection, and alloreactivity (Fanslow et al., 1990b). The proposed frequency of administration and dosage of a therapeutic agent is dependent on the half-life of the agent and the route of administration. The elimination or half-life of a drug usually depends on its physiochemical properties (molecular size, glycosylation, isoelectric point, and hydrophobic/hydrophilic properties) (DiPalma and DiGregorio, 1990; Katzung, 1984). The half-life will also depend on the mechanism of clearance for that specific receptor. Once pharmacokinetic data are available for soluble receptors, the therapeutic potential of these molecules can be better evaluated. Only limited pharmacokinetic data are currently available for soluble cytokine receptors (Jacobs et al., 1991b). For sIL-1R, the majority of an intravenously administered dose was cleared in the second elimination phase, with a reasonably long half-life (6.3 hr), such that the entire dose was not eliminated until 35 hr. If administration is by subcutaneous injection, the half-life was even more prolonged. One explanation for the prolonged half-life is the minimal distribution to liver and kidneys and thus low levels of clearance by these organs. In contrast, elimination of intravenously administered sIL-4R was relatively rapid, with a short half-life (2.3 hr). This appeared mainly due to liver distribution and clearance, which has been the highest observed for any soluble cytokine receptor. Administering sIL-4R by subcutaneous injection significantly prolonged the half-life. This was most likely due to delaying the rate of liver distribution by slowing the rate of sIL-4R absorption into the circulation. Thus, subcutaneous injection would be the recommended route of administration for this receptor. Construction of a larger dimeric sIL-4R fusion protein did not prolong the i.v. half-life compared to that of the monomer, as the sIL-4R fusion protein was distributed to, and was cleared by, the liver to a greater degree.(ABSTRACT TRUNCATED AT 400 WORDS)
Immunex Corporation, Seattle, Washington 98101.
C A
CA
Jacobs
M P
MP
Beckmann
K
K
Mohler
C R
CR
Maliszewski
W C
WC
Fanslow
D H
DH
Lynch
D000818:Animals; D007275:Injections, Intravenous; D007375:Interleukin-1; D015847:Interleukin-4; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C / Q000378:metabolism; D010599:Pharmacokinetics; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics; D012995:Solubility; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha
D007375:Interleukin-1; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4