Pharmacokinetics of recombinant human leukemia inhibitory factor in sheep

Alicia M Segrave, Donald E Mager, Susan A Charman, Glenn Edwards, Christopher John H Porter

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 μg/kg rhLIF (n = 2) or s.c. doses of 10, 20, or 50 μg/kg rhLIF (n = 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Noncompartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF. The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration.

Original languageEnglish
Pages (from-to)1085-1092
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume309
Issue number3
DOIs
Publication statusPublished - Jun 2004

Cite this

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title = "Pharmacokinetics of recombinant human leukemia inhibitory factor in sheep",
abstract = "The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 μg/kg rhLIF (n = 2) or s.c. doses of 10, 20, or 50 μg/kg rhLIF (n = 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Noncompartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF. The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration.",
author = "Segrave, {Alicia M} and Mager, {Donald E} and Charman, {Susan A} and Glenn Edwards and Porter, {Christopher John H}",
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Pharmacokinetics of recombinant human leukemia inhibitory factor in sheep. / Segrave, Alicia M; Mager, Donald E; Charman, Susan A; Edwards, Glenn; Porter, Christopher John H.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 309, No. 3, 06.2004, p. 1085-1092.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pharmacokinetics of recombinant human leukemia inhibitory factor in sheep

AU - Segrave, Alicia M

AU - Mager, Donald E

AU - Charman, Susan A

AU - Edwards, Glenn

AU - Porter, Christopher John H

PY - 2004/6

Y1 - 2004/6

N2 - The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 μg/kg rhLIF (n = 2) or s.c. doses of 10, 20, or 50 μg/kg rhLIF (n = 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Noncompartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF. The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration.

AB - The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 μg/kg rhLIF (n = 2) or s.c. doses of 10, 20, or 50 μg/kg rhLIF (n = 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Noncompartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF. The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration.

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U2 - 10.1124/jpet.103.063289

DO - 10.1124/jpet.103.063289

M3 - Article

VL - 309

SP - 1085

EP - 1092

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 3

ER -