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 g/kg rhLIF (n ϭ 2) or s.c. doses of 10, 20, or 50 g/kg rhLIF (n ϭ 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.

Partial derivative—Based sensitivity analysis of models describing target-mediated drug disposition

“…4 The quasi-equilibrium model (QEM) was applied to leukemia inhibitory factor (LIF) pharmacokinetic data in sheep; these data had been characterized previously using the TMDD model. 5 Predicted concentration-time profi les appeared to be identical in the 2 models, and there was good agreement in parameter estimates, with the exception of the K D term. Although several explanations might exist, it was hypothesized that the model may be insensitive to K D values.…”

“…12 A series of simulations were conducted with differing parameter values, which were varied 10-, 100-, and 1000-fold on the lower and higher side of the LIF base value. 5 Each simulation was conducted by altering 1 parameter at a time and fi xing all remaining parameter values. All simulations were performed using WinNonlin.…”

Theoretical Analysis of Interplay of Therapeutic Protein Drug and Circulating Soluble Target: Temporal Profiles of ‘Free’ and ‘Total’ Drug and Target

“…Recently, several versions using approximation have been proposed (9)(10)(11), including the rapidbinding approximation of TMDD model (RB-TMDD), which replaces the inestimable binding micro-constants (k on and k off ) with an equilibrium dissociation constant (K D ). The RB-TMDD model has been applied to some preclinical and clinical studies where the target is membrane-bound receptor (12) or the binding takes place interstitially (13), but its application to circulating soluble targets just started to emerge (14). In fact, the latter case may be better depicted by this model because the encounter of a drug with a target in the circulation would negate distribution of the drug to a binding site outside the vasculature.…”

Quasi-Equilibrium Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition

“…A general PK model of TMDD has been described (5) and has since been utilized to characterize the PK of several compounds in humans and animals, including: bosentan and imirestat (5), interferon-b1a (6,7), vascular endothelial growth factor (8), warfarin (9), thrombopoietin (10), and leukemia inhibitory factor (LIF) (11). This modeling approach essentially integrates the thermodynamics of drugtarget binding within the system of ordinary differential equations that describe drug disposition (see Theoretical), and drug-binding microconstants (k on and k off ) are included in the model.…”