Interspecies Scaling of Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Type I Interferons

Kagan, Leonid; Abraham, Anson K.; Harrold, John M.; Mager, Donald E.

doi:10.1007/s11095-010-0098-6

Cited by 41 publications

(42 citation statements)

References 39 publications

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“…The allometric exponents for CL c and k off are close to 0.75, and that for V c is close to 1, similar to typical theoretical values. As was observed for type I interferon PK (Kagan et al, 2010), other PK parameters did not show a meaningful trend with body weight.…”

Section: Discussionmentioning

confidence: 48%

Target-Mediated Pharmacokinetic and Pharmacodynamic Model of Exendin-4 in Rats, Monkeys, and Humans

Gao¹,

Jusko²

2012

Drug Metab Dispos

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ABSTRACT:A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model was developed for exendin-4 to account for receptor-mediated endocytosis via glucagon-like peptide 1 receptor (GLP-1R) as the primary mechanism for its nonlinear disposition. Time profiles of exendin-4 concentrations after intravenous, subcutaneous, and continuous intravenous infusion doses in rats, intravenous and subcutaneous doses in monkeys, and intravenous infusion and subcutaneous doses in humans were examined. Mean data for glucose and insulin after glucose challenges during exendin-4 treatment in healthy rats were analyzed. The PK model components included receptor binding, subsequent internalization and degradation, nonspecific tissue distribution, and linear first-order elimination from plasma. The absorption rate constant (k a ) decreased with increasing doses in all three species. The clearance from the central compartment (CL c ) (rats, 3.62 ml/min; monkeys, 2.39 ml ⅐ min ؊1 ⅐ kg ؊1 ; humans, 1.48 ml ⅐ min ؊1 ⅐ kg ؊1) was similar to reported renal clearances. Selected PK parameters (CL c , V c , and k off ) correlated allometrically with body weight. The equilibrium dissociation constant (K D ) was within the reported range in rats (0.74 nM), whereas the value in monkeys (0.12 pM) was much lower than that in humans (1.38 nM). The effects of exendin-4 on the glucose-insulin system were described by a feedback model with a biphasic effect equation driven by free exendin-4 concentrations. Our generalized nonlinear PK/PD model for exendin-4 taking into account of drug binding to GLP-1R well described PK profiles after various routes of administration over a large range of doses in three species along with PD responses in healthy rats. The present model closely reflects underlying mechanisms of disposition and dynamics of exendin-4.

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Section: Discussionmentioning

confidence: 48%

Target-Mediated Pharmacokinetic and Pharmacodynamic Model of Exendin-4 in Rats, Monkeys, and Humans

Gao¹,

Jusko²

2012

Drug Metab Dispos

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“…The degradation of mAbs is an intracellular process (within the endosomal space), and so the clearance of the drug through this pathway may be species independent and proportional to body size. A similar approach was applied for scaling the internalization rate constant (a cellular process) for interferons and exenatide (9,11). This hypothesis is further supported by the independent fitting of the model to the mouse data (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The bioavailability of mAbs in humans is often overestimated based on non-human primate data (1), and examples of scaling absorption kinetics between species are scarce (9,10). Nonlinearities frequently observed in systemic pharmacokinetics and absorption of therapeutic proteins may further complicate data analysis and require the application of more mechanistic models (11,12). …”

Section: Introductionmentioning

confidence: 99%

Interspecies Pharmacokinetic Modeling of Subcutaneous Absorption of Rituximab in Mice and Rats

2014

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Purpose To investigate the effect of dose level and anatomical site of injection on the pharmacokinetics of rituximab in mice, and to evaluate the utility of a pharmacokinetic model for describing interspecies differences in subcutaneous absorption between mice and rats. Methods Rituximab serum concentrations were measured following intravenous and subcutaneous administration at the back and abdomen of mice. Several approaches were compared for scaling model parameters from estimated values in rats. Results The bioavailability of rituximab following subcutaneous injection was inversely related to the dose level and was dependent on the site of injection in mice. The overall rate of absorption was faster in mice as compared to rats. Subcutaneous absorption profiles were well described using the proposed structural model, in which the total receptor concentration, the affinity of rituximab to the receptor, and the degradation rate constant were assumed to be species independent. Conclusions Subcutaneous absorption processes show similar trends in rats and mice, although the magnitude differs between species. A mathematical model that combines the absorption of free and bound antibody with presystemic degradation successfully captured rituximab pharmacokinetics in both species, and approaches for sharing and scaling parameters between species were identified.

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“…Several outliers (infliximab, IFNβ and EGFr3) with relatively high prediction errors (6- or 7-fold) were, however, observed in our analysis of macro-molecules (Figure 3), which may be the result of species-specific differences in binding activity and non-linear pharmacokinetics. While human IFNs bind to receptors in monkey, they lack binding activity in rodents (Kagan et al, 2010). This may help to explain why the prediction error of IFNβ was high when mouse or rat was used in single species scaling.…”

Section: Discussionmentioning

confidence: 99%

Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs

2011

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Human clearance prediction for small- and macro-molecule drugs was evaluated and compared using various scaling methods and statistical analysis.Human clearance is generally well predicted using single or multiple species simple allometry for macro- and small-molecule drugs excreted renally.The prediction error is higher for hepatically eliminated small-molecules using single or multiple species simple allometry scaling, and it appears that the prediction error is mainly associated with drugs with low hepatic extraction ratio (Eh). The error in human clearance prediction for hepatically eliminated small-molecules was reduced using scaling methods with a correction of maximum life span (MLP) or brain weight (BRW).Human clearance of both small- and macro-molecule drugs is well predicted using the monkey liver blood flow method. Predictions using liver blood flow from other species did not work as well, especially for the small-molecule drugs.

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Interspecies Scaling of Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Type I Interferons

Cited by 41 publications

References 39 publications

Target-Mediated Pharmacokinetic and Pharmacodynamic Model of Exendin-4 in Rats, Monkeys, and Humans

Target-Mediated Pharmacokinetic and Pharmacodynamic Model of Exendin-4 in Rats, Monkeys, and Humans

Interspecies Pharmacokinetic Modeling of Subcutaneous Absorption of Rituximab in Mice and Rats

Interspecies scaling and prediction of human clearance: comparison of small- and macro-molecule drugs

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