Interspecies Scaling of Interferon Disposition and Comparison of Allometric Scaling with Concentration-Time Transformations

Lavé, Thierry; Levet-Trafit, Bernard; Schmitt‐Hoffmann, Anne; Morgenroth, Brita; Richter, Wolfgang; Chou, Ruby C.

doi:10.1002/jps.2600841106

Cited by 35 publications

(17 citation statements)

References 21 publications

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“…The volume of distribution (V C ) and the rate constant of linear elimination (k el ) were scaled to body weight using allometric exponents of 1 and −0.25. Doses are IFN-β1a 4,867 pmole/kg in rats (▼; dashed line ) (39), IFN-α2a 947 pmole/kg in rats (■, dash-dot-dot line ) (42), IFN-β1a 578 pmole/kg in mice (●; solid line ) (39), and IFN-β1a 71 pmole/kg in mice (○; dotted line ) (38). …”

Section: Figmentioning

confidence: 99%

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

et al. 2010

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Purpose To develop an integrated mechanism-based modeling approach for the interspecies scaling of pharmacokinetic (PK) and pharmacodynamic (PD) properties of type I interferons (IFNs) that exhibit target-mediated drug disposition (TMDD). Methods PK and PD profiles of human IFN-β1a, IFN-β1b, and IFN-α2a in humans, monkeys, rats, and mice from nine studies were extracted from the literature by digitization. Concentration-time profiles from different species were fitted simultaneously using various allometric relationships to scale model-specific parameters. Results PK/PD profiles of IFN-β1a in humans and monkeys were successfully characterized by utilizing the same rate constant parameters and scaling the volume of the central compartment to body weight using an allometric exponent of 1. Concentration and effect profiles of other IFNs were also well described by changing only the affinity of the drug to its receptor. PK profiles in rodents were simulated using an allometric exponent of −0.25 for the first-order elimination rate constant, and no receptor-binding was included given the lack of cross-reactivity. Conclusions An integrated TMDD PK/PD model was successfully combined with classic allometric scaling techniques and showed good predictive performance. Several parameters obtained from one IFN can be effectively shared to predict the kinetic behavior of other IFN subtypes.

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Section: Figmentioning

confidence: 99%

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

et al. 2010

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“…As seen for small molecules, successful applications for renally eliminated macromolecules have been shown, including digoxin-specific Fab (Grene- Lerouge et al, 1996), interferon-␣ (Lave et al, 1995), Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (Kelley et al, 2001), and recombinant CD4 (Mordenti et al, 1991). The disposition of rHuEPO has been assessed in context of ablation of kidneys (Emmanouel et al, 1984;Fu et al, 1988;Yoon et al, 1997), liver (Sytkowski, 1980;Widness et al, 1996), and bone marrow (Piroso et al, 1991;Chapel et al, 2001) in various animals.…”

Section: Pkmentioning

confidence: 99%

Interspecies Comparisons of Pharmacokinetics and Pharmacodynamics of Recombinant Human Erythropoietin

Woo¹,

Jusko²

2007

Drug Metab Dispos

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ABSTRACT:Erythropoietin (EPO) has a highly conserved structure among mammals, and thus recombinant human EPO (rHuEPO) has biological activity in various species. This study explores the interspecies relationships of the pharmacokinetics (PK) and pharmacodynamics (PD) of rHuEPO. The PK parameters such as clearance (CL) and volume of distribution (V ss ) after i.v. doses of rHuEPO were obtained in several species via noncompartmental analysis and were assessed using the traditional allometric approach. c. bioavailability increased with dose in monkeys and humans but appeared to be dose-independent in rats. A correlation between S max or SC 50 and body weight was not obvious. However, RBC lifespans obeyed allometric principles. Size dependence was found for PK and lifespan parameters, whereas pharmacologic parameters were independent of body weight.Recombinant human erythropoietin (rHuEPO) has been widely used clinically for treatment of anemia associated with chronic renal failure and chemotherapy. Erythropoietin (EPO) is the primary hormone of erythropoiesis and mainly synthesized in the kidney in response to hypoxia. On binding to its receptor on progenitor cells in the bone marrow, EPO stimulates proliferation and differentiation of erythroid cells, leading to an increase in reticulocytes followed by increases in red blood cells (RBCs) and hemoglobin (Hb) in the blood.EPO is a glycosylated protein with molecular mass of 30.4 kDa. Amino acid sequences in the coding region of mature EPO protein show a high degree of homology among mammals. The human EPO sequence is 91% homologous to monkey EPO, 85% to cat and dog EPO, and 80 to 82% to sheep, pig, mouse, and rat EPO (Wen et al

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“…Rats treated with IntronA received over 8 days a single daily subcutaneous dose of 4MIU kg −1 rhIFN-a. Since ViraferonPeg is usually administered once a week in humans (Baker 2003) and since pegylated rhIFN-a clearance is greater in rats than in humans (Lave et al 1995), rats receiving pegylated rhIFN-a were subcutaneously treated three times a week (Days 1, 4 and 7) with a 60 mg kg −1 dose, which was equivalent to 4 MIU kg −1 of non-pegylated rhIFN-a (Schering Corporation 2003). The interferon doses were formerly defined in reference to the toxicity of rhIFN-a in rats (LD50 is >24 × 10 8 IU kg −1 ) (Ben Reguiga et al 2005) and to the usual dose given for cancer therapy in humans (an 18 MIU/dose for a man with 1.8 m 2 body surface area corresponds to a 2.3 MIU kg −1 dose in a rat; FDA Oncology Tools dose calculator; http://www.fda.gov/cder/cancer/index.htm).…”

Section: Animal Pre-treatmentmentioning

confidence: 99%

Bioavailability and tissular distribution of docetaxel, a P-glycoprotein substrate, are modified by interferon-α in rats

Reguiga

Bonhomme-Faivre

Farinotti

2007

Journal of Pharmacy and Pharmacology

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Interferon-alpha (IFN-alpha) inhibits intestinal P-glycoprotein (P-gp) expression in rats. In the present study, the effects of repeated pre-treatment with recombinant human INF-alpha (rhIFN-alpha) on oral and intravenous pharmacokinetics of a P-gp substrate, docetaxel (DTX; Taxotere) were investigated in a rat model. The bioavailability and distribution in different organs were also studied. Sprague-Dawley rats were subcutaneously pre-treated with either rhIFN-alpha for 8 days (4MIU kg(-1), once daily) or with pegylated-IFN-alpha (ViraferonPeg; 60 microg kg(-1), Days 1, 4 and 7). The rats were then distributed into sub-groups (n = 5-6) according to the pre-treatment type, and received one dose of [(14)C]DTX (20 mgkg(-1)) either orally or intravenously. Pharmacokinetics studies were then performed over 240 min, at the end of which tissues (intestine, liver, kidneys, lung, heart and brain) were immediately removed for radioactivity quantitation. Non-pegylated and pegylated IFN-alpha both increased DTX oral bioavailability parameters: C(max) (17.0+/-4.0 microg L(-1) (P < 0.02) and 18+/-5.5 microg L(-1) (P < 0.05), respectively, vs 7.4+/-2.5 microg L(-1) for the control) and AUC (0.036+/-0.010 microg h mL(-1) (P < 0.01) and 0.033+/-0.009 microg h mL(-1) (P < 0.01), respectively, versus 0.012+/-0.004 microg h mL(-1) for the control). IFN-alpha also delayed DTX absorption from 60 min in controls to about 95 min and 80 min in non-pegylated and pegylated treated animals, respectively. However, IFN-alpha did not affect intravenous DTX pharmacokinetics and it had a limited effect on tissue distribution at 240 min. [(14)C]DTX was decreased in intestine and enhanced in brain in both pre-treated groups. rhIFN-alpha modified the P-gp-dependent pharmacokinetics of DTX, limited its intestinal efflux and markedly enhanced its oral bioavailability.

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Interspecies Scaling of Interferon Disposition and Comparison of Allometric Scaling with Concentration-Time Transformations

Cited by 35 publications

References 21 publications

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

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

Interspecies Comparisons of Pharmacokinetics and Pharmacodynamics of Recombinant Human Erythropoietin

Bioavailability and tissular distribution of docetaxel, a P-glycoprotein substrate, are modified by interferon-α in rats

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