Pharmacokinetic and Pharmacodynamic Modeling of Exendin-4 in Type 2 Diabetic Goto-Kakizaki Rats

Gao, Wei; Jusko, William J.

doi:10.1124/jpet.110.175752

Cited by 37 publications

(46 citation statements)

References 40 publications

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“…The TMDD model uses receptor binding and receptor-mediated endocytosis as the primary mechanism of nonlinear drug disposition. We successfully captured the disposition of exendin-4 in diabetic rats using the TMDD model (Gao and Jusko, 2011). However, the PK of exendin-4 in other species has not been assessed using mechanistic modeling.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

Gao¹,

Jusko²

2012

Drug Metab Dispos

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“…3A). The conjugate showed an in vivo cleavage t 1/2 of 78 h and an elimination t 1/2 for released exenatide of 28 h, a 56-fold increase over the 0.5-h t 1/2 for bolus injection (21). Assuming a clearance t 1/2 for the PEG conjugate of 7 d in humans, applying Eq.…”

mentioning

confidence: 99%

Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

Santi

Schneider

Reid

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

177

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Conjugation to macromolecular carriers is a proven strategy for improving the pharmacokinetics of drugs, with many stable polyethylene glycol conjugates having reached the market. Stable conjugates suffer several limitations: loss of drug potency due to conjugation, confining the drug to the extracellular space, and the requirement for a circulating conjugate. Current research is directed toward overcoming such limitations through releasable conjugates in which the drug is covalently linked to the carrier through a cleavable linker. Satisfactory linkers that provide predictable cleavage rates tunable over a wide time range that are useful for both circulating and noncirculating conjugates are not yet available. We describe such conjugation linkers on the basis of a nonenzymatic β-elimination reaction with preprogrammed, highly tunable cleavage rates. A set of modular linkers is described that bears a succinimidyl carbonate group for attachment to an amine-containing drug or prodrug, an azido group for conjugation to the carrier, and a tunable modulator that controls the rate of β-eliminative cleavage. The linkers provide predictable, tunable release rates of ligands from macromolecular conjugates both in vitro and in vivo, with half-lives spanning from a range of hours to >1 y at physiological pH. A circulating PEG conjugate achieved a 56-fold half-life extension of the 39-aa peptide exenatide in rats, and a noncirculating s.c. hydrogel conjugate achieved a 150-fold extension. Using slow-cleaving linkers, the latter may provide a generic format for once-a-month dosage forms of potent drugs. The releasable linkers provide additional benefits that include lowering C max and pharmacokinetic coordination of drug combinations. metronomic chemotherapy | implant M any drugs and drug candidates are suboptimal or ineffective because of a short duration of action. For example, peptides and proteins with promising therapeutic value often have serum half-lives of only minutes to hours. One solution to this problem involves conjugation to carriers such as polyethylene glycol (PEG), the Fc portion of IgG, serum albumin, and other longlived macromolecules. The large carriers retard kidney filtration and hence increase plasma half-life of the attached drug. Much success has been realized thus far with PEG as the macromolecular carrier. PEG is nontoxic and nonimmunogenic, and the plasma half-life is a function of hydrodynamic size. Conjugation of drugs to PEG with molecular mass ∼40 kDa has been successfully used with peptides, nucleic acids, and small molecules and can afford half-lives of up to ∼7 d in humans; as of 2011, 10 PEGylated peptide-based drugs were approved by the Food and Drug Administration (FDA) and ∼40 were in clinical trials (1, 2).All of the currently marketed PEG-protein conjugates are permanently PEGylated. Attachment of large PEG moieties often reduces activity of the drug, and higher concentrations of conjugate are necessary to achieve the required biological activity. A further limitation is that permanen...

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“…Vessel cannulation in animals has been the cornerstone for performing PK experiments and is the standard practice in drug discovery as it has been shown to provide accurate and reliable results [12][13][14][15][16][17]. PK experiments involve administering the drug compound and taking blood samples in order to assess the biological effect.…”

Section: Ra-cusum Analysis For Jugular Vein Cannulationmentioning

confidence: 99%

“…In this study we evaluated the learning curve for cannulating the femoral and the external jugular vein, two of the most commonly used i.v. accesses (other including the saphenous vein and the carotid artery) [12,13,17,25].…”

Section: Ra-cusum Analysis For Jugular Vein Cannulationmentioning

confidence: 99%

“…The cannulation of these vessels was used in an animal model developed in-house in order to evaluate the pharmacokinetic properties (PK) of peptides developed as part of a drug discovery anti-obesity program. The use of animals for such PK experiments is standard practice and provides accurate and reliable results [12][13][14][15][16][17]. Optimal and timely vessel cannulation is important for this protocol; time is a critical component when performing PK experiments as there are limitations to time animals can remain under anaesthesia.…”

Section: Introductionmentioning

confidence: 99%

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Learning curve of vessel cannulation in rats using cumulative sum analysis

Christakis

Georgiou

Minnion

et al. 2015

Journal of Surgical Research

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Extensive experience in rodent surgery and training junior surgeons Cover LetterDear Ms/Mr, We would be grateful if you would consider our manuscript entitled "Learning curve of cannulation of jugular and femoral vein in rats using Cumulative Summation Analysis" for publication in The Journal of Surgical Research. Our study investigates the learning curve required for competency and proficiency at blood vessel cannulation in rodents.Vessel cannulation in rats, such as of the femoral and jugular vein, is a technically challenging procedure even for an experienced surgeon. In this study we analyse the results of 200 cannulations of the femoral and jugular vein in rats performed within one year by a single surgeon. The use of Cumulative Summation analysis allows calculating the required experience to most effectively cannulate the jugular and femoral vein, which is approximately 50 and 100 cases, respectively.These results highlight the difficulty involved in performing such micro-surgical operations in rodents. The knowledge of the average time taken to cannulate these vessels allows experiments to be optimally planned, avoiding unexpected time over-runs. Furthermore, our results bring into the spotlight the need for training and direct supervision for the inexperienced researchers, as there is an ongoing need to reduce animal use in research through minimising adverse events.To the authors' knowledge this is the first study to report the learning curve for mastering the technique of catheterisation of the femoral and jugular vein in rats. We feel it will be of interest to readers of The Journal of Surgical Research, and particularly those using rodent microsurgery. Subject category: ResearchAuthors' contributions I.C., J.C., R.S. carried out the design and coordinated the study, participated in all of the experiments and prepared the manuscript. J.M., P.G., V.C., F.P., K.M., S.B.provided assistance in the design of the study, coordinated and carried out most of the experiments and participated in manuscript preparation. T.T., F.P., K.M. and S.B.approved the final version of the manuscript. All authors have read and approved the content of the manuscript.-3 - AbstractBackground:

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Pharmacokinetic and Pharmacodynamic Modeling of Exendin-4 in Type 2 Diabetic Goto-Kakizaki Rats

Cited by 37 publications

References 40 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

Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

Learning curve of vessel cannulation in rats using cumulative sum analysis

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