Improved Pharmacokinetic and Bioavailability Support of Drug Discovery Using Serial Blood Sampling in Mice

Peng, Sean; Rockafellow, Beth A.; Skedzielewski, Tina; Huebert, Norman; Hageman, William

doi:10.1002/jps.21533

Cited by 42 publications

(41 citation statements)

References 19 publications

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“…The evening before the PK study, diets of all mice were switched to the HFC control diet to allow washout of the statin (half-time of orally dosed statins #5 hours in mice) (Lau et al, 2006;Peng et al, 2009;Tiwari and Pathak, 2011;Zhu et al, 2011;Iusuf et al, 2012). Subsequently, after 2 hours of fasting, mice were dosed with a 10 mg/kg concentration of the different statins [10 ml/g body weight of drug solution; 1 mg/ml in saline finally containing 8.…”

Section: Plasma and Tissue Pharmacokinetic Experimentsmentioning

confidence: 99%

Combined Analysis of Pharmacokinetic and Efficacy Data of Preclinical Studies with Statins Markedly Improves Translation of Drug Efficacy to Human Trials

Steeg

Kleemann

Jansen

et al. 2013

J Pharmacol Exp Ther

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Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) transgenic mice regarding the cholesterol-lowering efficacy of various statins in humans by combining pharmacokinetic with efficacy data. The efficacy of five currently marketed statins (atorvastatin, simvastatin, lovastatin, pravastatin, and rosuvastatin) in hypercholesterolemic patients (low-density lipoprotein $ 160 mg/dl) was ranked based on meta-analysis of published human trials. Additionally, a preclinical combined PK efficacy data set for these five statins was established in E3L mice that were fed a high-cholesterol diet for 4 weeks, followed by 6 weeks of drug intervention in which statins were supplemented to the diet. Plasma and tissue levels of the statins were determined on administration of (radiolabeled) drugs (10 mg/kg p.o.). As expected, all statins reduced plasma cholesterol in the preclinical model, but a direct correlation between cholesterol lowering efficacy of the different statins in mice and in humans did not reach statistical significance (R 2 5 0.11, P , 0.57). It is noteworthy that, when murine data were corrected for effective liver uptake of the different statins, the correlation markedly increased (R 2 5 0.89, P , 0.05). Here we show for the first time that hepatic uptake of statins is related to their cholesterol-lowering efficacy and provide evidence that combined PK and efficacy studies can substantially improve the translational value of the E3L mouse model in the case of statin treatment. This strategy may also be applicable for other classes of drugs and other preclinical models.

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Section: Plasma and Tissue Pharmacokinetic Experimentsmentioning

confidence: 99%

Combined Analysis of Pharmacokinetic and Efficacy Data of Preclinical Studies with Statins Markedly Improves Translation of Drug Efficacy to Human Trials

Steeg

Kleemann

Jansen

et al. 2013

J Pharmacol Exp Ther

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“…The tail clip method allowed for a cross-over design without the use of anesthesia, but required the use of cannulated animals for IV dosing. A previously published saphenous bleeding technique was initially used (25) and then compared to a method published by Peng et.al (29) and optimized for application in mouse PK studies. With saphenous bleeding, bruising and puncture marks were absent in nearly all of the animals and the vein continued to be visible.…”

Section: Technical Feasibility Of Various Micro-sampling Methodsmentioning

confidence: 99%

“…Although multiple sampling techniques have been established for sampling in mice (25,(27)(28)(29); a comprehensive evaluation of the respective PK profiles with cross-over designs using DBS methods has not been reported. Tail vein sampling (tail clip and tail vein with needle hub) seems to be the most commonly used micro-sampling technique in mice (2,12,30,31) while saphenous bleeds and retroorbital bleeds have also been used (3,4,12).…”

Section: Introductionmentioning

confidence: 99%

“…The use of tail clips and tail vein with a hub needle should be avoided to reduce contamination of samples with administered dose, especially in small rodents such as mice when drug/test compounds are administered IV via the tail vein. Although saphenous vein puncture bleeding has been demonstrated to be a useful and practical method for repeated sampling from mice and other rodents (25,26,29) its implementation has been very limited as it may require further optimization to enable the conduct of cross-over studies (29). This work combines an optimized microsampling technique with dried blood spot (DBS) collection and LC-MS/MS analysis as a most efficient and practical way of performing mouse PK studies in drug discovery and development.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation and Optimization of Blood Micro-Sampling Methods: Serial Sampling in a Cross-Over Design from an Individual Mouse

et al. 2016

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-Purpose: Current practices applied to mouse pharmacokinetic (PK) studies often use large numbers of animals with sporadic or composite sampling that inadequately describe PK profiles. The purpose of this work was to evaluate and optimize blood microsampling techniques coupled with dried blood spot (DBS) and LC-MS/MS analysis to generate reliable PK data in mice. In addition, the feasibility of cross-over designs was assessed and recommendations are presented. Methods: The work describes a comprehensive evaluation of five blood microsampling techniques (tail clip, tail vein with needle hub, submandibular, retro-orbital, and saphenous bleeding) in CD-1 mice. The feasibility of blood sampling was evaluated based on animal observations, ease of bleeding, and ability to collect serial samples. Methotrexate, gemfibrozil and glipizide were used as test compounds and were dosed either orally or intravenously, followed by DBS collection and LC-MS/MS analysis to compare PK with various bleeding methods. Results: Submandibular and retro-orbital methods that required non-serial blood collections did not allow for inter-animal variability assessments and resulted in poorly described absorption and distribution kinetics. The submandibular and tail vein with needle-hub methods were the least favorable from a technical feasibility perspective. Serial bleeding was possible with cannulated animals or saphenous bleeding in non-cannulated animals. Conclusions: Of the methods that allowed serial sampling, the saphenous method when executed as described in this report, was most practical, reproducible and provided for assessment of inter-animal variability. It enabled the collection of complete exposure profiles from a single mouse and the conduct of an intravenous/oral cross-over study design. This methodology can be used routinely, it promotes the 3Rs principles by achieving reductions in the number of animals used, decreased restraints and animal stress, and improved the quality of data obtained in mouse PK studies.

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“…The study was performed according to guidelines from the Danish Animal Experiments Council, the Danish Ministry of Justice. Mice were dosed 1 mg/kg, with the exception of FVII_C (0.5 mg/kg), as a single intravenous bolus in the tail vein and blood was obtained according to a sparse sampling design as previously described, 22 including 3 blood samples per mouse and 2 or 3 mice per time point. The mice were anesthetized by isoflurane/O 2 /N 2 O for blood sampling, and 4 droplets of blood were sampled from the orbital plexus using a capillary glass tube at t ϭ 0.08, 0.25, 0.5, 1, 2, 3, 4, 5, and 7 hours after administration of FVII, FVIIa, and FXa i , and at t ϭ 0.08, 0.25, 0.5, 1, 3, 7, 17, 24, and 30 hours after administration of all other proteins investigated.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Activation peptides prolong the murine plasma half-life of human factor VII

Johansson¹,

Karpf

Hansen

et al. 2011

Blood

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Improved Pharmacokinetic and Bioavailability Support of Drug Discovery Using Serial Blood Sampling in Mice

Cited by 42 publications

References 19 publications

Combined Analysis of Pharmacokinetic and Efficacy Data of Preclinical Studies with Statins Markedly Improves Translation of Drug Efficacy to Human Trials

Combined Analysis of Pharmacokinetic and Efficacy Data of Preclinical Studies with Statins Markedly Improves Translation of Drug Efficacy to Human Trials

Evaluation and Optimization of Blood Micro-Sampling Methods: Serial Sampling in a Cross-Over Design from an Individual Mouse

Activation peptides prolong the murine plasma half-life of human factor VII

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