Nonclinical Safety Assessment for Biopharmaceuticals: Challenges and Strategies for Juvenile Animal Testing

Coogan, Timothy P.

doi:10.1002/9781118168226.ch3

Cited by 1 publication

(1 citation statement)

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“…Adequate design of juvenile toxicity studies in rats, for instance with respect to setting appropriate dose levels per age group, requires an understanding of age-dependent pharmacokinetics. Indeed, immaturity of drug elimination pathways in developing animals may easily result in over-or underexposure of young animals (Baldrick, 2004;Coogan, 2012), unless the particular age-dependent effects on expression and activity of enzymes and transporters and/or on renal function are taken into account. In vivo pharmacokinetic/toxicokinetic assessment at various ages prior to the actual juvenile toxicity study represents one approach to obtain insight into the required age-dependent doseexposure relationship but is both time-and animal-consuming.…”

Section: Introductionmentioning

confidence: 99%

Effect of Age on The Hepatocellularity Number for Wistar rats

Fattah

Augustijns

Annaert

2015

Drug Metabolism and Disposition

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Recently there has been a substantial increase in the number of juvenile animal toxicity studies that are conducted to support pediatric drug safety evaluation. Adequate design of juvenile toxicity studies in rats, for instance with respect to dose levels per age group, requires an understanding of age-dependent pharmacokinetics. In vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) modeling can help to anticipate age-dependent drug exposure in juvenile toxicity studies provided age-dependent profiles for animal physiology and scaling factors are available. For instance, when hepatocytes are used to predict hepatic drug clearance, the hepatocellularity (number of hepatocytes per gram liver, HPGL) is required as one of the scaling factors. Although HPGL is known for adult rats, information on the influence of age on HPGL is missing. The present work profiles the hepatocellularity number in male Wistar rats as a function of age. Using the NADPH-cytochrome P450 reductase (NCR) activity method, the mean HPGL for the adult rat (8 weeks) was 104 3 10 6 cells/gram liver (relative standard deviation 17%). This value was calculated as a ratio between NRC activities in liver homogenates and suspended hepatocytes. The HPGL values were significantly higher (p <0.001) for rat pups until 3 weeks of age compared with adults. Our results revealed that the HPGL value showed a rapid decrease after 3 weeks (end of weaning), essentially reaching adult values by 4 weeks. This age-dependent HPGL profile will be instrumental for hepatic drug clearance prediction when designing juvenile toxicity studies in Wistar rats.

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Section: Introductionmentioning

confidence: 99%