A new extrapolation method from animals to man: Application to a metabolized compound, mofarotene

Lavé, Thierry; Schmitt‐Hoffmann, Anne; Coassolo, Philippe; Vallès, B.; Ubeaud, G.; Ba, Burrows; Brandt, Roger D.; Chou, Ruby C.

doi:10.1016/0024-3205(95)00234-w

Cited by 34 publications

(16 citation statements)

References 7 publications

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“…Despite concerns related to species differences, several correction factors such as maximum life span potential and brain weight have been proposed for the projection of human clearance (47). For compounds eliminated through metabolism, metabolic turnover from in vitro liver microsomes or hepatocyte incubations has been used to improve human clearance projections (48). However, there is evidence that wholesale application of these correction factors has not substantially improved the accuracy of such projections (49).…”

Section: Discussionmentioning

confidence: 98%

Projection of Exposure and Efficacious Dose Prior to First-in-Human Studies: How Successful Have We Been?

Huang

Zheng²,

Yang

et al. 2007

Pharm Res

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Section: Discussionmentioning

confidence: 98%

Projection of Exposure and Efficacious Dose Prior to First-in-Human Studies: How Successful Have We Been?

Huang

Zheng²,

Yang

et al. 2007

Pharm Res

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“…Until recently, PK prediction has been predominantly descriptive, using empirical methods. Although in some cases these methods give good predictions, their physiological basis is low and inaccurate results can be obtained, in particular when there are large interspecies differences in metabolic clearance (Lave et al, 1995;Zuegge et al, 2001;Shiran et al, 2006). To improve on these predictive approaches, it is necessary to explore more mechanistic methods, such as physiologically based pharmacokinetic (PBPK) models (Theil et al, 2003).…”

mentioning

confidence: 99%

The Prediction of Drug Metabolism, Tissue Distribution, and Bioavailability of 50 Structurally Diverse Compounds in Rat Using Mechanism-Based Absorption, Distribution, and Metabolism Prediction Tools

Buck

Sinha²,

Fenu³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The aim of this study was to assess a physiologically based modeling approach for predicting drug metabolism, tissue distribution, and bioavailability in rat for a structurally diverse set of neutral and moderate-to-strong basic compounds (n ‫؍‬ 50). Hepatic blood clearance (CL h ) was projected using microsomal data and shown to be well predicted, irrespective of the type of hepatic extraction model (80% within 2-fold). Best predictions of CL h were obtained disregarding both plasma and microsomal protein binding, whereas strong bias was seen using either blood binding only or both plasma and microsomal protein binding. Two mechanistic tissue composition-based equations were evaluated for predicting volume of distribution (V dss ) and tissue-to-plasma partitioning (P tp ). A first approach, which accounted for ionic interactions with acidic phospholipids, resulted in accurate predictions of V dss (80% within 2-fold). In contrast, a second approach, which disregarded ionic interactions, was a poor predictor of V dss (60% within 2-fold). The first approach also yielded accurate predictions of P tp in muscle, heart, and kidney (80% within 3-fold), whereas in lung, liver, and brain, predictions ranged from 47% to 62% within 3-fold. Using the second approach, P tp prediction accuracy in muscle, heart, and kidney was on average 70% within 3-fold, and ranged from 24% to 54% in all other tissues. Combining all methods for predicting V dss and CL h resulted in accurate predictions of the in vivo half-life (70% within 2-fold). Oral bioavailability was well predicted using CL h data and Gastroplus Software (80% within 2-fold). These results illustrate that physiologically based prediction tools can provide accurate predictions of rat pharmacokinetics.Obtaining rapid information regarding the pharmacokinetics (PK) of new drug candidates can be a bottleneck in early drug discovery. Considerable resources are required to assess the PK properties of potential drug candidates in vivo in animals. To optimize the use of such in vivo testing, there has been a growing interest in predicting the PK behavior of drug candidates as early as possible (Norris et al., 2000;van de Waterbeemd and Gifford, 2003). If sufficiently reliable, such simulations could also help to select the best candidates for development and to reject those with a low probability of success.The characterization of a drug's PK requires elucidation of each of the coincident processes of absorption, distribution, metabolism, and elimination (ADME). A large number of methodologies have been established for this purpose, including empirical and physiologically based methods (Boxenbaum and Ronfeld, 1983;Theil et al., 2003). Until recently, PK prediction has been predominantly descriptive, using empirical methods. Although in some cases these methods give good predictions, their physiological basis is low and inaccurate results can be obtained, in particular when there are large interspecies differences in metabolic clearance (Lave et al., 1995;Zuegge et al., ...

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“…We are currently using these procedures in our laboratory, to predict human pharmacokinetics of newly developed compounds. 34 The results of these more recent studies, which are all performed in a single unit, will be reported at a later date. Initial indications, however, are that they will confirm the conclusion that concentration-time transformations make more adequate use of the data available in the different species of laboratory animals, to give better predictions of the pharmacokinetic parameters in man.…”

Section: Discussionmentioning

confidence: 99%

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

Lavé

Levet-Trafit

Schmitt‐Hoffmann

et al. 1995

Journal of Pharmaceutical Sciences

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A new extrapolation method from animals to man: Application to a metabolized compound, mofarotene

Cited by 34 publications

References 7 publications

Projection of Exposure and Efficacious Dose Prior to First-in-Human Studies: How Successful Have We Been?

Projection of Exposure and Efficacious Dose Prior to First-in-Human Studies: How Successful Have We Been?

The Prediction of Drug Metabolism, Tissue Distribution, and Bioavailability of 50 Structurally Diverse Compounds in Rat Using Mechanism-Based Absorption, Distribution, and Metabolism Prediction Tools

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

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