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Table 5 References on translational success in pharmacokinetics

From: Animal to human translation: a systematic scoping review of reported concordance rates

Study ID

Field of research

Summary of findings

Akabane_2010A

Absolute bioavailability

Bioavailability in cynomolgus monkeys is unsuitable for predicting PK in humans

Bachmann_1989

Clearance

Predicted values are in the same order of magnitude as actual values

Bachmann_1996A

Volume of distribution

Human volume of distribution and half-life values can be predicted from those in rats

Boxenbaum_1982A

Clearance

It is not possible to reasonably predict human pharmacokinetic parameters from knowledge of these parameters in dogs

Caldwell_2004A

Clearance

There is a reasonable correlation between human and rat clearance and half-life; and a good correlation for volume of distribution, but only 52–65% of drugs show < twofold error. Go/no go decisions based on only rat data should be avoided

Campbell_1994A

Clearance

Predictive accuracy for clearance from rat, dog and monkey is acceptable. The dog is a poorer predictor of clearance than the rat

Cao_2006A

Oral bioavailability

Oral bioavailability does not correlate between rats and humans; R2 = 0.29 while intestinal permeability correlates better; R2 = 0.70

Cheng_2008

Oral absorption

Human intestinal absorption cannot be precisely predicted by a single screening assay

Chiou_1998A

Oral bioavailability

Oral bioavailability correlates between rats and humans, and to some extent between dogs and humans

Chiou_2000a

Oral absorption

Similar gastrointestinal absorption may be obtained when doses in humans (/kg body weight) are 5–7 times lower than in rats

Chiou_2000bA

Oral absorption

R2 = 0.51–0.90 for oral absorption between dogs and humans; plasma level peak times seem to be shorter for dogs. R2 = 0.95 for oral absorption between rats and humans.

Chiou_2002A

Oral absorption

Oral absorption correlates well between monkeys and humans: R2 = 0.97; bioavailability correlates to some extent between monkeys and humans: R2 = 0.50; clearance correlates between monkeys and humans: R2 = 0.82; time to peak concentration was generally similar in humans and monkeys

DeBuck_2007A

Volume of distribution

Predictions of plasma concentrations after oral dosing are reasonable. Prediction of volume of distribution improves when accounting for interspecies differences in plasma protein binding. 18 out of 19 drugs had a predicted half-life within twofold of the actual observed half-life

Dong_2011A

Volume of distribution

For Monoclonal antibodies with non-linear kinetics, prediction is poor, with up to 6.3-fold differences

Evans_2006

Clearance, distribution volume and residence time

Percentages of correct predictions for clearance, distribution volume and residence time for rat, dog and monkey varied from 29 to 91%, and the average margin of error from 44 to 159%. The authors note that the outcomes are different from similar analyses of other compound datasets

Fagerholm_1996

Jejunal permeability

For passively absorbed compounds (n = 8), the correlation is high; R2 = 1.0. For passively absorbed compounds, rat permeability estimates can be used to predict human oral absorption

Fagerholm_2007a

Fraction excreted unchanged

Out of 25 compounds, 11 had a fraction of 0 excreted unchanged in both humans and rats. For 9 out of 14 compounds with renal excretion in rats and humans the major route of elimination differed between species. Findings for monkey–human comparisons were roughly comparable

Fagerholm_2007b

Unbound fraction in plasma

The fraction unbound in plasma correlates between rats and humans; R2 = 0.67. Different prediction methods show different accuracies

Goteti_2010A

Clearance

Two-species scaling can be useful, but the prediction of clearance from ≥ 3 species is more accurate

Grime_2013A

Clearance

For 19 out of 22 drugs, rat unbound biliary clearance exceeded human clearance by factors ranging from 9- to 2500-fold. Human–dog differences in biliary clearance were less dramatic than human-rat differences

He_1998A

Oral bioavailability

In human and rat there is generally a good correlation for oral bioavailability, in human and dog there is no apparent correlation.

Hosea_2009A

Clearance

Single species scaling is as accurate or more accurate than multiple-species allometry

Ito_2005A

Intrinsic clearance

Human clearance is better predicted by modelling based on in vitro microsomal data than on animal data

Jolivette_2005A

Clearance, volume of distribution

Molecular properties may be used to improve extrapolation from animal to human clearance

Jones_2012A

Clearance, mean residence time

Prediction was within twofold for 5 out of 7 compounds

Jones_2016C

Intestinal availability

There is little evidence that one animal species is sufficiently predictive of human first-pass metabolism to be used as a stand-alone model

Kalvass_2007A

In vivo potency (EC50), clearance

In vivo mouse brain half-lives are almost identical to human half-lives. In vivo preclinical to clinical extrapolations are superior to extrapolations from in vitro tests

Lave_1999

Clearance

Human clearance is most accurately predicted from a combination of in vivo animal and in vitro animal and human data

Lave_2002

Clearance

Predictions based only on in vitro data are at least as accurate as those based on multiple species data

Lennernas_2007

Jejunal permeability

A rat model can be used to predict oral drug absorption, but not drug metabolism or oral bioavailability

Ling_2009

Clearance

Human clearance might be accurately predicted from monkey data

Mahmood_1996a

Clearance

Human clearance can be estimated from animal data, but caution and scientific judgement are needed for interpretation

Mahmood_1996bA

Clearance, volume of distribution

A new approach incorporating brain weight in the model improves prediction of clearance

Mahmood_1996cA

Clearance, volume of distribution

Three or more species are needed for reliable prediction of clearance, while volume of distribution is predicted equally well using data from two species or more

Mahmood_1998a

Clearance

Mean residence time can be predicted reasonably well for man and can be used for prediction of half-life

Mahmood_1998bA

Clearance, volume of distribution

Caution should be employed when interpreting clearance predictions for renally excreted drugs. Predicted volumes (error − 65.6% to 139.4%) and half-lives (error − 41.8% to 100%) were comparable with observed values in man.

Mahmood_1999

Selection of 1st in human dose

The half-life and bodyweight correlate poorly; body weight is not useful as a predictor

Mahmood_2000a

Bioavailability

All tested approaches predicting human bioavailability from animal data are inaccurate

Mahmood_2000b

Protein binding

Unbound human clearance cannot be predicted any better than total human clearance from animal data

Mahmood_2001

Maximum tolerated dose

Maximum tolerated dose can be predicted with reasonable accuracy using interspecies scaling

Mahmood_2003

Selection of 1st in human dose

Animal PK data from a dose not producing adverse events can be used to estimate a suitable human starting dose

Mahmood_2004

Clearance

More than two species are needed for reliable clearance predictions of protein drugs

Mahmood_2006

Clearance

There is no single method for predicting human clearance from animal data for all classes of drugs

Mahmood_2009

Clearance

Predictions based on at least 3 animal species remain more accurate than one or two-species methods

Mahmood_2012

Clearance, volume of distribution

The human clearance of drugs that are excreted in the bile can be predicted with reasonable accuracy from animal data. The volume of distribution does not appear to be affected by biliary excretion

Mahmood_2013

Concentration–time profiles

Human concentration–time profiles of therapeutic proteins can be predicted reasonably accurate from animal data

Mahmood_2013

Clearance, volume of distribution

Concentration–time profiles are accurately predicted for most time points

Mahmood_2016

Clearance, volume of distribution

Human plasma time–concentration profiles, oral clearance and volume of distribution can be predicted with reasonable accuracy

McGinnity_2007

Clinical dose, maximum concentration & volume of distribution

There is a reasonable to good correlation between projected and clinical human dose, observed and predicted maximum concentration for a given human dose and predicted and observed human volume of distribution

Musther_2014

Oral bioavailability

Bioavailability in animals is not quantitatively predictive of bioavailability in humans

Nagilla_2004

Clearance

Prospective allometric scaling is a suboptimal technique for estimating human clearance data from in vivo preclinical data

Naritomi_2001

Clearance

Animal data improve predictions of human clearance from in vitro liver microsomes

Obach_1997

Volume of distribution, clearance

Methods for accurate prediction of human PKPD based on animal data do not currently exist, but many methods result in adequate predictions

Paine_2011

Clearance

The most accurate predictions of human renal clearance are obtained from a direct correlation with dog renal clearance. Adding data from rats decreases predictability

Pogessi_2004

Volume of distribution, clearance

In most cases, animal-based predictions are within two or threefold of those observed in humans

Rocchetti_2007

Active dose

Therapeutically active concentrations of anticancer drugs can be estimated from preclinical studies

Sanoh_2012

Clearance

PXB chimeric mice can be used for at least semi-quantitative prediction of human clearance and half life

Sanoh_2014

Metabolism

Human metabolites were sufficiently predicted from the animal data for 10 out of 16 compounds; predictions were insufficient for 6 out of 16 compounds

Sawada_1985A

Clearance, volume of distribution

Predictions for human clearance, volume of distribution and half-life from rat data were successful for most drugs, with marked exceptions

Sawada_1985B

Volume of distribution

Prediction of human volume of distribution based on animal plasma unbound fraction was successful for most drugs

Schneider_1999

Clearance

Dog and rat in vivo hepatic drug clearance data appear unrelated with human data

Sietsema_1989

Oral bioavailability

Absolute bioavailability does not correlate well between species

Takahashi_2009

Bioavailability

The bioavailability in cynomolgus monkeys was low compared to that in humans for most drugs tested

Tang_2005

Clearance

A new mathematical model based on unbound fractions can improve prediction of human clearance from animal data

Tang_2006

Clearance

There is no strong evidence that human systemic clearance is more predictable from animal data than human oral clearance

Wajima_2002

Clearance

Multiple linear regression of animal data generally predicts human clearance better than allometric methods

Wajima_2003

Oral clearance

The partial least square method based on animal data generally predicts human oral clearance better than allometric approaches

Walton_2004

Clearance

Average differences in the internal doses between humans and animals were 1.6 for dogs, 3.3 for rabbits, 5.2 for rats and 13.0 for mice

Wang_2010

Clearance

Human clearance can generally be predicted well from animal data with simple allometric scaling

Ward_2004a

Clearance

Generating data in multiple non-human species does not always result in improved prediction

Ward_2004b

Volume of distribution

The monkey provides the most accurate PKPD predictions for humans. The allometric exponent cannot be used as a reliable marker of predictive success

Ward_2005

Clearance

The rat is not as accurate a predictor as the monkey, but still affords reasonable human predictivity

Ward_2005

Oral systemic exposure

Liver-corrected oral exposure was within twofold of human for 30% of compounds for rats, and for 48% for dogs. The monkey was the preclinical species most similar to humans

Ward_2008

Clearance

Reasonable predictive accuracy of pharmacokinetic parameters in humans can be achieved with African green monkeys

Ward_2009

Bioavailability

The African green monkey provides similar predictivity for human oral exposure as other monkeys

Whiteside_2010

Maximum concentration

Rat models for pain predict effective exposure levels in humans. Effective plasma concentrations also correspond.

Wong_2004

Clearance

The chimpanzee serves as a valuable surrogate model for human pharmacokinetics