Summary of pharmacokinetic prediction methods
| Method | Abbreviation in text | Data required | Underlying assumptions |
|---|---|---|---|
| A. Volume of distributions |
| Average fraction unbound in tissues | V1 | Plasma protein binding in two or more species and human Intravenous pharmacokinetics in two or more species | Average fut(preclinical species) = fut(human) Re/i is uniform across species and is the same for all binding proteins |
| Dog-human proportionality | V2 | Plasma protein binding in dog and human | fut(dog) = fut(human) |
| Intravenous pharmacokinetics in dog | |||
| Allometric scaling, excluding interspecies protein binding differences | V3a | Intravenous pharmacokinetic data in two or more species | No intrinsic differences in plasma protein or tissue binding across preclinical species and human |
| Allometric scaling, including interspecies protein binding differences | Intravenous pharmacokinetic data in two or more species | No intrinsic differences in tissue binding across preclinical species and human | |
| V3b | Plasma protein binding in two or more species and human |
| B. Clearance |
| In vitro t1/2, excluding protein binding, well-stirred model | C1a | Turnover rate in humanin vitro system | In vitro rates and activities are representative of those that occur in vivo Liver is major organ of CL CLmetabolism ≫ CLrenal + CLbiliary Oxidative microsomal metabolism ≫ other metabolism fu(incubation matrix) = unity [S] < KM No inactivation of enzyme Equilibrium not approached |
|---|---|---|---|
| In vitro t 1/2, including protein bind- | C1b | Plasma protein binding in human | |
| ing, well-stirred model | Turnover rate in human in vitro system | ||
| In vitro t 1/2, excluding protein binding, parallel tube model | C1c | Turnover rate in human in vitrosystem | |
| In vitro t 1/2, including protein binding, parallel tube model | C1d | Plasma protein binding in human Turnover rate in human in vitro system | |
| Enzyme kinetics, excluding fu, well-stirred model | C2a | Substrate saturation experiment in humanin vitro system (V max/KM) | In vitro rates and activities are representative of those that occurin vivo Liver is major organ of CL CLmetabolism ≫ CLrenal+ CIbiliary Oxidative microsomal metabolism ≫ other metabolism |
| Enzyme kinetics, including fu, well-stirred model | C2b | Substrate saturation experiment in human in vitro system (V max/KM) Plasma protein binding in human | |
| Enzyme kinetics, excluding fu, parallel tube model | C2c | Substrate saturation experiment in humanin vitro system (V max/KM) | |
| Enzyme kinetics, including fu, parallel tube model | C2d | Substrate saturation experiment in human in vitro system (V max/KM) | fu(incubation matrix) = unity |
| Plasma protein binding in human | No inactivation of enzyme | ||
| Allometric scaling, including interspecies fu and MLP differences | C3a | Plasma protein binding in two or more species and human | Mechanism of CL is similar across species Assumes no interspecies differences in intrinsic CL |
| Intravenous pharmacokinetics in two or more species | |||
| Allometric scaling, excluding interspecies fudifferences, including MLP differences | C3b | Intravenous pharmacokinetics in two or more species | |
| Allometric scaling, including interspecies fu differences, excluding MLP differences | C3c | Plasma protein binding in two or more species and human | |
| Intravenous pharmacokinetics in two or more species | |||
| Allometric scaling, excluding interspecies fu and MLP differences | C3d | Intravenous pharmacokinetics in two or more species |
| C. t 1/2 and oral bioavailability |
| Humanvs. monkey | T1 | Intravenous pharmacokinetics in monkey | Empirical approach; assumes uniform intrinsic properties between preclinical species and humans |
| Human vs. dog | T2 | Intravenous pharmacokinetics in dog | |
| Human vs. rat | T3 | Intravenous pharmacokinetics in rat | |
| Combinations of volume and CL predictions | Tv(x)c(x) | Data for particular CL and volume prediction methods | Same assumptions for individual VD and CL prediction methods |
| VDss prediction inappropriate fort 1/2 prediction if multicompartmental pharmacokinetic behavior is anticipated | |||
| Corresponding CL methods | Fc(x) | Data for particular CL methods | Same assumptions for individual CL prediction methods |
| Fraction absorbed is unity and no first-pass extraction by intestinal mucosa |