Abstract
Purpose
To predict the absolute oral bioavailabilities (BAs) of drugs in humans without using pharmacokinetic data from intravenous administration in humans.
Methods
The distribution volume of the terminal phase (\({\text{Vd}}_{\beta } \)) in humans was predicted by three methods using animal pharmacokinetic data. Then, total body clearance (CLtot) was calculated by multiplying the elimination rate constant and \({\text{Vd}}_{\beta } \), and the BA was calculated as a ratio between CLtot and oral clearance. The predicted and observed values were compared for 67 drugs for which pharmacokinetic data after intravenous administration in humans were available.
Results
For \({\text{Vd}}_{\beta } \), predicted values within twice the observed value were obtained for 72.1% of drugs by both methods Ia and Ib, respectively, in which only rat pharmacokinetic data were used. The corresponding percentage was 75.0% for method II, in which pharmacokinetic data from animals other than rats were used. For BA, predicted values within 1.3 times the observed values were obtained for 66.7% and 57.4% of drugs by methods Ia and Ib, respectively, and 75.0% by method II.
Conclusions
Using the present methods, it is possible to predict BA from human oral administration data combined with animal pharmacokinetic data to a certain level without using intravenous injection data.
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Abbreviations
- β :
-
elimination rate constant in the terminal phase
- AUCiv :
-
area under the plasma concentration–time curve after intravenous administration
- AUCpo :
-
area under the plasma concentration–time curve after oral administration
- BA:
-
bioavailability
- CLpo :
-
oral clearance
- CLtot :
-
total body clearance
- f P :
-
free fraction in plasma
- f T :
-
free fraction in tissue
- Hc:
-
hematocrit value
- R B :
-
blood-to-plasma concentration ratio
- R E/I :
-
ratio of amount of the binding protein in the extracellular fluid to that in plasma
- V B :
-
volume of blood
- Vdβ :
-
distribution volume of the terminal phase
- Vdss :
-
distribution volume at steady state
- V E :
-
volume of extracellular fluid outside the plasma
- V T :
-
volume of tissue (except blood cells)
- V T/f T :
-
volume of distribution for the unbound drug
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Imawaka, H., Ito, K., Kitamura, Y. et al. Prediction of Human Bioavailability from Human Oral Administration Data and Animal Pharmacokinetic Data Without Data from Intravenous Administration of Drugs in Humans. Pharm Res 26, 1881–1889 (2009). https://doi.org/10.1007/s11095-009-9902-6
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DOI: https://doi.org/10.1007/s11095-009-9902-6