Research ArticlesPrediction of Human Pharmacokinetic Profile in Animal Scale up Based on Normalizing Time Course Profiles
Section snippets
INTRODUCTION
Predicting the pharmacokinetics of a drug in humans is very important in the process of developing new drugs for decisions on appropriate dosage and best clinical trial design. In our previous articles, we have reported new regression equations for predicting clearance (CL) and volume of distribution at steady state (Vdss) in humans,1,2 which offer better predictive performance than allometric approaches. In the present study, we aimed to develop a simple method for predicting the
THEORY AND PROCEDURE
Our method for predicting the concentration–time profile in humans is based on the assumption that concentration–time profiles are similar among species including humans, and that normalized curves derived from a variety of animal species can be superimposed. It is also assumed that all the pharmacokinetic processes are linear. The normalized curve is derived by dividing the concentration and time scales by Css (= Dose/Vdss) and MRT (mean residence time) for the corresponding curve,
RESULTS AND DISCUSSION
The pharmacokinetic parameters in animals and humans after intravenous injection for ceftizoxime, cefodizime, cefotetan, and cefmenoxime are shown in Table 1. Other independent variables such as MW and Ha for these drugs are also presented in Table 1. CL and Vdss are presented in mL/min/kg and mL/kg, respectively.
Normalized curves for animal data for ceftizoxime, cefodizime, cefotetan, and cefmenoxime are shown in Figure 1. Although the normalized curve for cefotetan for the mouse deviated
CONCLUSION
A new method for predicting concentration–time profiles in humans is presented. This method is based on the assumption that concentration–time profiles are similar among species, and therefore the normalized curves using Css and MRT from a variety of animal species can be superimposed. We confirmed that this assumption was true for the data sets used in the present study, and that the accuracy of the prediction seemed acceptable for these drugs. This method can be applied to any drug on the
REFERENCES (28)
- et al.
Prediction of human clearance from animal data and molecular structural parameters using multivariate regression analysis
J Pharm Sci
(2002) - et al.
Physiologically based pharmacokinetic (PBPK) modeling of disposition of Epiroprim in human
J Pharm Sci
(2003) - et al.
Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution
J Pharm Sci
(2002) - et al.
Prediction of human pharmacokinetics from animal data and molecular structural parameters using multivariate regression analysis: volume of distribution at steady state
J Pharm Pharmacol
(2003) - et al.
Interspecies correlation of plasma concentration, history of methotrexate (NSC-740)
Cancer Chemother Rep
(1970) Interspecies pharmacokinetic scaling and the evolutionary-comparative paradigm
Drug Metab Rev
(1984)- et al.
Interspecies pharmacokinetic scaling and the Dedrick plots
Am J Physiol
(1983) - et al.
Animal pharmacokinetics and interspecies scaling from animals to man of Lamifiban, a new platelet aggregation inhibitor
J Pharm Pharmacol
(1996) - et al.
Comparative pharmacokinetics and interspecies scaling of amphotericin B in several mammalian species
J Pharm Pharmacol
(1997) - et al.
Pharmacokinetics in applications of the artificial kidney
Chem Eng Prog Symp Ser
(1968)