Interspecies scaling: predicting pharmacokinetic parameters of antiepileptic drugs in humans from animals with special emphasis on clearance.
The objective of this study was to test the interspecies-scaling approach in a series of antiepileptic drugs. Clearance, volume of distribution, and elimination half-life were scaled up from animal data obtained from literature. Four different methods were utilized to generate plots to scale up the clearance values: (i) clearance vs body weight (simple allometric equation); (ii) the product of clearance and maximum life-span potential (MLP) vs body weight (an approach recommended in literature); (iii) the two-term power equation which incorporates both body weight and brain weight suggested by Boxenbaum; and (iv) the product of clearance and brain weight vs body weight (a new approach being introduced in this study). When the predicted values for clearance were qualitatively compared with the observed values in humans, it was found that our proposed method predicted the clearance better than the other three methods. Using the simple allometric equation, the prediction of volume of distribution as a function of body weight was found to be satisfactory. The elimination half-life could not be predicted from simple allometric equations for any of the drugs studied; however, utilizing the equation CL = VK, prediction for half-life was feasible. The results of this study indicate that it is possible to predict reliably the pharmacokinetic parameters of these antiepileptic drugs in humans from animal data using an allometric approach.
Division of Pharmaceutical Evaluation I, Food & Drug Administration, Rockville, MD 20852, USA.
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I
Mahmood
J D
JD
Balian
D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D003975:Diazepam / Q000493:pharmacokinetics; D005013:Ethosuximide / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008954:Models, Biological; D013045:Species Specificity; D014635:Valproic Acid / Q000493:pharmacokinetics
D000927:Anticonvulsants; D005013:Ethosuximide; D014635:Valproic Acid; D003975:Diazepam