Prediction of clearance and volume of distribution in the obese from normal weight subjects: an allometric approach.
OBJECTIVE
The principles of allometry can be applied within a given species (intra-species scaling), for example extrapolation of pharmacokinetic parameters from adults to adolescents and older children (>5 years of age). Similarly, allometric scaling may also be used to predict pharmacokinetic parameters from normal weight subjects to the obese. The objective of this investigation was to evaluate the predictive performance of several allometric methods for the prediction of drug clearance (CL) and volume of distribution (V(d)) in the obese from normal weight subjects.


METHODS
CL and V(d) values for 12 drugs for obese and normal weight subjects were obtained from the literature. Three methods (simple allometry and fixed exponents of 0.75 and 1.0) and two methods (simple allometry and a fixed exponent of 1.0) were used to predict CL and V(d), respectively, using total body weight in the obese from normal weight subjects. When data were available, ideal body weight, percentage ideal body weight and body mass index were also used for prediction purposes.


RESULTS
The results of the study indicated that CL could be predicted with accuracy in the obese from normal weight subjects using total body weight and simple allometry as well as fixed exponent of 0.75. The prediction of V(d) in the obese from normal weight subjects was less accurate than the prediction of CL in this population. For the prediction of CL and V(d) in the obese, simple allometry performed better than the fixed exponent of 0.75 or 1.0, respectively.


CONCLUSIONS
The study indicated that allometric scaling can be applied to predict CL in the obese from normal weight subjects with high accuracy. The predicted CL can then be used to select a dose to initiate a clinical trial (pharmacokinetics, safety and efficacy).
Office of Blood Review & Research (OBRR), Center for Biologic Evaluation and Research, Food and Drug Administration, Rockville, MD 20862, USA. Iftekhar.mahmood@fda.hhs.gov
Iftekhar
I
Mahmood
D000328:Adult; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008954:Models, Biological; D009765:Obesity / Q000150:complications*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D014018:Tissue Distribution
D004364:Pharmaceutical Preparations