BAYESIAN-ESTIMATION OF P-AMINOHIPPURATE CLEARANCE BY A LIMITED SAMPLING STRATEGY

This study describes a methodology to calculate p- aminohippurate (PAH ) clearance (CL) and volume of distribution (V) with both the populati on parameters and one or two samples taken during the disposition and the elimination phase after a single intravenous infusion. The compute r program P-PHARM was used, and a log-normal distribution and a hetero scedastic residual error distribution were assumed. Ninety-six patient s with and without renal insufficiency were available for analysis, an d a two-compartment model was used for data modeling. Population param eters were evaluated for 70 patients (mean number of observed concentr ation per individual, 6) by a three-step approach. In step 1, the comp uter program was used td estimate the average pharmacokinetic paramete rs without taking into account the demographic and/or biological facto rs. In step 2, the relationship between the posterior individual estim ates and the covariables was investigated with multiple linear stepwis e algorithm. In step 3, the population parameters were re-estimated co nsidering the relationship with the covariables. From the regression p erformed in step 2, the following covariables were included: serum cre atinine, body surface area, and body weight. The population averages o f CL and V were 30.7 +/- 2.36 L/h and 10.6 +/- 1.29 L, respectively. T o evaluate the predictive performance of the population parameters, th e remaining 26 patients were used. The population parameters combined with one or two individual PAH plasma concentrations led to a bayesian estimation of individual CL and V. This estimation was compared with the classical procedure of parameter estimation (individual fitting fr om multiple blood samples). For CL and V, bias was not statistically d ifferent from zero and the precision of these parameters was good. Thi s procedure enables the estimation of individual pharmacokinetic param eters for PAH at minimal cost and minimal disturbance for the patient.