Four different parameter estimation criteria, the geometric mean functional relationship (GMFR), the maximum likelihood (ML), the perpendicular least-squares (PLS) and the non-linear weighted least squares (WLS), were used to fit a model to the observed data when both regression variables were subject to error. Performances of these criteria were evaluated by fitting the co-operative drug-protein binding Hill model on simulated data containing errors in both variables. Six types of data were simulated with known variances. Comparison of the criteria was done by evaluating the bias, the relative standard deviation (S.D.) and the root-mean-squared error (RMSE), between estimated and true parameter values. Results show that (1) for data with correlated errors, all criteria perform poorly; in particular, the GMFR and ML criteria. For data with uncorrelated errors, all criteria perform equally well with regard to the RMSE. (2) Use of GMFR and ML lead to lower values far S.D. but higher biases compared with WLS and PLS. (3) WLS performs less well when equal dispersion is applied to the two observed variables. Copyright (C) 2000 John Wiley & Sons, Ltd.

The aim was to study the ursodeoxycholic acid (UDC) effect on thr cyclosporin A (CsA) pharmacokinetics after oral administration of the microemulsion Formulation Neoral(R) (CsA-ME) in liver transplant recipients, and test the potential protective effect of this bile acid on liver and renal CsA-ME-induced toxicity. At entry into the study, 12 patients who underwent orthotopic liver transplantation received CsA-ME. for at least 6 months. They then received a cotreatment CsA-ME plus UDC (13.8 mg.kg (1).day(-1)) for three months. Blood concentrations of CsA were measured using a monoclonal antibody specific For the parent compound. The kinetic data were analysed by a mathematical model incorporating a time dependent rate coefficient for CsA intestinal absorption, before and after UDC treatment. Changes in serum markers of hepatic and renal injury were assessed. Individual serum bile acids were determined by chromatography. Serum levels of UDC increased from 3 to about 45 % of total serum bile acids after UDC treatment. The estimated model parameters indicate that UDC administration modulates CsA intestinal absorption. In the nine non-cholestatic patients, UDC reduced the absorption late and the bioavailability of CsA without modifying the elimination rate constant of CsA and the CsA pre-drug levels. In contrast, in the three cholestatic patients, the bioavailability tended to be higher and the absorption rate faster when CsA was combined with UDC. UDC significantly decreased elevated gamma -glutamyl transferase and creatinine serum levels and induced some clinical improvements such as disappearance of headaches in four patients. In conclusion, a 3-month UDC treatment modifies CsA intestinal absorption without affecting CsA elimination rate constant. On the other hand, UDC supplementation appears to improve CsA tolerability. (C) 2000 Editions scientifiques et medicales Elsevier SAS.