Population pharmacokinetic analysis of recombinant human Chorionic Gonadotrophin (Ovidrel) compared with that of urinary human Chorionic Gonadotrophin (Profasi) in women undergoing superovulation
Ho-Nguyen T.X.Q1., Girard P2.,Chabaud S2., Munafo A1.
1) Ares-Serono International S.A, Experimental Medecine, Geneva, Switzerland. 2) Clinical Pharmacology Department, Claude Bernard University, Lyon, France.
INTRODUCTION Human Chorionic Gonadotrophin is a hormonal preparation either extracted from the urine of pregnant women (u-hCG - Profasi) or obtained by recombinant technology (r-hCG - Ovidrel). It possesses predominantly luteinizing properties. The primary objective of this analysis was to characterize and compare the pharmacokinetic (PK) profile of r-hCG and u-hCG. Two double-blind, double-dummy, randomized, multicentre phases III studies were undertaken to compare the efficacy and the safety of r-hCG and u-hCG in In Vitro Fertilization and Embryo Transfer (IVF-ET) and in inducing ovulation, respectively.
METHODS Patients randomized received either a subcutaneous (SC) injection of 250 µg r-hCG and placebo, or a SC injection of 5000 IU u-hCG and placebo. The serum hCG concentrations were measured using an immunoassay.
NONMEM with FO method was used to fit the models to the data. In a first step, r-hCG and u-hCG were fitted simultaneously, in each study. Several models were compared: a one and a two compartment model with a zero and a first order absorption. Inter-individual variability of apparent central volume (V/F) and elimination rate constant (K) was described by an exponential model. Intraindividual variability included additive and proportional error. Identification of the covariates which had a predominant influence was based on the tree-based model. Those covariates (treatment, age, weight, body mass index) were introduced in the population model, one at a time. Those leading to a decrease of at least 4 points (p<0.05) in objective function (OF) were kept to build the full model. Confirmatory step involved the one at a time deletion test from the full model. Final model included only parameters leading to a difference of at least 7 points in OF (p<0.01). In a final step, r-hCG and u-hCG were fitted separately to obtain PK parameters corresponding to each drug.
RESULTS and CONCLUSION The best model consisted in a one-compartment model with first order absorption. The elimination rate K was different for r-hCG (t 1/2=30-34 h) and u-hCG (t 1/2=29-38 h), whereas the absorption rate constant was similar for the 2 drugs (t ½ Ka=7 h). The apparent volume of distribution (V/F) increased linearly with the BMI. Relationship between V/F and BMI were comparable for r-hCG and u-hCG in the Study 1, whereas found to be slightly different (statistically borderline) in the Study 2.
The overall profiles of r-hCG and u-hCG were globally comparable. However, differences in K and V/F were observed between the 2 forms and resulted in a greater post-hoc AUC for r-hCG.
This work is ongoing. Next step will consist in pooling data of the 2 studies to jointly estimate the PK profiles of r-hCG and u-hCG.