The influence of correcting endogenous concentrations in the bioequivalence assessment of testosterone

Z.Chik, A.Johnston, A.T.Tucker , C.A.Alam. 1Clinical Pharmacology, 3Experimental Pathology, William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. 2The Ernest D. Cooke Clinical Microvascular Unit, St. Bartholomew’s Hospital, London EC1A 7BE, UK.

Circulating concentrations of endogenous compounds such as testosterone, complicate the analysis of pharmacokinetic parameters when these compounds are administered exogenously. This study examines the influence of three correction methods of accounting for endogenous concentrations on the determination of bioequivalence between two testosterone formulations

Twelve healthy males received 50 mg TDS®-Testosterone, TDS®-Placebo, and 50 mg Androgel® in a randomised placebo controlled study with a minimum of one week washout period. Three correction methods to remove the influence of endogenous testosterone from the exogenous blood concentrations data were carried out before the calculation of the AUC and Cmax. Correction 1, the mean pre-dose testosterone concentration (-0.5 and 0 h) was subtracted from each testosterone concentration after dosing; Correction 2, the endogenous data were modelled from the placebo data using a polynomial equation and subtracted from the measured treatment values; Correction 3, the concentrations on the placebo day were subtracted from the active treatment concentrations. The relative bioavailabilities between two treatments were then performed for the AUC and C max for all the corrected and uncorrected data. The product is considered to be bioequivalent if the 90% Confidence Interval (CI) value falls between 80-125%.

TDS®- Testosterone showed the higher AUC and Cmax values than TDS® - Placebo and Androgel® for uncorrected and all the corrected data 1,2, and 3. In the relative bioavailability comparison of the AUC and Cmax, TDS®- Testosterone and Androgel® was bioequivalent by using uncorrected data (Table 1). However, they were not bioequivalent when using all the corrections data ( Table 1).

Table 1 : Relative bioavailability (90% CI) for Uncorrected and all Corrections data

Different results obtained in the relative bioavailability between TDS®- Testosterone and Androgel® for uncorrected data and corrected data, suggests that correcting endogenous concentrations is important for the proper determination of bioequivalent for endogenous compound such as testosterone. Without endogenous data corrections, an incorrect conclusion about bioequivalence may result with products being declared bioequivalent when they were actually not bioequivalent or vice versa.