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Testosterone, an endogenous hormone is the most important androgen secreted into the blood by the Leydig cells in the testes. In women, testosterone also is probably the prin- cipal androgen and is synthesized both in the corpus luteum and the adrenal cortex by simi- lar pathways [Snyder 2001]. Testosterone de- ficiency in men (hypogonadal) is always as- sociated with incomplete development of male sex characteristics. At this stage, testos- terone replacement therapy may be indicated. There are a few treatments currently available to increase the amount of testosterone in the systemic circulation such as oral and sub- lingual preparations [Johnsen et al. 1974, Stuenkel et al. 1991], transdermal patches [Dobs et al. 1999, Korenman et al. 1987], sub- cutaneous implants [Handelsmam et al. 1990] and also the gel applications [Jockenhovel 2003, Swerdloff et al. 2003]. However, the fact that ingestion of testosterone is not an ef- fective way to replace testosterone [Snyder 2001] due to first pass metabolism, topical ap- plications of testosterone containing gels and patches avoid the hepatic catabolism and are among the more successful attempts to de- liver testosterone systemically.
Correction of endogenous concentrations of testosterone 263
In the evaluation of new drug prepara- tions, a bioequivalence (BE) study in healthy volunteers normally has to be conducted in order to show that the new preparation is as effective as current preparations. Guidelines for the determination of bioequivalence of pharmaceutically active formulations are fully documented by Food and Drug Admin- istration (FDA) in the USA [US FDA 2006] and by the Committee for Proprietary Medici- nal Products (CPMP) for the European Union [EMEA 2006]. Bioequivalence studies com- pare the rate and extent of absorption for a new treatment against that of the reference product using the parameters of maximum se- rum concentration (Cmax) and area under the curve (AUC). For exogenously administered endogenous compounds, like testosterone, the comparison needs to allow for the normal circulating concentrations of the compound. The calculations of AUC and Cmax are normally performed by the measurement of blood concentrations time profiles from pre- dose (0 h) with zero value of drug concentra- tions up to several hours post-dose with the concentrations of drug at the last measuring point approaching zero. However, the circu- lating concentrations of testosterone, compli- cate the analysis of pharmacokinetic parame- ters when this compound is administered exogenously. Therefore, correction of the data to remove the influence of endogenous testosterone is necessary to obtain the con- centration of testosterone that is attributable to the exogenous source. Except levothyroxine sodium [US FDA 2006] and potassium chloride [US FDA 2006], the current BE guidelines offer no guidance on the correction for the endoge- nous concentrations. In this study, we have demonstrated four approaches to the correc- tion for serum concentration data for the pres- ence of endogenous concentrations and docu- mented how these methods influenced the apparent bioequivalence of testosterone in healthy males.
This was a single-dose, randomized, three- way crossover study (with 3 treatments, 3 pe-
riods and 6 sequences) with a minimum of 1 week washout period between each treat- ment. Twelve healthy males successfully completed the study. The three treatments were TDS®-testosterone 50 mg/ml (metered pump spray), TDS®-placebo (metered pump spray), and Androgel® 1% (50 mg/5 g gel). The dose was applied to the left arm and gently rubbed into the skin. Approximately 4 ml of blood was collected at –0.5 and 0 h to establish a baseline measurement of serum testosterone concentration. Subsequently, se- rial blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12 and 24 h post-dose. The serum concentrations of tes- tosterone were analyzed using ELISA method. Full details of the study are described elsewhere [Chik et al. 2006].
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