Testosterone undecanoate

When testosterone is esterified in the 17ß-position with a long fatty acid side chain such as undecanoic acid and given orally, its route of absorption from the gastrointestinal tract is slightly shifted from the vena portae to the lymph and

Fig. 14.2 Single-dose pharmacokinetics of testosterone undecanoate after oral administration of 120 mg of the ester to 8 hypogonadal patients. Because of high interindividual variability of testosterone serum concentrations after administration of testosterone undecanoate, individual curves were all centralized about the time of maximal serum concentrations (time 0). Asterisks indicate significantly higher testosterone serum concentrations compared to pretreatment values (basal) (mean ± SEM).

Fig. 14.2 Single-dose pharmacokinetics of testosterone undecanoate after oral administration of 120 mg of the ester to 8 hypogonadal patients. Because of high interindividual variability of testosterone serum concentrations after administration of testosterone undecanoate, individual curves were all centralized about the time of maximal serum concentrations (time 0). Asterisks indicate significantly higher testosterone serum concentrations compared to pretreatment values (basal) (mean ± SEM).

reaches the circulation via the thoracic duct (Coert et al. 1975; Horst et al. 1976; Shackleford et al. 2003). Absorption is improved if the ester is taken in arachis oil (Nieschlag etal. 1975) and with a meal (Frey etal. 1979; Bagchus etal. 2003). After oral ingestion of a 40 mg capsule, of which 63% i.e. 25 mg is testosterone, maximum serum levels are reached two to six hours later (Nieschlag et al. 1975). Thus, with 2 to 4 capsules (80 to 160 mg) per day substitution of hypogonadism can be achieved.

Testosterone undecanoate pharmacokinetics after single-dose administration were tested in eight hypogonadal patients and twelve normal men (Schürmeyer et al. 1983). Directly before and at hourly intervals after oral application of three times 40 mg of testosterone undecanoate in arachis oil taken together with a standardized breakfast, matched saliva samples, as a parameter for free testosterone at the tissue level, and blood samples were collected hourly for up to 8 h. After administration of testosterone undecanoate, serum and saliva testosterone always showed a parallel rise and fall, as demonstrated by a constant saliva/serum testosterone ratio. On average maximum levels could be observed five hours after testosterone undecanoate administration. However, the serum testosterone profile showed high interindividual variability of the time when maximum concentrations were reached, as well as of the maximum levels themselves that ranged from 17 to 96 nmol/l. When the individual serum concentration versus time curves were centralized about the time of maximal serum concentrations, serum concentrations significantly different from basal values were seen only two hours before and one hour after the time of maximal serum concentrations in hypogonadal patients (Fig. 14.2) (Schürmeyer etal. 1983). Based on this observation it can be deduced that even with administration of testosterone undecanoate 3 times daily, only short-lived testosterone peaks resulting in high fluctuations can be obtained.

This judgment is in agreement with the data of a two-month multiple-dose study with testosterone undecanoate for replacement therapy in hypogonadal men (Skakkebaek etal. 1981). Applying a double blind cross-over design, serum testosterone levels were studied in 12 hypogonadal patients to whom 80 mg of testosterone undecanoate had been administered twice per day 12 hours apart. Whereas four hours after administration of testosterone undecanoate a significant increase of testosterone serum levels was observed compared to the placebo group, twelve hours after administration no significant difference in testosterone serum levels between treatment and placebo control group was seen. Even four hours after administration, in four of twelve patients testosterone levels were still below the lower level of the normal range after both one month and two months of treatment. A significant marked variability between subjects as well as within the same subjects has also been observed in other clinical studies (Cantrill et al. 1984; Conway et al. 1988).

The original preparation of oral testosterone undecanoate had to be refrigerated (2-8°C) in the pharmacy for reasons of stability, whereas patients must store it at room temperature to ensure optimal absorption. The shelf-life at room temperature is only three months. Therefore, a new, more stable pharmaceutical formulation of testosterone undecanoate was developed in which the oleic acid solvent was replaced by castor oil and propylene glycol laurate. This new formulation can be stored at room temperature (15-30°C) for three years (Bagchus etal. 2003). According to an unpublished randomized multicenter study in 49 hypogonadal men, oral administration of 2 x 80 mg or 3 x 80 mg of the reformulated testosterone undecanoate might result in more physiological and stable serum testosterone levels.

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