Subdermal application

14.3.7.1 Testosterone pellets

Subdermal testosterone pellet implantation was among the earliest effective modalities employed for clinical application of testosterone which became an established form of androgen replacement therapy by 1940 (Deansley and Parks 1938; Vest and Howard 1939). With the advent of other modalities, e.g. intramuscular testosterone ester injections, they went out of general use. However, investigations in the 1990s redefined the favourable pharmacokinetic profiles and clinical pharmacology of testosterone implants (Handelsman etal. 1990; Jockenhovel etal. 1996).

The original testosterone implants were manufactured by high-pressure tablet-ing of crystalline steroid with a cholesterol excipient. These proved brittle, hard to standardize or sterilize and exhibited surface unevenness and fragmentation during in-vivo absorption to produce an uneven late release rate. These limitations were overcome in the 1950s by switching to high-temperature moulding whereby molten testosterone was cast into cylindrical moulds to produce more robust implants. These have more uniform composition, resulting in a more steady and prolonged release and reduced tissue reaction. Sterilization is achieved by a combination of high-temperature exposure during manufacture together with surface sterilization or, more recently, gamma-irradiation. The testosterone implants are currently available in two sizes with a common diameter of 4.5 mm: 6 mm length for the 100 mg and 12 mm length for the 200 mg implant. Pellets are usually implanted under the skin of the lower abdominal wall under sterile conditions using a trochar and cannula.

The estimated half-life of absorption of testosterone from subdermal implants is 2.5 months. On average, approximately 1.3 mg of testosterone are released per day from the 200 mg pellet. Testosterone implants demonstrate a minor and transient accelerated initial "burst" release, which lasts for 1-2 days (Jockenhovel etal. 1996). The most comprehensive pharmacokinetic evaluation of testosterone implants was done in a random-sequence, cross-over clinical study of 43 androgen-deficient men with primary or secondary hypogonadism (Handelsman etal. 1990). Patients were treated sequentially with 3 regimens - six 100 mg, three 200 mg or six 200 mg implants - at intervals of at least six months. Implantation of testosterone pellets resulted in a highly reproducible and dose-dependent time-course for circulation of total and free testosterone. Testosterone concentrations reached baseline by six months after either of the 600 mg dose regimens but remained significantly elevated

Time (months)

Fig. 14.15 Blood total testosterone in 43 hypogonadal men receiving four 200 mg pellets (800 mg) implanted either under the skin of the lateral abdominal wall (in 4 tracks [filled circles], n = 9; or in 2 tracks [open circles], n = 16) or in the hip region (filled squares, n = 18) (adapted with permission from Kelleher etal. 2001, copyright 2001, Blackwell Publishing).

Time (months)

Fig. 14.15 Blood total testosterone in 43 hypogonadal men receiving four 200 mg pellets (800 mg) implanted either under the skin of the lateral abdominal wall (in 4 tracks [filled circles], n = 9; or in 2 tracks [open circles], n = 16) or in the hip region (filled squares, n = 18) (adapted with permission from Kelleher etal. 2001, copyright 2001, Blackwell Publishing).

after six months following the 1200 mg dose. The standard dose for hypogonadal men is 800 mg every six months, which can be titrated individually (Fig. 14.15).

Pellet implantation has few side-effects and is generally well tolerated. Adverse events after implantations were extrusions (8.5-12% per procedure), bruising (2.3-8.8%) and infections (0.6-4%) (Handelsman etal. 1997; Kelleher etal. 1999). Due to the long-lasting effect and the inconvenience of removal, preferably pellets should be used by men in whom the beneficial effects and tolerance for androgen replacement therapy have already been established by treatment with shorter-acting testosterone preparations.

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