PHARMACOKINETICS AND PHARMACODYNAMICS OF SUBCUTANEOUS TESTOSTERONE IMPLANTS IN HYPOGONADAL MEN

OBJECTIVE There are advantages and disadvantages with all of the prese ntly available types of testosterone replacement for hypogonadal men. We performed this investigation to establish detailed data about the p harmacokinetics, pharmacodynamics, feasibility and side-effects of sub cutaneously implanted testosterone (T) pellets. DESIGN AND MEASUREMENT In a single-dose, open-label, non-randomized study, 6 T-pellets, each containing 200 mg of fused crystalline T, were implanted in the subde rmal fat tissue of the lower abdominal wall of 14 hypogonadal men. Blo od samples for determination of T, LH, FSH, 5 alpha-dihydrotestosteron e (DHT), sex hormone binding globulin (SHBG) and oestradiol (E(2)) wer e obtained at 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48 hours and on day 21 a fter implantation and then every 3 weeks until day 189, and on days 24 6 and 300 during follow-up. In another 36 hypogonadal men the feasibil ity and side-effects of T-pellets were evaluated. PATIENTS Fourteen pa tients participated in the detailed pharmacokinetic study and another 36 patients in the assessment of feasibility and side-effects. All pat ients (age range 18-61 years) suffered from primary or secondary hypog onadism (T < 3.6 nmol/l). RESULTS The pharmacokinetic study in 14 hypo gonadal men revealed an initial short-lived burst release of T with a peak concentration of 49.0 +/- 3.7 nmol/l at 0.5 +/- 0.13 days which w as followed by a stable plateau lasting until day 63 (day 2, 35.2 +/- 2.3; day 63, 34.8 +/- 2.6 nmol/l). Thereafter serum T gradually declin ed and was close to baseline concentrations on day 300. Apparent termi nal elimination half-life (t(1/2)) was 70.8 +/- 10.7 days and apparent mean residence time 87.0 +/- 4.5 days. On average, serum T was below 10 nmol/l after 180 days, Absorption of T followed a zero-order releas e kinetic with an absorption half-time of 74.7 days (95% confidence in terval: 77.1-78.5) and was almost complete by day 189 (95.9 +/- 0.84%) . Serum DHT and E(2) were significantly elevated from day 21 to day 10 5 and correlated significantly with T (DHT, r=0.65, P<0.0001, E(2), r= 0.67, P<0.0001). SHBG was significantly decreased from day 21 to day 1 68. In 6 men with primary hypogonadism T suppressed LH and FSH to the eugonadal range from day 21 to 126 and 42 to 105, respectively, with n adirs occurring at day 84 (LH) and day 63 (FSH). LH and FSH were highl y inversely correlated with T (r = -0.47 and -0.57). The only side-eff ect observed during 112 implantations in the total group of 50 men wer e 6 local infections (5.4%) leading to extrusion of 5 pellets in 3 men . When given the choice, all patients except one preferred T-pellets t o their previous T medication for permanent substitution therapy. CONC LUSION T-pellets are the androgen formulation with the longest biologi cal action and strongest pharmacodynamic efficacy in terms of gonadotr ophin suppression. The pharmacokinetic features are advantageous compa red to other T preparations and the patient acceptance is high.