He is only 3 weeks in!
Much more involved when it comes to libido let alone erectile function than TT, FT, estradiol, DHT, prolactin.
Hate to burst your bubble but there is an initial burst release of T (small short-lived peak) within the first 2 days (48 hrs) and
levels will stay elevated off the hop as there is a plateau phase lasting roughly 60 days which is then followed by a gradual decline over the following months.
*The pharmacokinetic study in 14 hypogonadal men revealed an initial short-lived burst release of T with a peak concentration of 49.0 ± 3.7 nmol at 0.5 ± 0.13 days which was followed by a stable plateau lasting until day 63 (day 2, 35.2 ± 2.3; day 63, 34.8 ± 2.6 nmol). Thereafter serum T gradually declined and was close to baseline concentrations on day 300.
Summary
0BJECTIVE There are advantages and disadvantages with all of the presently available types of testosterone replacement for hypogonadal men. We performed this investigation to establish detailed data about the pharmacokinetics, pharmacodynamics, feasibility, and side-effects of subcutaneously implanted testosterone (T) pellets.
DESIGN AND MEASUREMENT In a single-dose, open-label, non-randomized study, 6 T-pellets, each containing 200mg of fused crystalline T, were Implanted in the subdermal fat tissue of the lower abdominal wall of 14 hypogonadal men.
Blood samples for determination of T, LH, FSH, 5a-dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG), and oestradiol (E2) were obtained at 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48 hours and on day 21 after implantation and then every 3 weeks until day 189, and on days 246 and 300 during follow-up. In another 36 hypogonadal men, the feasibility and side-effects of Tpellets were evaluated.
PATIENTS Fourteen patients participated in the detailed pharmacokinetic study and another 36 patients in the assessment of feasibility and side-effects. All patients (age range 18-61 years) suffered from primary or secondary hypogonadism (T < 3.6 nmol).
RESULTS The pharmacokinetic study in 14 hypogonadal men
revealed an initial short-lived burst release of T with a peak concentration of 49.0 ± 3.7 nmol at 0.5 ± 0.13 days which was followed by a stable plateau lasting until day 63 (day 2, 35.2 ± 2.3; day 63, 34.8 ± 2.6 nmol). Thereafter serum T gradually declined and was close to baseline concentrations on day 300. Apparent terminal elimination half-life (t1⁄2) was 70.8 ± 10.7 days and apparent mean residence time 87.0 ± 45 days. On average, serum T was below 10 nmol after 180 days. Absorption of T followed a zero-order release kinetic with an absorption half-time of 74.7 days (95% confidence Interval: 71.1-78.5) and was almost complete by day 189 (95.9± 0.84%). Serum DHT and E2 were significantly elevated from day 21 to day 105 and correlated significantly with T (DHT, r = 0-65, P < 00001, EP, r = 067, P < 0.0001). SHBG was significantly decreased from day 21 to day 168. 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 nadirs occurring at day 84 (LH) and day 63 (FSH). LH and FSH were highly inversely correlated with T (r = -0.47 and -057). The only side-effect observed during 112 implantations in the total group of 50 men were 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 to their previous T medication for permanent substitution therapy.
CONCLUSION T-pellets are the androgen formulation with the longest biological action and strongest pharmacodynamic efficacy in terms of gonadotrophin suppression. The pharmacokinetic features are advantageous compared to other T preparations and the patient acceptance is high.
Pharmacokinetics
Implantation of T-pellets led to an initial short-lived burst release of testosterone within the first 2 days after application (Fig. 1, Table 2). The burst release was seen in all patients within 48 hours of implantation and accounted for much less than 1.49 ± 0.109% of the total testosterone released ((AUC 0-2/AUC)O-300) x l00), since it actually consisted only of the small peak on top of the plateau phase. A stable plateau was maintained from day 2 to 63 (day 2, 35.2 ± 2.3; day 63, 34.8± 2.6 nmol/l). Thereafter the testosterone serum levels gradually declined and were close to baseline concentrations on day 300.
Apparent terminal elimination half-life (t1⁄2) was 70.8 ± 10.7 days, and mean residence time (apparent MRT) 87.0 ± 4.45 days. Mean testosterone serum concentration was below 10 nmol/l after 180 days (Fig. 1).
T stayed above the lower normal limit (>10nmol/l) until day 246 in 2 patients, day 189 in 6, day 168 in 5, and day 147 in 1. Though not statistically significant, there was a tendency of men with larger body mass to have a lower apparent t1⁄2 and apparent MRT. The volume of distribution (VZ) showed a significant positive correlation with the body mass index (VZ = 0.83
± 0.22 x BMI + 0.14
± 0.02, r = 0.49, P < 0.01).
The plot of percentage testosterone absorbed vs time showed a nearly linear (zero-order) release of testosterone (Fig. 2). High linearity was demonstrated up to day 89 (r = 0.9995), with still an excellent linear regression up to day 147 (r = 0.9912). Absorption half-time was 74.7 days (95% confidence interval: 71.1-78.5) with almost complete absorption by day 189 (95.9 3
± 0.84%).
The daily release rate was 1.18 ± 0.03 mg per 200 mg pellet and the recalculated average testosterone released was 1228.95 ± 118.55 mg from the 1200 mg dose.
View attachment 12704
Fig. 1 Time course of serum testosterone concentrations (mean ± SEM) in 14 hypogonadal men. Note the burst release within the first 2 days and the plateau phase until day 63.
Discussion
This is the first study presenting detailed data on the pharmacokinetics and dynamics of T-pellets. Although T-pellets have been in clinical use for 50 years (Biskind et al ., 1990).
This stability in the absorption is probably due to the mechanism of steroid absorption from the fused pellets, which is a regular erosion mechanism, depending on pellet surface area and site-specific dissolution of the crystalline steroid into the extracellular fluid (Handelsman et al., 1990).
Unlike the early T-pellets, the new T-pellets possess high stability and do not break apart after implantation, thus keeping their original shape and surface geometry. The previous higher estimate of testosterone release of 1.1 mg/ day from 100mg pellets recovered from antecubital and subscapular implantation sites may be due to site-specific absorption kinetics, possibly related to local blood flow, muscular activity, and temperature (Bishop & Folley, 1951). Furthermore, the weighing of remnants from extruded pellets could be hampered by the potential loss of material by handling. On the other hand, the calculation from percentage absorbed vs time plots assumes a constant metabolic clearance rate (MCR) for testosterone throughout the study period. In addition, individual variations of the MCR of testosterone have been reported (Meikle et al., 1988; Horton et al., 1965). Despite these disadvantages, the two methods are in good agreement.
In contrast to other testosterone preparations, T-pellets did not produce a disproportionate elevation of DHT. However, the DHT/testosterone ratio decreased owing to a larger increase of testosterone than of DHT. Nevertheless, DHT levels temporarily exceeded the upper normal limit at peak concentrations. This has also been observed for other long-acting androgen formulations (Bhasin et al., 1992; Behre & Nieschlag, 1992).
Interestingly, as with testosterone microcapsules (Bhasin et al., 1992), the DHT peak occurred later than the testosterone peak. This might indicate androgen-mediated induction of 5a-reductase activity.