FD&C Yellow #6, and titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Endogenous androgens, including testosterone and dihydrotestosterone (DHT), are responsiblefor the normal growth and development of the male sex organs and for maintenance of secondarysex characteristics. These effects include the growth and maturation of prostate, seminalvesicles, penis and scrotum; the development of male hair distribution, such as facial, pubic,chest and axillary hair; laryngeal enlargement, vocal cord thickening, alterations in bodymusculature and fat distribution.
Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone,has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such asKlinefelter syndrome or Leydig cell aplasia, whereas secondary hypogonadism (also known ashypogonadotropic hypogonadism) is the failure of the hypothalamus (or pituitary) to producesufficient gonadotropins (FSH, LH).
12.2 Pharmacodynamics
No specific pharmacodynamic studies were conducted using JATENZO.
12.3 Pharmacokinetics
Absorption
JATENZO delivers physiologic amounts of testosterone, producing testosterone concentrationsthat approximate normal concentrations seen in healthy men.
JATENZO was taken orally at a starting dose of 237 mg twice per day with meals in amulticenter, open-label, randomized, 2-arm, active-controlled trial in hypogonadal males. Thedose was adjusted, as needed, on Days 14 and 56 between a minimum of 158 mg twice per dayand a maximum of 396 mg twice per day based on the average plasma testosterone concentrationobtained over 24 hours after the morning dose. The average daily NaF-EDTA plasmatestosterone concentration was 403 (± 128) ng/dL at the endof treatment, where the normaleugonadal range in NaF-EDTA plasma was 252-907 ng/dL in this study. Note that the titrationscheme for use in clinical practice is based on serum total testosterone [see Dosage andAdministration (2.2)].
Table 3 summarizes the pharmacokinetic (PK) parameters for plasma total testosterone inpatients completing at least 105 days of JATENZO treatment administered twice daily.
Table 3: NaF-EDTA Plasma Testosterone Cavg and Cmax at Final PK Visit
PK
Parameter
All Doses
(N=151)
Cavg (ng/dL) Mean 403
SD 128
Cmax (ng/dL) Mean 1008
SD 581
PK = pharmacokinetic; Cavg = 24-hour average concentration; Cmax = maximum concentration
Figure 2 summarizes the mean plasma total testosterone profile for the patients at the final PK
visit.
Figure 2: Mean (±SEM) Concentration-Time Profile for NaF-EDTA Plasma Total
Testosterone in JATENZO Treated Subjects at Final PK Visit
SEM = standard error of the mean; T = testosterone
When JATENZO was dosed with different breakfasts containing various amounts of fat, thebioavailability with the 30 g fat, 45 g fat, and high-calorie high-fat breakfasts was comparable,but there was a food effect with the 15 g fat breakfast compared to the 30 g fat breakfast. The 15g fat breakfast had a 25% decrease in testosterone exposure compared to the 30 g fat breakfast.
Distribution
Circulating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG)and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remainsunbound (free) and the rest is loosely bound to albumin and other proteins.
Metabolism
The androgenic activity of testo |
