a median percent increase in luteinizing hormone of 12% at 6months and 19% at both 12 and 24months.
Other Effects: Plasma lipid panel and bone mineral density were eva luated following 52weeks of dutasteride 0.5mg once daily in healthy volunteers. There was no change in bone mineral density as measured by dual energy x-ray absorptiometry compared with either placebo or baseline. In addition, the plasma lipid profile (i.e., total cholesterol, low density lipoproteins, high density lipoproteins, and triglycerides) was unaffected by dutasteride. No clinically significant changes in adrenal hormone responses to ACTH stimulation were observed in a subset population (n=13) of the 1-year healthy volunteer study.
12.3 Pharmacokinetics
The pharmacokinetics of dutasteride and tamsulosin from JALYN are comparable to the pharmacokinetics of dutasteride and tamsulosin when administeed separately.
Absorption: The pharmacokinetic parameters of dutasteride and tamsulosin observed after administration of JALYN in a single dose, randomized, 3-period partial cross-over study are summarized in Table2 below.
Table 2. Arithmetic Means (SD) of Serum Dutasteride and Tamsulosin in Single-dose Pharmacokinetic Parameters Under Fed Conditions Component N AUC(0-t) (nghr/mL) Cmax (ng/mL) Tmax (hr)a t½ (hr)
Dutasteride 92 39.6 (23.1) 2.14 (0.77) 3.00 (1.00-10.00)
Tamsulosin 92 187.2 (95.7) 11.3 (4.44) 6.00 (2.00-24.00) 13.5 (3.92)b
a Median (range).
b N=91.
Dutasteride: Following administration of a single 0.5-mg dose of a soft gelatin capsule, time to peak absolute bioavailability in 5healthy subjects is approximately 60% (range: 40% to 94%).
Tamsulosin: Absorption of tamsulosin is essentially complete (>90%) following oral administration of 0.4-mg tamsulosin hydrochloride capsules under fasting conditions. Tamsulosin exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-daily dosing.
Effect of Food: Food does not affect the pharmacokinetics of dutasteride following administration of JALYN. However, a mean 30% decrease in tamsulosin Cmax was observed when JALYN was administered with food, similar to that seen when tamsulosin monotherapy was administered under fed versus fasting conditions.
Distribution:Dutasteride: Pharmacokinetic data following single and repeat oral doses show that dutasteride has a large volume of distribution (300 to 500L). Dutasteride is highly bound to plasma albumin (99.0%) and alpha-1 acid glycoprotein (96.6%).
In a study of healthy subjects (n=26) receiving dutasteride 0.5mg/day for 12months, semen dutasteride concentrations averaged 3.4ng/mL (range: 0.4 to 14ng/mL) at 12months and, similar to serum, achieved steady-state concentrations at 6months. On average, at 12months 11.5% of serum dutasteride concentrations partitioned into semen.
Tamsulosin: The mean steady-state apparent volume of distribution of tamsulosin after intravenous administration to 10healthy male adults was 16L, which is suggestive of distribution into extracellular fluids in the body.
Tamsulosin is extensively bound to human plasma proteins (94% to 99%), primarily alpha-1 acid glycoprotein (AAG), with linear binding over a wide concentration range (20 to 600ng/mL). The results of 2-way in vitro studies indicate that the binding of tamsulosin to human plasma proteins is not affected by amitriptyline, dic |
