Doubting the T nasal spray will result in better absorption.
The concentration of 4.5% T in Natesto would allow the application of a smaller amount of gel to the nasal cavity improving the absorption and effectiveness.
Only blood work will tell what Tmax levels are truly achieved using lower doses of T nasal spray.
Post labs?
2.2.4 How were the dose and the dosing regimen of NATESTO for the Phase 3 study and TBM product determined?
Reference is made to the minutes of the End of Phase 2 (EOP2) meeting held between the Division and the Sponsor on March 14, 2011 (dated May 4, 2011, under IND 70512 in DARRTS). A Phase 2 study, Nasobol-01-2009, examined the efficacy and tolerability of the 3.2% TBS-1 nasal gel formulation. In this study, the results for the 11 mg T BID dose did not meet the Agency‘s principle acceptance criterion for standard T therapies (i.e., at least 75% of subjects should achieve an average total T concentration within the normal range of 300-1,050 ng/dL). In addition, a linear increase in T concentrations with escalating doses was not achieved. The sponsor believed that the lack of a linear increase suggested that T absorption was limited by the inability of the nasal cavity to hold the tested volumes of the 3.2% TBS-1 formulation.
The dosing regimen selected for the Phase 3 efficacy and safety study (Study TBS-1-2011-03) was based on results from Studies TBS-1-2010-01 and TBS-1-2011-01. Based on the results of Study Nasabol-01-2009, the Sponsor conducted a Phase 2, dose-finding study, TBS-1-2010-01, evaluating higher concentrations of TBS-1 (i.e., 4.0% and 4.5% T w/w) formulations in reduced volumes. Study TBS-1-2010-01 was an open-label, randomized, balanced, 3-treatments (4.0% TID, 4.5% BID, and 4.5% TID), parallel design, dose-finding, PK study of TBS-1 administered intranasally in 22 hypogonadal males (age of 35-73 years). Subjects were randomized to one of the following 3 treatment groups:
Treatment A (N=8): TBS-1 syringes pre-filled with 125 μL 4.0% gel to deliver 5.0 mg of T per nostril (intranasal) given TID at 9 pm, 7 am, and 1 pm (total dose: 30 mg/day).
Treatment B (N=7): TBS-1 syringes pre-filled with 150 μL 4.5% gel to deliver 6.75 mg of T per nostril (intranasal) given BID at 9 pm and 7 am (total dose: 27.0 mg/day).
Treatment C (N=7): TBS-1 syringes pre-filled with 125 μL 4.5% gel to deliver 5.625 mg of T per nostril (intranasal) given TID at 9 pm, 7 am, and 1 pm (total dose 33.75 mg/day).
TBS-1 was administered for 7 days as per treatment group assignment. On Day 7, subjects for all treatment groups returned to their study centers and underwent a 24-hour PK sample collection after the 9 pm dosing. Total T PK profiles and parameters are presented in Figure 4 and Table 6.
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Concentrating TBS-1 from 3.2% to 4.5% T (w/w) allowed for administration of a smaller amount of gel, resulting in improved and consistent absorption of T, and a higher response rate (i.e., achieving serum T average concentration [Cavg] values within the normal range) of subjects using 4.0% T and 4.5% T (w/w) versus 3.2% T (w/w) TBS-1 formulation. Regardless of the concentration of formulation and the dose, approximately 86-88% of the subjects had a total T Cavg within the normal range of 300-1,050 ng/dL. Two (2) out of 7 subjects (i.e., Subject 01-005 Cmax = 1,670 ng/dL; Subject 02-006 Cmax = 1,570 ng/dL) who were in the 13.5 mg BID (4.5% w/w) treatment group had a T Cmax > 1,500 ng/dL. While both the BID and TID doses administered in this study had similar Cavg (approximately 400 ng/mL) within the normal range, the 13.5 mg BID (4.5% T w/w) regimen had a Cmax value above the normal range, while the 11.25 mg TID (4.5% T w/w) regimen did not. All 3 treatments also demonstrated expected increases in mean serum DHT and E2 concentrations following TBS-1 administration (data not shown). The major limitation of this study was that it was a parallel study design instead of being a crossover design (that would allow a direct and accurate comparison between treatment groups). Modeling and simulation of profiles for 200 subjects based on data from the 22 subjects from Study TBS-1- 2010-01 supported a reduction from 11.25 mg to 11 mg T per dose without compromising efficacy. Reference is made to Dr. LaiMing Lee’s Clinical Pharmacology review dated September 21, 2011, under IND 70512 in DARRTS.
Study TBS-1-2011-01 was a Phase 1, randomized, crossover study conducted in 12 healthy men (age of 18-28 years), to compare the BA following a single dose of 11 mg T of TBS-1 from a multiple-dose dispenser (i.e., the proposed commercial method of administration) to that following a single dose of 11 mg T of TBS-1 from a prefilled syringe (i.e., the method of administration used in several studies earlier in the TBS-1 development program). A 12-hour baseline T profile was characterized for each subject to determine their endogenous T concentrations. The TBS-1 treatment was administered at 9 pm. A total of 13 blood samples were collected for each subject over a 12-hour post-dose period. Each treatment period was separated by a washout period of at least 6 days.
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As shown in Figure 5, the multiple-dose dispenser had higher AUC(0-12) values compared to those with the prefilled syringe, while also having a higher Cmax. Based on this finding, the sponsor decided to select the multiple-dose dispenser as the proposed commercial method of administration.
Based on the findings from Studies TBS-1-2010-01 and TBS-1-2011-01, an 11.0 mg T dose of TBS-1 administered as a 22.0 mg T daily dose (i.e., BID dosing) or 33.0 mg T daily dose (i.e., TID dosing) using the multiple-dose dispenser was selected for the Phase 3 efficacy and safety study (Study TBS-1-2011-03).
Based on the results of the Phase 3 study, TBS-1-2011-03, the final proposed dosing regimen for NATESTO was determined to be 11 mg T TID (i.e., 33 mg/day).
