Abstract


Male hypogonadism is a clinical syndrome resulting from failure of the testis to produce physiologic levels of testosterone as a disruption to the hypothalmic-pituitary-testicular axis. Advantages of the testosterone (T) nasal gel, Natesto®, include ease of administration and no black box warning for risk of secondary transference. The nasal mucosa offers high permeability and high bioavailability, as the drug is not subject to first-pass metabolism. view more

Male hypogonadism is a clinical syndrome resulting from failure of the testis to produce physiologic levels of testosterone as a disruption to the hypothalmic-pituitary-testicular axis. Advantages of the testosterone (T) nasal gel, Natesto®, include ease of administration and no black box warning for risk of secondary transference. The nasal mucosa offers high permeability and high bioavailability, as the drug is not subject to first-pass metabolism. Physicians may be concerned about the absorption and use of nasal testosterone therapy when patients present with seasonal allergies and medicating with antihistamines and/or decongestants.

Two separate studies measured the absorption of total testosterone from following nasal application in participants with allergic rhinitis (AR). During a Phase 1 trial in healthy males with seasonal AR, patients were randomized into a 3 treatment arm crossover study (1. Allergen, 2. Allergen + oxymetazoline, 3. Control = no allergies), where patients took Natesto 3 times daily (TID). Baseline corrected pharmacokinetic parameters (Cavg and Cmax) were nearly indistinguishable over the 3 treatment arms and periods. The Cmax and Cavg for each treatment arm were as follows for each time period: Arm 1: Cmax 413 ng/dL and Cavg 399; Arm 2: Cmax 416 ng/dL and Cavg 377; and Arm 3: Cmax 378 ng/dL and Cavg 514. Cmax for the morning dose was consistently higher than for the other two peaks in the 24 h time frame due inadequacy of linear baseline subtraction to capture underlying morning endogenous production. During Phase 3 trials, T levels were measured in men with “active” nasal allergies treated with Natesto. Patients were randomized into a 90-day, open-label, dose-ranging study [including potential dose-titration, twice daily (BID) to TID], with 90- and 180-day sequential safety extension was done in hypogonadal men with and without AR. 306 men were randomized into two arms, n=228 for BID dosing and n=78 for TID dosing. The percentage of patients with serum T level (Cavg) within the normal range (~300 ng/dL – 1050 ng/dL) established the primary endpoint. Natesto® was self-administered intranasally using a multiple dose dispenser, as 2 or 3 daily doses (11.0 mg single dose). Thus, the total daily doses were 22.0 mg (BID) or 33.0 mg (TID). 19 (32.2%) subjects in the Phase 3 trial with AR reported mild nasal symptoms indistinguishable from those without AR. Surprisingly, there was a very low incidence of seasonal allergy symptoms (3/52 or 5.8%) reported by AR susceptible patients while on Natesto® treatment for ≥6 months. The formulation, which includes a plant-based, natural oil, serves as an emollient to help retain moisture and sooth sensitive skin for these patients. The oil in the formulation of the gel also provides a protective barrier that may reduce direct contact of allergens with the skin and thereby reduce allergy flare-up.

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