Long-term safety and efficacy studies of epinephrine HFA metered-dose inhaler (Primatene® Mist): a two-stage randomized controlled trial.

Objective: A new epinephrine hydrofluoroalkane (HFA) asthma metered-dose inhaler (MDI) was reformulated to replace the previously marketed epinephrine chlorofluorocarbon (CFC) MDI. In addition to the HFA propellant change, several enhanced modifications (i.e. changed from solution to suspension, 43% dose reduction, etc.) were made to the formulation of epinephrine HFA MDI. This study evaluates the 6-month long-term safety and efficacy profile of the new epinephrine HFA MDI.Method: The long-term safety study consists of two 3-month, multi-center, double- or evaluator-blinded, parallel-group, placebo, and active controlled stages. In each stage, subjects aged ≥12 years with intermittent or mild-to-moderate persistent asthma were randomized to receive epinephrine HFA (2 × 125 mcg/inhalation), placebo HFA, or epinephrine CFC (2 × 220 mcg/inhalation). Bronchodilator efficacy was assessed in Stage 1 and was determined primarily by the change in the forced expiratory volume in 1 s (ΔFEV1) at Week 12, relative to the same day baseline.Results: The primary efficacy endpoint (AUC0-6hrs of %ΔFEV1 at Week 12) for epinephrine HFA (47.3 ± 54.2) closely paralleled those for the active control, epinephrine CFC (41.0 ± 43.4). Both groups were found to be overall comparable in bronchodilator efficacy. Both also showed low incidence rates of AEs with tremor being most commonly reported for epinephrine HFA. All AEs found were non-serious and non-significant. The observed changes in vital signs, ECG, serum glucose, and potassium were minimal and not clinically relevant.Conclusion: This study demonstrated that the new epinephrine HFA is overall comparable, in both safety and efficacy, to the previous epinephrine CFC.

Pharmacokinetic Study of Epinephrine Hydrofluoroalkane (Primatene MIST) Metered-Dose Inhaler.

Background: Primatene® MIST CFC, an epinephrine metered-dose inhaler (MDI), was discontinued from the market owing to environmental concerns from its use of chlorofluorocarbon (CFC) propellant. As a result, a new epinephrine MDI was developed using hydrofluoroalkane (HFA) propellant. This article reports the pharmacokinetic (PK) profile of the newly Food and Drug Administration-approved epinephrine HFA MDI. Methods: A randomized, evaluator-blinded, active-controlled, single-dose, two-arm crossover study was conducted to evaluate the PK profile of epinephrine HFA (Primatene® MIST) and epinephrine CFC (Primatene® MIST CFC) in 23 healthy volunteers to characterize the epinephrine absorption extent and rate. The study was performed at a high dose of five times the normal dose to obtain measurable plasma epinephrine levels. Plasma epinephrine levels were measured and safety was assessed by adverse events (AEs), vital signs, clinical laboratory tests, and physical examinations. Results: Epinephrine HFA demonstrated a greater systemic drug exposure (greater area under the curve) than that of epinephrine CFC (∼37% higher). The Cmax occurred at ∼2 minutes and was significantly higher in the epinephrine HFA group (0.18 ng/mL) compared with the CFC version (0.046 ng/mL) at normal dose. Within 20 minutes, both groups demonstrated comparable plasma epinephrine levels. No clinically significant adverse effects were found to be associated with epinephrine HFA, even after an ultrahigh dose (i.e., 10 inhalations). Conclusions: The systemic exposure of epinephrine HFA was found to be higher for the first 20 minutes, and then comparable with epinephrine CFC. Minimal AEs were found in this study despite the very high 1250-2200 µg inhaled doses (i.e., 10 inhalations) used for PK characterization.

A Dose-Ranging Study of Epinephrine Hydrofluroalkane Metered-Dose Inhaler (Primatene® MIST) in Subjects with Intermittent or Mild-to-Moderate Persistent Asthma.

Background: Two sequential single-dose crossover dose-ranging studies were performed to evaluate the clinical efficacy and safety profile of epinephrine hydrofluroalkane (HFA) metered-dose inhaler (MDI) formulation at various doses in subjects with asthma. Methods: In these multicenter, multiarm, double-blinded, or evaluator-blinded studies, subjects were randomized to receive the epinephrine HFA (Primatene® MIST HFA) MDI medication at doses ranging from 90 to 440 µg/dose, as well as to a placebo (PLA) control and an active control of epinephrine CFC (chlorofluorocarbon) MDI (Primatene® MIST CFC) at 220 µg/inhalation. Results: Spirometry testing for FEV1 (Forced Expiratory Volume in one second) demonstrated statistically significant improvements over PLA for epinephrine HFA MDI at all doses above 125 µg, as the amount out of the actuator (i.e., mouthpiece). The efficacy results for epinephrine HFA MDI in the dose range of 125-250 µg were also comparable to epinephrine CFC MDI (220 µg/inh). Safety assessments demonstrated minimal safety concerns for all treatment groups. No notable safety differences were observed between the studied doses of epinephrine HFA MDI and the active control formulation of epinephrine CFC MDI. Conclusion: The findings indicate that epinephrine HFA MDI provided clinically significant bronchodilator efficacy with minimal safety concerns in a dose range of 125-250 µg. These findings confirmed the optimal treatment doses of 125-250 µg that were appropriate for use in longer term 12 and 26 week chronic dosing studies of epinephrine HFA MDI for patients with intermittent or mild to moderate persistent asthma. Clinical trials registration number: NCT01025648.

Pharmacokinetic study of thymol after intravenous injection and high-dose inhalation in mouse model.

Thymol is generally recognized as a safe substance by the FDA and has been widely used in the pharmaceutical, food, and cosmetic industries. Pharmacokinetic (PK) studies of thymol have been previously conducted for oral administration, but there has been no PK study for inhalation administration or intravenous (IV) injection. This study aims at exploring and comparing the inhalation and IV PK profile of thymol in a mouse model. The inhalation PK for mouse model was corrected with fur/skin absorption. Thirty-two male CD-1 mice were randomized into two study arms, Arm-A for intravenous (n = 16) and Arm-B for inhalation (n = 16). The amount of thymol in the mouse serum was measured for Arm-A and for Arm-B at the highest dose. Furthermore, 48 mice were utilized for fur/skin absorption of thymol. In total, 320 mouse serum samples for thymol were analyzed by LC/MS method. After inhalation, the peak concentration of thymol in mouse serum was 42.3 ng/mL (Cmax ) and occurred at 2 minutes (tmax ). The AUC of the inhaled thymol at 0-60 minutes (AUC0-60) was 464 ng/mL/min. From 10-60 minutes post-dose, the PK inhalation curve appeared to be higher than that for the IV injection. This is likely attributed to the effect of absorption of thymol through the fur/skin of mice. After an adjustment by fur/skin absorption, the PK profile for net inhalation closely matched the two-compartment model. In fact, the bioavailability for the net inhalation of thymol was 74% and 77% relative to that for IV injection per AUC0-60min and AUC0-infinite, respectively.

Chronic toxicity of inhaled thymol in lungs and respiratory tracts in mouse model.

Epinephrine HFA (Primatene® Mist) is a newly formulated asthma metered dose inhaler developed to replace the previous Primatene® Mist CFC. The formulation of Epinephrine HFA contains thymol, a substance recognized to be safe by the FDA. Although the content of thymol contained in Epinephrine HFA is much lower compared to many common foods and medications available, there are no known nonclinical data about the chronic toxicity of thymol through inhalation. Two sequential 6-month studies of identical design were conducted to assess the chronic toxicity of inhaled thymol in mice. Four treatment groups, (a) Air; (b) vehicle control; (c) Article-1 (thymol 0.1%); and (d) Article-2 (thymol 0.5%) were assessed in 128 mice for 26 weeks. The mice were sacrificed at the end of the treatment period and a histopathologic evaluation was performed with respect to lungs, bronchial lymph nodes, nasal passages/nasopharynx, and trachea. Forty-five pathologic assessment parameters (PAPs) were evaluated. In total, 5591 data points from 487 mouse organs were assessed. Chronic toxicity index was calculated for 16 PAPs that had multiple histopathologic abnormal observations. The t tests were conducted for these 16 PAPs (Articles-1 and 2 versus Air and vehicle control, respectively), and all P-values were greater than .05 indicating no significant differences between all treatment groups. An evaluation was also conducted for 25 PAPs that had only a very small number of pathologic abnormalities. No significant differences for chronic toxicity were found when comparing mice under long-term repeated exposure of high doses of inhaled thymol and mice that inhaled no thymol.