Bruce P. Ekholm

Twenty-eight-day Double-blind Safety Study of an HFA-134a Inhalation Aerosol System in Healthy Subjects

A 28‐day double‐blind parallel group study has been conducted to compare the safety and tolerability of HFA‐134a, a chlorofluorocarbon‐free propellant in a pressurized metered‐dose inhaler (MDI A), with a chlorofluorocarbon propellant (MDI C).

Pharmacokinetic Differences between Chlorofluorocarbon and Chlorofluorocarbon‐free Metered Dose Inhalers of Beclomethasone Dipropionate in Adult Asthmatics

We have compared the serum pharmacokinetics of the metabolites of beclomethasone dipropionate after inhalation from chlorofluorocarbon (CFC) and hydrofluoroalkane HFA‐134a (HFA) formulations in asthmatic patients.

Clinical equivalence of a novel non-chlorofluorocarbon-containing salbutamol sulfate metered-dose inhaler and a conventional chlorofluorocarbon inhaler in patients with asthma

BACKGROUND New formulations of non-chlorofluorocarbon-containing propellants for pressurized metered-dose inhaler delivery systems must be developed in response to the forthcoming ban on chlorofluorocarbon (CFC) production. OBJECTIVE This study compared the bronchodilator effects of 100, 200, and 300 micrograms (base equivalent) of salbutamol in a novel CFC-free propellant system (Airomir in the 3M CFC-Free System; 3M Pharmaceuticals, St. Paul, Minn.; 108 micrograms of salbutamol sulfate or 90 micrograms of salbutamol base equivalent per inhalation) with that of 100 and 200 micrograms of salbutamol base in a conventional CFC propellant system (Ventolin, CFC-11/12; Allen and Hanburys, Division of Glaxo Inc., Research Triangle Park, N.C.; 90 micrograms of salbutamol base per inhalation) and placebo. METHODS Twenty-six patients with chronic, stable asthma, who had a forced expiratory volume in 1 second (FEV1) between 50.0% and 75.0% of predicted normal value, entered this randomized, double-blind, double-dummy, 6-period, crossover study. FEV1 was measured before and at multiple time points (ranging from 10 to 480 minutes) after administration of one, two, and three inhalations of salbutamol/CFC-free (100, 200, and 300 micrograms); one and two inhalations of salbutamol/CFC (100 and 200 micrograms); and placebo. Safety parameters included adverse events, heart rate, blood pressure, physical examinations, electrocardiograms, and clinical laboratory tests. Parametric analysis of variance models appropriate for a 6-period crossover design were used, along with multiple comparisons according to Tukeys method. RESULTS All active treatments produced significantly (p < 0.0001) greater bronchodilation than placebo. The bronchodilator effect, as measured by FEV1 (peak percent change, peak as a percent of predicted value, duration, and area under the curve) after two inhalations of salbutamol/CFC-free was clinically comprable to two inhalations of salbutamol/CFC, with no clinically meaningful differences in safety parameters between the two delivery systems or between different dose levels. CONCLUSION These results suggest that salbutamol/CFC-free may offer a suitable alternative for salbutamol/CFC when the need arises to change from CFC-containing salbutamol products.

Acute safety of the CFC-free propellant HFA-134a from a pressurized metered dose inhaler.

The acute safety of the alternative chlorofluorocarbon-free (CFC-free) propellant HFA-134a from a pressurized metered-dose inhaler (MDI) was assessed in 12 healthy male subjects according to a double-blind, randomized, crossover design. On each of three consecutive days, cumulative doses of 1, 2, 4, 8 and 16 inhalations were administered 30 min apart from one of three MDIs. The three MDIs contained either the HFA-134a CFC-free system without drug (HFA-Placebo), the CFC-free system with salbutamol sulphate (HFA-Salbutamol), or a conventional CFC propellant mixture without drug (CFC-Placebo). Pulmonary function (FEV1, FEF25–75%), cardiovascular performance (heart rate and blood pressure), objective tremor measurements and serum potassium were measured after each incremental dose.Similar responses for pulmonary function, cardiovascular performance, tremor and serum potassium were observed between the HFA-Placebo and CFC-Placebo groups. No statistically significant difference was seen in change from baseline of any parameter between the two propellant systems. The administration of HFA-Salbutamol produced statistically significant dose-related increases in heart rate, systolic blood pressure and tremor and a significant dose-related decrease in serum potassium; these responses were expected based on cumulative doses of active drug. Blood samples for HFA-134a analysis were collected to measure systemic absorption of this propellant. Levels of HFA-134a between 200 and 700 ng · ml−1 were detected in all subjects given the CFC-free system. This study shows that acute inhalation of HFA-134a in a CFC-free system is as safe as a CFC propellant system. Salbutamol sulphate in the CFC-free system can be delivered in a dose-linear fashion, without any noticeable change in the safety profile of active drug.

Cumulative Dose Response Study Comparing HFA-134a Albuterol Sulfate and Conventional CFC Albuterol in Patients with Asthma

BACKGROUND As a result of the pending ban on chlorofluorocarbon production, the non-chlorofluorocarbon propellant 1,1,1,2-tetrafluoroethane (HFA-134a) is being evaluated as a replacement for CFCs in metered-dose inhalers. OBJECTIVES This cumulative dose response study compared the safety and bronchodilator efficacy of 16 cumulative inhalations of albuterol sulfate in an HFA-134a, CFC-free propellant system (108 microg of albuterol sulfate, equivalent to 90 microg of albuterol base) with that of equivalent doses of albuterol in a conventional CFC propellant system. METHODS Twenty-two patients with at least a 12-month history of stable asthma, who were currently taken an inhaled beta-adrenergic bronchodilator, and who had a FEV1 between 40% and 80% of predicted, were enrolled in this randomized, modified-blind, two-period crossover study. One, 1, 2, 4, and 8 inhalations of study drug were self-administered at 30-minute intervals, resulting in 16 cumulative inhalations. Pulmonary function and safety measures were assessed after each dosing interval. RESULTS A significant dose response was found for HFA-134a albuterol sulfate and CFC albuterol with regard to changes in FEV1, serum potassium, heart rate, and blood pressure after 16 cumulative inhalations. No significant differences were demonstrated between HFA-134a albuterol sulfate and CFC albuterol for any FEV1 or safety parameter at any cumulative dose level. No clinically meaningful laboratory or physical examination abnormalities were found with administration of either HFA-134a albuterol sulfate or CFC albuterol. CONCLUSIONS HFA-134a albuterol sulfate provides bronchodilation comparable to CFC albuterol and has a similar safety profile.

Switching patients with asthma from chlorofluorocarbon (CFC) albuterol to hydrofluoroalkane-134a (HFA) albuterol

Chlorofluorocarbon (CFC) propellants deplete stratospheric ozone. Production and use of CFCs, except for certain critical exemptions, has been prohibited by the Montreal Protocol. Use of CFCs as propellants in metered-dose inhalers (MDIs) is still allowed, but the U.S. Food and Drug Administration is planning the transition to alternative propellants for use in MDIs. Hydrofluoroalkane-134a (HFA), a non-ozone-depleting propellant, has been used to reformulate albuterol (HFA albuterol). This study evaluates whether comparable safety and efficacy continues for 12 weeks after patients with asthma are switched from CFC albuterol to HFA albuterol. Patients with asthma stabilized on CFC albuterol during a 12-week safety and efficacy trial were randomized to either continue receiving CFC albuterol or to be switched to receive HFA albuterol in a yearlong safety and efficacy trial. Safety and efficacy were compared over the first 12 weeks of the yearlong trial between patients who had remained on CFC albuterol and those who had been switched to HFA albuterol. Bronchodilator efficacy was evaluated by serial spirometry for 6 hr after the patients self-administered the study drug in the clinic. Safety was assessed by measuring changes in pulse rate, blood pressure, and electrocardiogram (ECG) intervals after dosing with study drug, monitoring adverse events, and performing prestudy and poststudy laboratory testing and physical examinations. No significant differences in bronchodilator efficacy between the patients continuing to receive CFC albuterol and those switched to HFA albuterol were found in the 12 weeks after the switch. No differences between the two products were found for changes in pulse rate, blood pressure, and ECG intervals. Adverse event profiles were similar for the two products, except the patients remaining on CFC albuterol reported increased asthma symptoms and rhinitis significantly more often than the patients switched to HFA albuterol. No clinically meaningful changes in laboratory tests or physical examinations were found in either treatment group. Patients with asthma switched from CFC albuterol to HFA albuterol receive comparable bronchodilation with a similar safety profile as those continuing to receive CFC albuterol.

Comparable Bronchodilation with Hydrofluoroalkane-134a (HFA) Albuterol and Chlorofluorocarbons-11/12 (CFC) Albuterol in Children with Asthma

This was an open-label, parallel group, randomized, age-stratified, multicenter study designed to compare the safety and efficacy of regular use of albuterol formulated in hydrofluoroalkane-134a (HFA albuterol) and albuterol formulated in chlorofluorocarbons-11/12 (CFC albuterol) in children with asthma. Children age 4-11 years using a short-acting inhaled beta2-agonist for 6 months to manage stable asthma, and with a prestudy forced expiratory volume in 1 sec (FEV1) of >50% predicted after withholding short-acting inhaled beta2-agonists for at least 6 hr, an increase in FEV1 ≥ 12% within 30 min after two puffs of CFC albuterol, and the capability to comply with medication withholding requirements were eligible for study entry. After screening evaluation, patients entered a minimum 7-day run-in period. On study day 1 spirometry and a baseline 12-lead electrocardiogram (ECC) were performed, pulse and blood pressure were measured, and patients self administered two puffs of their randomized study drug, either HFA albuterol or CFC albuterol. Serial spirometry was performed over 6 hr after study drug dosing. Pulse and blood pressure were measured just prior to each spirometry and a 12-lead ECG was performed at 60 min postdose. Patients took two puffs of their study drug four times a day for 4 weeks. At study week 4, study day 1 procedures were repeated. Patients maintained a daily diary of morning (a.m.) and evening (p.m.) peak expiratory flow (PEF), daytime asthma symptom scores, nighttime asthma sleep disturbance scores, and study drug use. Demographics and baseline characteristics of the 63 patients randomized to HFA albuterol (33) and CFC albuterol (30) were similar. No significant differences were found between the HFA albuterol and CFC albuterol treatment groups for any of the primary or secondary FEV, efficacy variables either at study day 1 or study week 4. No significant differences were noted between treatment groups for a.m. and p.m. PEF, individual asthma symptom scores, nighttime asthma sleep disturbance scores, and rescue study drug use over the 4-week study. No significant differences were found between the two treatment groups for change from predose in heart rate, systolic and diastolic blood pressure, and 12-lead ECG intervals at either study day 1 or study week 4. Adverse event reporting was similar for the two treatment groups. In this study, with regular use of HFA albuterol in children with asthma, there was a similar safety profile and comparable bronchodilator efficacy as with CFC albuterol.

Proventil HFA Prevents Exercise-Induced Bronchoconstriction in Children

Short-acting inhaled beta2-agonists used just prior to exercise are an effective method for preventing exercise-induced bronchoconstriction (EIB) in children. This was a randomized, single-blind, placebo-controlled, four-period crossover study that compared the effectiveness of albuterol formulated in hydrofluoroalkane-134a (HFA) to albuterol formulated in chlorofluorocarbons (CFCs) and to placebo in protecting asthmatic children age 6-11 from EIB. Patients self-administered either HFA albuterol, two different CFC albuterol products, or placebo 30 min prior to exercise challenge. Spirometry was performed predose and 5, 10, 15, 30, 45, 60, 75, and 90 min after the exercise challenge was completed. The smallest percent change from the predose forced expiratory volume in 1 sec (FEV1) after exercise challenge was similar for the three active treatments, and each of the active treatments was significantly better than placebo. Each active treatment had significantly fewer patients unprotected from EIB (unprotected defined as having >20% fall in FEV1 after exercise challenge) than placebo. Changes in heart rate, blood pressure and electrocardiogram (ECG) intervals were similar for the three active treatments following exercise. HFA albuterol is as effective as albuterol products formulated in CFCs and more effective than placebo in protecting asthmatic children from EIB.

Systemic concentrations of salbutamol and HFA-134a after inhalation of salbutamol sulfate in a chlorofluorocarbon-free system

The objective of this study was to determine if salbutamol was absorbed from a new salbutamol sulfate chlorofluorocarbon (CFC)-free metered-dose inhaler (MDI). Measurement of HFA-134a, the CFC-free propellant, was included to provide proof of delivery of this MDI. Eight healthy men received two inhalations (90 micrograms salbutamol base equivalents per inhalation ex adapter) from the CFC-free inhaler (MDI A) in period 1 and from a reference CFC inhaler (MDI V) in period 2. Eight postdose samples were collected for the determination of salbutamol serum levels over a 4-h period. Salbutamol levels were not quantifiable in most samples. Four subjects given MDI A and two given MDI V had a few transient salbutamol levels, which occurred in the first hour after dosing, within a narrow range of 1-2 ng/ml and close to the lower limit of detection (1 ng/ml). No pharmacokinetic analyses were possible. Blood samples were also collected after MDI A for propellant quantitation. HFA-134a levels were seen in all subjects, verifying absorption. We conclude that the transient salbutamol serum levels can be attributed to the two-inhalation dose and not to either propellant system.

Bioequivalence of Press- and- Breathe and Breath-Actuated Inhalers of Beclomethasone Dipropionate Extrafine Aerosol

AbstractObjective: To assess the bioequivalence of beclomethasone dipropionate (BDP) delivered from a press-and-breathe (PB) inhaler and a breath-actuated inhaler (Autohaler™, AH). Design: Two randomised, open-label, single-dose, four-period crossover studies. Patients: Patients with mild asthma were enrolled in two separate studies: study 1 [n = 49; ages 18 to 45 years (mean 27.7 years); 73.5% males; 45 patients completed] and study 2 [n = 71; ages 18 to 51 years (mean 27.4 years); 35.2% males; 53 patients completed]. Methods: Patients received single doses of BDP 400 and 800μg (study 1) or 200 and 400μg (study 2) from the AH and PB inhalers, in four separate periods. In study 1, total beclomethasone (tot-BOH) was measured in serum as the BOH concentration after sample hydrolysis to convert BDP, and the monopropionates [17-beclomethasone monopropionate (17-BMP) and 21-BMP], to BOH. In study 2, concentrations of 17-BMP were measured in plasma. Bioequivalence was concluded if 95% confidence intervals for the ratio of adjusted geometric means of maximum drug concentration (Cmax) and area under the concentration-time curve (AUC) were completely contained within the interval [0.80, 1.25]. Results: BDP was rapidly absorbed; tot-BOH levels peaked at 0.4h and 17-BMP levels at 0.6h. Concentrations of tot-BOH and 17-BMP were comparable for the common 400μg dose between studies (Cmax of approximately 1200 ng/L and AUC of 4600 ng·h/L). 17-BMP levels declined monoexponentially with a half-life (t1/2) of 2.8h. The two inhalers were bioequivalent at all dose levels tested using tot-BOH or 17-BMP Cmax and AUC. In addition, the two inhalers were dose proportional. Conclusions: The AH inhaler is bioequivalent to the PB inhaler when used with correct technique. The tot-BOH assay was an acceptable surrogate analyte for the major metabolite 17-BMP.