Lester I. Harrison

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.

Adrenal Effects and Pharmacokinetics of CFC-free Beclomethasone Dipropionate: a 14-Day Dose-Response Study

Since equivalent efficacy is achieved with lower doses of the reformulated beclomethasone dipropionate in the chlorofluorocarbon (CFC)‐free propellant HFA‐134a (HFA) than with the original CFC‐beclomethasone dipropionate formulation, it is possible the HFA‐beclomethasone dipropionate may have less safety concerns than the CFC formulation. Despite its chronic use, the steady‐state pharmacokinetics of beclomethasone dipropionate has never been studied before. This double‐blind study examined adrenal effects and pharmacokinetics after 14 days of dosing with HFA‐beclomethasone dipropionate.

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.

Pharmacokinetics and dose proportionality of beclomethasone from three strengths of a CFC‐free beclomethasone dipropionate metered‐dose inhaler

As part of a development program to offer alternatives to chlorofluorocarbon (CFC) containing metered‐dose inhalers, beclomethasone dipropionate has been formulated in a CFC‐free system at three strengths: 50, 100, and 200 μg/actuation ex valve. To measure serum levels and dose proportionality of the beclomethasone derived from beclomethasone dipropionate, 13 mild to moderate asthmatic patients received a single dose of eight inhalations from each strength according to a double‐blind crossover design. Seven patients were studied over 4 h and six patients over 12 h. For the total doses of 400, 800, and 1600 μg studied over 12 h, Cmax and AUC increased in a ratio of 1:1·8:3·1. A good correlation was seen between the fine‐particle mass delivered and the in vivo performance of the three strengths. From a clinical point of view, the predictable increases in serum levels with an increase in dose will permit the clinician to effectively titrate a patient with this product.

Beclomethasone relative availability of oral versus inhaled beclomethasone dipropionate from an HFA‐134a metered dose inhaler

3M has formulated a new chlorofluorocarbon‐free (CFC‐free) beclomethasone dipropionate (BDP) metered‐dose inhaler (MDI) with the use of the propellant HFA‐134a (HFA). Lung deposition studies demonstrated that the HFA BDP MDI delivers to the lungs approximately 56% of the BDP dose (ex‐adaptor), a substantially higher percentage than the 5–30% delivered by conventional CFC BDP MDIs. As new sensitive bioanalytical methods are becoming available to quantitate systemic levels of inhaled corticosteroids, pharmacokinetic evaluations are emerging as sensitive and reproducible methods that can be used as a complement to the data obtained from lung deposition studies to assess and compare the performance of MDIs. The present study was designed to determine the beclomethasone (BOH) availability of oral BDP relative to inhaled HFA BDP as a first step to alloy MDI product comparisons in the future. Forty mild asthmatic patients completed this open‐label, randomized, single‐dose, two‐period crossover study. Each patient received an oral dose of BDP (0.2, 0.5, 1, 2 or 5 mg) in one period and an inhaled dose of BDP (0.2 or 0.8 mg) in the other period, with four patients allocated to each of ten different treatment sequences. The BOH availability of orally administered BDP was approximately 40% relative to inhaled HFA BDP. In addition, the fraction of an oral dose that reaches the systemic circulation was estimated from the 40% relative availability and previous lung deposition data to be 0.26. These estimated pharmacokinetic parameters will be used in the future to further characterize the pharmacokinetics of inhaled BDP and to compare the performance of different MDI products.

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.

Comparative serum estradiol profiles from a new once-a-week transdermal estradiol patch and a twice-a-week transdermal estradiol patch

Two identical open-label, randomized crossover studies were conducted to compare serum estradiol profiles from the new 12.5- and 25-cm2 once-a-week adhesive patches with those from the 10- and 20-cm2 commercially available twice-a-week Estraderm patches when applied as directed during a 1-week patch-wear period. Both studies were conducted in healthy postmenopausal women; serum estradiol levels were determined by gas chromatography/mass spectroscopy (GC/MS). Although both sizes of both patch treatments produced mean serum estradiol levels in the therapeutic range, the once-a-week patch provided more constant mean levels, avoiding large peak-to-trough fluctuations. As expected, the differences in mean serum estradiol concentrations between the two patch treatments occurred during the second application of the twice-a-week patch. Based on these results, the once-a-week drug in adhesive patch appears to be an acceptable means of hormone replacement therapy.

Determination of the chlorofluorocarbon substitute 1,1,1,2-tetrafluoroethane (HFA-134a) in human and animal blood using gas chromatography with headspace analysis.

A gas chromatographic procedure with headspace analysis and flame-ionization detection is described for the determination of the chlorofluorocarbon substitute 1,1,1,2-tetrafluoroethane (HFA-134a). A 0.5-2 ml sample of heparinized whole blood from a laboratory animal or human is added directly into a presealed headspace vial from which an equivalent volume of air has been removed. The internal standard 1,1,2,2-tetrafluoroethane is added and the sample frozen until analysis. Chromatographic separation is achieved using a PoraPlot Q porous-layer capillary column. The analytical range is 5.8-3298 ng/ml when 2-ml human blood samples are used. The concentration range of the calibration curve can be easily adapted to accommodate the concentrations expected in either pharmacokinetic or toxicokinetic studies. Automation of the assay permits the maximum number of samples to be processed in a day.

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.