Hydrofluoroalkane-134a (HFA) has been shown to be a safe replacement for chlorofluorocarbons (CFCs) as a pharmaceutical propellant, with the advantage that it has no ozone-depleting potential.1 Metered dose inhalers (MDIs) of beclomethasone dipropionate (BDP), using CFCs as propellant system in a press-and-breathe (P & B) inhalation device (CFC-BDP), have been used for many years in patients with bronchial asthma, but the Montreal Protocol represents international agreement to cease CFCs production and use. HFA is a suitable replacement propellant for CFCs in MDIs, as it does not deplete stratospheric ozone. The BDP solution product using HFA as propellant system (HFA-BDP) has a smaller particle size distribution (by mass) than the CFC-BDP suspension product, which results in improved intrapulmonary deposition and airway availability of HFA-BDP when compared with CFC-BDP.2 The HFA-BDP has an equivalent effect to the twice dose of CFC-BDP3 and has been approved and used in adult patients in numerous countries. As CFC-BDP has also been essential in the treatment of children with bronchial asthma, the indications and usage of HFA-BDP for children need to be established urgently. Although the pharmacokinetics of HFA-BDP in American children with bronchial asthma have already been reported,4, 5 they have not yet been reported in Japanese children. The objective of this clinical trial was to clarify the pharmacokinetics of HFA-BDP in Japanese children with bronchial asthma.

Five Japanese patients with stable mild asthma, between the ages of 6 years and 15 years (3 men and 2 women), were enrolled in this open-label study. Written informed consent was obtained from all patients and their parents or legal guardians in accordance with the Declaration of Helsinki. The independent medical ethics review committee of Gifu University approved the protocol. Each patient received 200 μg BDP per period, as four inhalations of 50 μg/actuation P & B. Time zero for each dose was defined as the time when the inhaler was first actuated. Blood samples were collected before administration, and at 0.5, 1, 2, 4, 6, 9, 12 and 24 hours after administration. Immediately after collection, the tube was inverted and the blood was cooled on ice and centrifuged at 2000 rpm for 10 minutes at 7°C, and the isolated plasma was pippeted into two tubes (0.5 mL per tube). In each tube, 15 μL of acetic acid was added and mixed. Mixed samples were frozen immediately in a dry ice/methanol bath and stored frozen at under -70°C until analysis. As almost all the BDP-derived material in plasma is reported to be the active metabolite, beclomethasone 17-monopropionate (17-BMP), 4 the plasma 17-BMP concentration was determined using an LC/MS/MS method with a lower limit of quantitation of 75 pg/mL developed by Harrison et al.5 with a few modifications. The pharmacokinetic parameters, area under concentration-time curve from time zero to the last quantifiable time (AUC_0-t), maximum concentration observed (C_max), time to reach C_max (T_max) and apparent elimination half-life (t_1/2) were calculated by a non-compartmental analysis of each plasma concentration-time profile using WinNonlin ver.4.0 (Pharsight Corporation). The effects of age (6 to 14 years) and body weight (22.8 to 85.0 kg) on AUC_0-t, C_max and t_1/2 were analyzed by linear regression analysis of log-transformed parameters against age or body weight.

The parameters of Japanese children obtained in this study were compared with the previously reported parameters of American children with bronchial asthma provided by 3M Pharmaceuticals (USA).6 For log-transformed parameters of AUC_0-t, C_max and t_1/2, means and their 90% confidence intervals were calculated for the differences between Japanese and American parameters and back-transformed to geometric means and their 90% confidence intervals for the ratios of Japanese parameters to American parameters. The log-transformed means of parameters were also compared by Student's t-test, considering p values of less than 0.05 to indicate statistically significant differences.

The individual plasma concentration profiles of 17-BMP in Japanese children with bronchial asthma and their mean profile are shown in Figure 1. Pharmacokinetic parameters are shown in Table 1. The arithmetic mean ± standard deviation (SD) of AUC_0-t was 1659 ± 850 pg·h/mL, C_max was 825 ± 453 pg/mL and t_1/2 was 2.1 ± 0.7 hours. T_max was 0.5 hours in all patients. The coefficient of variability of AUC_0-t and C_max (51.2% and 54.9%, respectively) was larger than that of t_1/2 (31.4%), which indicated a higher variability of the rate and extent of absorption than the elimination rate, possibly because of variability in the patients' inhalation techniques. No significant effect of age (6 to 14 years) or body weight (22.8 to 85.0 kg) on pharmacokinetic parameters was observed (Table 2, p = 0.145). This result suggests that no dose adjustment based on age or body weight in the range of this study is needed, though much more data are required to derive a conclusion.

The plasma concentration profiles of 17-BMP in Japanese and American children with bronchial asthma following a 200 μg BDP dose using the HFA-propellant system are shown in Figure 2. Pharmacokinetic parameters and their ratios (Japanese/American) are shown in Table 3. The differences of log-transformed mean 17-BMP parameters (AUC_0-t, C_max and t_1/2) between Japanese and Americans were not significant (p = 0.13). The median of T_max in American children was the same as that in Japanese children. The estimated Japanese/American AUC_0-t ratio was 1.36 with a 90% confidence interval of 0.870 to 2.13. The estimated Japanese/American C_max ratio was 1.04 with a 90% confidence interval of 0.671 to 1.62. The estimated Japanese/American t_1/2 ratio was 1.4 with a 90% confidence interval of 0.96 to 1.9. All confidence intervals contained 1, suggesting the possibility of the equivalence of the parameters between Japanese and Americans. The wide confidence intervals obtained may be due to variability in patients' inhalation techniques, and an insufficient limit of quantitation, which may affect the last quantifiable time-point and the apparent elimination half-life.

In conclusion, the pharmacokinetics of HFA-BDP in Japanese children with bronchial asthma were investigated and the following parameters (arithmetic mean ± SD or median for T_max) were obtained; AUC_0-t (1659 ± 850 pg·h/mL), C_max (825 ± 453 pg/mL), t_1/2 (2.1 ± 0.7 hours) and T_max (0.5 hours). These parameters were similar to those of American children with bronchial asthma.

In this study, the pharmacokinetic properties of HFA-BDP did not show much difference between the two countries. Therefore, propellant systems using CFCs should be replaced by systems using HFA as soon as possible in countries where such products have already been launched, from the standpoint of protection of the ozone layer. In addition, the introduction of HFA products, e.g. HFA-BDP, is strongly recommended in countries where such products are not clinically available.

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