Pharmacokinetics of Beclomethasone Dipropionate in an Hydrofluoroalkane-134a Propellant System in Japanese Children with Bronchial Asthma

ABSTRACTBackgroundHydrofluoroalkane-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. This is the first report of the pharmacokinetics of beclomethasone dipropionate (BDP) delivered from a pressurized solution formulation using an HFA propellant system (HFA-BDP) in Japanese children with bronchial asthma.MethodsPlasma concentrations of beclomethasone 17-monopropionate (17-BMP), a major metabolite of BDP, following an inhaled dose of HFA-BDP (200 μg as four inhalations from 50 μg/actuation) in five Japanese children with bronchial asthma were quantified and analyzed by a non-compartmental analysis to obtain pharmacokinetic parameters.ResultsThe area under the concentration-time curve from time zero to the last quantifiable time (AUC0-t) was 1659 ± 850 pg • h/mL (arithmetic mean ± standard deviation (SD)), the maximum concentration observed (Cmax) was 825 ± 453 pg/mL and the apparent elimination half-life (t1/2) was 2.1 ± 0.7 hours. The time to reach Cmax (Tmax) was 0.5 hours in all patients. No special relationship was observed between these parameters and age or body weight. These parameters were compared with the previously reported parameters of American children with bronchial asthma. The Japanese/American ratio of the geometric means of each parameter was 1.36 for AUC0-t, 1.04 for Cmax and 1.4 for t1/2. The median of Tmax was 0.5 hours in American patients as well as Japanese patients.ConclusionsThe pharmacokinetics of HFA-BDP in Japanese children with bronchial asthma are reported for the first time and a similarity to those in American children is suggested

Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes

The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIowa) is the first mutation that was associated with familial AApoA1 amyloidosis. The N-terminal fragments (amino acid residues 1–83) of apoA-I containing this mutation deposit as amyloid fibrils in patients’ tissues and organs, but the mechanisms of cellular degradation and cytotoxicity have not yet been clarified. In this study, we demonstrated degradation of apoA-IIowa fibrils via the autophagy-lysosomal pathway in human embryonic kidney 293 cells. ApoA-IIowa fibrils induced an increase in lysosomal pH and the cytosolic release of the toxic lysosomal protease cathepsin B. The mitochondrial dysfunction caused by apoA-IIowa fibrils depended on cathepsin B and was ameliorated by increasing the degradation of apoA-IIowa fibrils. Thus, although apoA-IIowa fibril transport to lysosomes and fibril degradation in lysosomes may have occurred, the presence of an excess number of apoA-IIowa fibrils, more than the lysosomes could degrade, may be detrimental to cells. Our results thus provide evidence that the target of apoA-IIowa fibrils is lysosomes, and we thereby gained a novel insight into the mechanism of AApoA1 amyloidosis

Population pharmacokinetics of pranlukast hydrate dry syrup in children with bronchial asthma

Background: This is the first report about the pharmacokinetics (PK) of pranlukast in children. The aim of the present study was to assess the PK parameters of pranlukast in children and to compare them with those in adults. Methods: Six healthy adult male volunteers and 22 children with bronchial asthma at 3–14 years of age were enrolled in the study. Both 225 and 112.5 mg pranlukast hydrate dry syrup was administered orally to adults, whereas 3.5 mg/kg pranlukast hydrate dry syrup was given to children. Blood samples were obtained at approximately 20 time points per adult (n=121) and at two or three time points per child (n=54). Population PK analysis was performed using NONMEM (Globomax, Hanover, MD, USA). The concentration-time-course of pranlukast was described by using a one-compartment model with first-order absorption. The robustness of the final model was evaluated using 200 bootstrap samples. Results: Apparent clearance (CL/F) was 1.81 and 1.14 L/h per kg in children and adults, respectively. According to subgrouping of children, no significant difference was observed in CL/F between infants (3–6 years of age) and schoolchildren (7–14 years of age). The interindividual variability of CL/F accounted for 48.7%. The additive and proportional residual variability was 7.33 ng/mL and 73.8%, respectively. All fixed effect parameters fell within 10% of the bootstrapped mean. Conclusions: Compared with adults, children showed a higher CL/F and more rapid elimination after ingestion of pranlukast hydrate dry syrup. However, no significant variation was seen in CL/F between infants and schoolchildren