Budesonide administered using chlorofluorocarbon and hydrofluoroalkane pressurized metered-dose inhalers: pharmacokinetics, pharmacodynamics and clinical equivalence.
OBJECTIVE
The traditional chlorofluorocarbon (CFC) propellants used in pressurized metered-dose inhalers (pMDIs) have unacceptable environmental effects and are being replaced by alternatives such as hydrofluoroalkanes (HFAs). However, there is a need to ensure that pMDIs with these novel propellants are as effective and safe as their older counterparts.


METHODS
Single-dose pharmacokinetic and multiple high-dose Phase I studies in healthy volunteers and randomized, controlled 12-week Phase III clinical trials in children, adolescents and adults with mild-to-moderate asthma have been performed to compare the efficacy and safety of HFA-based budesonide inhaler therapy with the traditional CFC-based pMDI.


RESULTS
The pharmacokinetic study in 40 persons showed comparable characteristics of CFC and HFApMDIs, with good dose-proportionality, at doses of 400, 800 and 1,600 microg. The high-dosage (1,600 microg/day) study in 48 subjects showed both inhaler types to be similar in terms of effects on hypothalamic-pituitary-adrenal axis function over 4 weeks. The pediatric clinical study involved 159 children and showed noninferiority of the HFA pMDI in terms of 12-week change in forced expiratory volume in 1 sec, other spirometric parameters and symptomatic measures. The adolescent/adult study in 321 subjects also showed similarity between the two formulations, in terms of 12-week primary endpoint (changes in morning peak expiratory flow rates) and other lung function and symptom measures. Both formulations were well-tolerated, with no safety issues being identified for the novel HFA inhaler in any study.


CONCLUSIONS
Budesonide HFA pMDI is pharmacokinetically and clinically comparable to the traditional CFC-based inhaler, with similar safety profile.
Singh
D
D
Respiratory Pharmacology, South Manchester University Hospitals Trust, University of Manchester, Manchester, UK. dsingh@meu.org.uk
Tutuncu
A
A
Lohr
I
I
Carlholm
M
M
Polanowski
T
T
D000293:Adolescent; D000328:Adult; D000335:Aerosol Propellants; D000368:Aged; D001249:Asthma / Q000188:drug therapy; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019819:Budesonide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D017402:Chlorofluorocarbons; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D010366:Peak Expiratory Flow Rate; D010913:Pituitary-Adrenal System / Q000187:drug effects; D013810:Therapeutic Equivalency; D005466:Fluorocarbons
D000335:Aerosol Propellants; D001993:Bronchodilator Agents; D019819:Budesonide; D017402:Chlorofluorocarbons; D006845:Hydrocarbons, Fluorinated; C094049:apaflurane; D005466:Fluorocarbons