Performance of the Population Bioequivalence (PBE) Statistical Test Using an IPAC-RS Database of Delivered Dose from Metered Dose Inhalers.

This article reports performance characteristics of the population bioequivalence (PBE) statistical test recommended by the US Food and Drug Administration (FDA) for orally inhaled products. A PBE Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) assembled and considered a database comprising delivered dose measurements from 856 individual batches across 20 metered dose inhaler products submitted by industry. A review of the industry dataset identified variability between batches and a systematic lifestage effect that was not included in the FDA-prescribed model for PBE.

Bronchodilator efficacy of extrafine glycopyrronium bromide: the Glyco 2 study.

An extrafine formulation of the long-acting muscarinic antagonist glycopyrronium bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate - a "fixed triple". This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 μg versus placebo; Part 2: repeat-dose (7-day), four-period crossover, GB 12.

A Two-Period Open-Label, Single-Dose Crossover Study in Healthy Volunteers to Evaluate the Drug-Drug Interaction Between Cimetidine and Inhaled Extrafine CHF 5993.

Background And Objectives: CHF 5993 is an extrafine 'triple therapy' combination of the long-acting muscarinic antagonist glycopyrronium bromide (GB), the long-acting β-agonist formoterol fumarate (FF), and the inhaled corticosteroid beclometasone dipropionate (BDP). It is in development for chronic obstructive pulmonary disease and asthma delivered via pressurised metered-dose inhaler.

Methods: This two-period, open-label, crossover study examined the drug-drug interaction of CHF 5993 and cimetidine.

Pharmacokinetics and pharmacodynamics of an extrafine fixed pMDI combination of beclometasone dipropionate/formoterol fumarate in adolescent asthma.

Aim: The aim was to investigate the pharmacokinetics and pharmacodynamics of an extrafine pressurized metered-dose inhaler (pMDI) fixed combination of beclometasone dipropionate (BDP)/formoterol fumarate (FF) in adolescent and adult asthma.

Methods: This was a three-way crossover study, on 30 asthmatic adolescents receiving BDP/FF pMDI with or without a valved holding chamber (VHC) or a free licenced combination of BDP pMDI and FF pMDI plus a parallel arm of 30 asthmatic adults receiving BDP/FF pMDI. All patients received a single dose of BDP and FF of 400 µg and 24 µg, for each treatment, respectively.

The systemic exposure to inhaled beclometasone/formoterol pMDI with valved holding chamber is independent of age and body size.

Background: Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage in children compared to older patients in order to minimize the systemic exposure and risk of unwanted side effects. In children, pressurized metered dose inhalers (pMDI) are recommended in combination with a valved holding chamber (VHC) to overcome the problem of coordinating inhalation with actuation. However, the influence of age and body size on the systemic exposure of drugs to be administered via a pMDI with VHC is still not fully elucidated.

Pharmacokinetic and tolerability profiles of tobramycin nebuliser solution 300 mg/4 ml administered by PARI eFlow(®) rapid and PARI LC Plus(®) nebulisers in cystic fibrosis patients.

Background: Tobramycin nebuliser solution (TNS) is indicated for maintenance therapy in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa (PA) infections. Adherence to recommended therapy in CF has always been a challenge and new generation nebulisers are increasingly used "off label" to reduce the time required for inhalation, potentially improving patient compliance.

Methods: In this open-label, randomised, multi-centre, two-period crossover study, 27 CF patients with PA infection received TNS 300 mg/4 mL (TNS4) via the PARI eFlow(®) rapid or PARI LC Plus(®) nebuliser twice daily for 28 days in two study periods separated by a 4-week washout.

Pharmacokinetic comparison of inhaled fixed combination vs. the free combination of beclomethasone and formoterol pMDIs in asthmatic children.

Aim: The fixed combination of beclomethasone (BDP) and formoterol pressurized metered dose inhaler (pMDI) (Foster®, Chiesi Farmaceutici) is being developed in the lower strength (BDP/formoterol: 50/6 μg) to provide an appropriate dosage for children with asthma. The aim of this work was to investigate the systemic bioavailability of beclomethasone-17-monoproprionate (B17MP, the active metabolite of BDP) and formoterol after single inhalation of Foster® pMDI 50/6 μg vs. the free combination of BDP and formoterol pMDIs in asthmatic children.

Rapid effects of extrafine beclomethasone dipropionate/formoterol fixed combination inhaler on airway inflammation and bronchoconstriction in asthma: a randomised controlled trial.

Background: The dose-dependent anti-inflammatory effects of a recent fixed combination of extrafine beclomethasone dipropionate/formoterol (BDP/F) were investigated using non-invasive markers of inflammation, exhaled nitric oxide (NO) and adenosine monophosphate (AMP) provocative challenge. The aim was to assess the onset of the anti-inflammatory action of low and high doses and evaluate the suitability of non-invasive assessments to demonstrate dose response.

Methods: Steroid naïve adult out-patients with mild asthma, sensitive to AMP with baseline exhaled NO > 25 parts per billion entered a double-blind, placebo-controlled, 3-way, cross-over study.

Effect of AeroChamber Plus™ on the lung and systemic bioavailability of beclometasone dipropionate/formoterol pMDI.

Aim: To assess the effect of AeroChamber Plus™ on lung deposition and systemic exposure to extra-fine beclometasone dipropionate (BDP)/formoterol (100/6 µg) pMDI (Foster®). The lung deposition of the components of the combination given with the pMDI was also evaluated using the charcoal block technique.

Methods: Twelve healthy male volunteers received four inhalations of extra-fine BDP/formoterol (100/6 µg) using (i) pMDI alone, (ii) pMDI and AeroChamber Plus™ and (iii) pMDI and charcoal ingestion.

Lung deposition of BDP/formoterol HFA pMDI in healthy volunteers, asthmatic, and COPD patients.

Background: When inhaling medication, it is essential that drug particles are delivered to all sites of lung inflammation, including the peripheral airways. The aim of this study was to assess the lung deposition and lung distribution of beclomethasone dipropionate (BDP)/formoterol (100/6 microg), both dissolved in hydrofluoroalkane (HFA) and delivered by pressurized metered dose inhaler (pMDI) in healthy subjects, asthmatic, and chronic obstructive pulmonary disease (COPD) patients, to investigate how the in vitro characteristics of the formulation translate into the in vivo performance in diseases with different airway obstruction.

Methods: Healthy volunteers (n = 8), persistent asthmatics (n = 8), and patients with stable COPD (n = 8) completed this open-label, single-dose parallel-group study.

Systemic exposure and implications for lung deposition with an extra-fine hydrofluoroalkane beclometasone dipropionate/formoterol fixed combination.

Background And Objectives: Foster is a fixed combination of beclometasone dipropionate/formoterol (BDP/F). It is formulated as an extra-fine solution and delivered via a pressurized metered-dose inhaler (pMDI) using a hydrofluoroalkane (HFA) propellant. The aims of this study were to compare the systemic exposure to BDP, to its active metabolite beclometasone-17-monopropionate (B17MP) and to formoterol after administration of BDP/F versus separate administration of a chlorofluorocarbon (CFC) formulation of BDP and formoterol HFA, and to explore a possible relationship between pharmacokinetic and pharmacodynamic findings.

Tolerability of high cumulative doses of the HFA modulite beclomethasone dipropionate/formoterol combination inhaler in asthmatic patients.

The corticosteroid beclomethasone dipropionate (BDP) has been formulated with the long acting beta agonist formoterol (BDP/formoterol 100 microg/6 microg, Foster) in a single inhaler using Modulite technology. We have investigated the acute tolerability of high, cumulative doses of BDP/formoterol compared to formoterol alone and placebo. This was a double blind, 3-way cross-over comparison of 10 puffs of BDP/formoterol 100 microg/6 microg or formoterol 6 microg or placebo during maintenance treatment with BDP/formoterol two puffs per day.

Lung deposition of formoterol HFA (Atimos/Forair) in healthy volunteers, asthmatic and COPD patients.

In this study, the influence of lung function on lung deposition of a radioactively labeled Formotoerol HFA MDI (Forair) was investigated. Eighteen subjects were measured: 6 healthy subjects (FEV(1) = 107% pred), 6 patients with Asthma (FEV(1) = 72% pred), and 6 patients with COPD (FEV(1) = 40% pred). The lung deposition of the radioactive-labeled drug was measured with a gamma camera.

Clinical pharmacology study of Bramitob, a tobramycin solution for nebulization, in comparison with Tobi.

Background And Objectives: To compare in vitro characteristics and pharmacokinetics of Bramitob, a preservative-free tobramycin solution for nebulization, and Tobi in patients with cystic fibrosis (CF) and Pseudomonas aeruginosa infection.

Methods: In vitro characteristics of Bramitob and Tobi were evaluated using Pari TurboBoy/LC Plus and the Systam 290 LS nebulizers. In the randomized, double-blind, two-way crossover pharmacokinetic study, 11 patients with CF received a single nebulized dose (300mg) of Bramitob or Tobi, separated by a 7-day washout period.

A tolerability and pharmacokinetic study of a new injectable formulation of disodium clodronate in healthy female volunteers.

Disodium clodronate (dichloromethylene bisphosphonic acid, disodium salt; CAS 22560-50-5) is a bisphosphonate that has demonstrated efficacy in patients with a variety of diseases of enhanced bone resorption. Intramuscular clodronate can determine pain at the injection site, it is therefore particularly useful to co-administer a local anaesthetic with clodronate to reduce pain at the injection site. The tolerability and pharmacokinetic of a new formulation of 100 mg disodium clodronate containing 1% lidocaine (test formulation, Chiesi Farmaceutici S.

Single oral dose pharmacokinetic interaction study of manidipine and delapril in healthy volunteers.

Objective: The objective of the study was to assess potential pharmacokinetic interactions between delapril, an angiotensin conversion enzyme inhibitor, and manidipine, a calcium channel antagonist, prior to the development of a fixed combination drug product.

Methods: Eighteen healthy male volunteers received a single oral dose of 10 mg manidipine dihydrochloride (CAS 89226-75-5), or 30 mg delapril hydrochloride (CAS 83435-67-0), or both simultaneously, according to a fully balanced three-way cross-over design. The three treatments were separated by a one-week washout period.

Pharmacokinetics and tolerability of a new manidipine and delapril fixed oral combination in young and elderly subjects.

Objectives: The aim of the present study was to compare the pharmacokinetic and pharmacodynamic properties of a fixed combination tablet containing 10 mg of manidipine dihydrochloride (CAS 89226-75-5), a calcium channel antagonist, and 30 mg of delapril hydrochloride (CAS 83435-67-0), an angiotensin converting enzyme (ACE) inhibitor, during once daily repeated dosing in young and elderly subjects and to assess the bioequivalence of the fixed combination tablet and the single ingredient tablets taken simultaneously in young healthy subjects after a single dose administration.

Methods: Eighteen young healthy male volunteers received a single oral dose of 10 mg manidipine and 30 mg delapril as two separate tablets or a fixed combination tablet, followed by a week of once daily dosing with the fixed combination. Eight male and eight female elderly volunteers also received a week of once daily dosing with the fixed combination.

Characterization of Ganstigmine metabolites in hepatocytes by low- and high-resolution mass spectrometry coupled with liquid chromatography.

In order to deepen the understanding of the metabolism of Ganstigmine, a new acetylcholinesterase inhibitor under evaluation for the treatment of Alzheimer's disease, samples obtained by incubating the drug with female rat hepatocytes were investigated by low-resolution liquid chromatography/tandem mass spectrometry (LC/MS/MS). The results confirmed the formation of most of the phase I metabolites already demonstrated, but also three new species. The combination of high-resolution quadrupole time-of-flight (Q-TOF) LC/MS and LC/MS/MS measurements, and the evaluation of the more reasonable metabolic routes, allowed the identification of the new metabolites as Geneseroline-glucuronide and oxidized and rearranged Ganstigmine.

Pharmacokinetic profile of a new controlled-release isosorbide-5-mononitrate 60 mg scored tablet (Monoket Multitab).

The influences of food, tablet splitting, and fractional dosing on the pharmacokinetics of a new controlled-release double-scored tablet containing 60 mg isosorbide-5-mononitrate (Monoket Multitab) were investigated in healthy male volunteers. Food interaction was evaluated after single dose administration under fasted conditions and after a standard high-fat breakfast. The effect of tablet splitting was assessed at steady-state, after 5 days of once daily dosing with the tablet taken intact or trisected.