Annalisa Piccinno

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. Pharmacokinetics over 12h during maintenance treatment was measured on day 7. High cumulative doses were then administered on three separated days. Eighteen patients with asthma were recruited (mean FEV(1) 65% predicted). The primary endpoint was serum potassium over the 12h period after high doses. QTc, blood pressure and heart rate over 12h, and plasma lactate and glucose over 3h following dosing were assessed. Formoterol caused a significantly greater decrease in serum potassium than BDP/formoterol or placebo (difference in mean minimum concentrations; 0.11 and -0.15 mmol/l, respectively, p<0.05 for both comparisons). No significant differences in serum potassium parameters were found between BDP/formoterol and placebo. QTc, plasma lactate and vital signs values observed with the combination were not statistically different from those with formoterol alone. For glucose, the mean maximum increase after formoterol treatment was 0.4 mmol/l (p<0.01 compared to placebo), while BDP/formoterol treatment caused a maximum increase of 0.7 mmol/l (p<0.01 compared to formoterol and placebo). The active metabolite of BDP is beclomethasone-17-monopropriate (B17MP), which reached Cmax at 0.25 h, with an elimination half-life of 3.7 h. Formoterol also reached Cmax at 0.25 h, and concentrations were measurable up to 12 h. High doses of BDP/formoterol did not significantly reduce serum potassium, while formoterol alone did to a greater extent. The BDP/formoterol combination was well tolerated, and exhibited a safety profile generally similar to formoterol alone when administered in high doses to stable asthmatic patients.

A first-in-human clinical study of a new SP-B and SP-C enriched synthetic surfactant (CHF5633) in preterm babies with respiratory distress syndrome

Objective CHF5633 (Chiesi Farmaceutici S.p.A., Parma, Italy) is the first fully synthetic surfactant enriched by peptide analogues of two human surfactant proteins. We planned to assess safety and tolerability of CHF5633 and explore preliminary efficacy. Design Multicentre cohort study. Patients Forty infants from 27+0 to 33+6 weeks gestation with respiratory distress syndrome requiring fraction of inspired oxygen (FiO2) ≥0.35 were treated with a single dose of CHF5633 within 48 hours after birth. The first 20 received 100 mg/kg and the second 20 received 200 mg/kg. Outcome measures Adverse events (AEs) and adverse drug reactions (ADRs) were monitored with complications of prematurity considered AEs if occurring after dosing. Systemic absorption and immunogenicity were assessed. Efficacy was assessed by change in FiO2 after dosing and need for poractant-alfa rescue. Results Rapid and sustained improvements in FiO2 were observed in 39 (98%) infants. One responded neither to CHF5633 nor two poractant-alfa doses. A total of 79 AEs were experienced by 19 infants in the 100 mg/kg cohort and 53 AEs by 20 infants in the 200 mg/kg cohort. Most AEs were expected complications of prematurity. Two unrelated serious AEs occurred in the second cohort. One infant died of necrotising enterocolitis and another developed viral bronchiolitis after discharge. The single ADR was an episode of transient endotracheal tube obstruction following a 200 mg/kg dose. Neither systemic absorption, nor antibody development to either peptide was detected. Conclusions Both CHF5633 doses were well tolerated and showed promising clinical efficacy profile. These encouraging data provide a basis for ongoing randomised controlled trials. Trial registration number ClinicalTrials.gov NCT01651637.

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. METHODS Children aged 5-11 years old inhaled BDP 200 μg and formoterol 24 μg as fixed vs. free combination in an open label, randomized, two way crossover single dose study. Blood was collected pre-dose up to 8 h post-dose for pharmacokinetic evaluation (AUC(0,t), AUC(0,∞), AUC(0,0.5 h, Cmax , tmax , t1/2 ). Pharmacodynamics included heart rate, plasma potassium, urinary glucose and cortisol excretion. Peak expiratory flow and adverse events were monitored. RESULTS Twenty subjects were evaluable. The systemic exposure of B17MP and formoterol administered as fixed combination did not exceed the free combination: B17MP AUC(0,t) (pg ml(-1)  h) ratio test : reference (90% CI), 0.81 (0.697, 0.948) and formoterol AUC(0,t) (pg ml(-1)  h) ratio test : reference 0.97 (0.85, 1.10). All pharmacokinetic and pharmacodynamic end points showed non-superiority in favour of the test drug. One adverse event (vertigo) occurred but was not considered treatment-related. CONCLUSION BDP and formoterol pharmacokinetic and pharmacodynamic effects are non-superior after administration of the two actives as fixed vs. the free combination in 5-11-year-old asthmatic children.

Systemic exposure to inhaled beclometasone/formoterol DPI is age and body size dependent

AIM Prescription of inhaled corticosteroids to children with asthma is recommended at half the nominal dose of adults in order to reduce the risk of systemic side effects. However, there is a lack of pharmacokinetic trials supporting such dose reduction regimens. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed dose combination of beclometasone-dipropionate (BDP) and formoterol after dry powder inhaler (DPI) administration in children, adolescents and adults. METHODS The pharmacokinetic profiles of formoterol and beclometasone-17-monopropionate (B17MP; active metabolite of BDP) were evaluated over 8 h from two independent studies comprising children (6-11yrs, n = 27), adolescents (12-17 yrs, n = 28) and adults (≥18 yrs, n = 30) receiving a single, fixed dose of BDP/formoterol (children: 200 μg/24 μg, adolescents and adults: 400 μg/24 μg) via DPI. RESULTS The systemic exposure (AUC) for children versus adults was almost doubled for formoterol and similar for B17MP despite the halved BDP dose administered in children. In adolescents the AUC for formoterol and B17MP were approximately one third higher than in adults for both compounds. Upon normalization for the BDP/formoterol dose in the three populations the AUC and peak concentration (C(max)) correlated inversely with age and body surface area of the patients (r ≤ -0.53; p < 0.0001). CONCLUSION The systemic exposure to the active ingredients of BDP/formoterol administered as DPI correlates inversely with age and body size suggesting that dry powder dosage regimens should be adjusted for age and body size to avoid high systemic drug levels in children.

First clinical evaluation of ganstigmine in patients with probable Alzheimer's disease.

The objective of this study was to evaluate the safety, tolerability, maximum tolerated dose, pharmacokinetics, and pharmacodynamics of five fixed doses of ganstigmine (CHF 2819) in patients with probable Alzheimers disease (AD). This randomized, double-blind, placebo-controlled trial evaluated five dose levels (5, 7.5, 10, 12.5, and 15 mg) administered orally once daily for 7 days. Adverse events and continuous telemetry were collected on successive panels of six patients (five active, one placebo). Acetylcholinesterase, butyrylcholinesterase, and plasma drug levels were measured. A total of 29 patients were randomized and 18 completed the study. A total of seven patients, including five of five in the 12.5-mg panel, discontinued because of adverse events. Four patients were withdrawn administratively from the first panel while an episode of atrial fibrillation (the only serious adverse event) was investigated. This panel was then repeated. Mild, transient headache or nausea were the most commonly reported adverse events. Multiple moderate adverse events in the 12.5-mg panel (including nausea, vomiting, and anorexia) led to the decision not to proceed with a 15-mg panel. Ten milligrams was determined to be the maximum tolerated dose. Ganstigmine exhibited nonlinear pharmacokinetics, was absorbed rapidly, and reached peak concentrations within 1 hour. Acetylcholinesterase inhibition was dose dependent and lasted as long as 24 hours. Ganstigmine, a novel cholinesterase inhibitor, was well tolerated within a dosing range of 5 to 10 mg. Once-daily dosing is supported by data on acetylcholinesterase inhibition.

A clinical pharmacology study of fixed vs. free combination of inhaled beclometasone dipropionate and formoterol fumarate dry powder inhalers in asthmatic adolescents

Inhaled corticosteroids and long-acting β2-agonists are medications taken daily on a long-term basis to keep asthma under clinical control. Studies have shown that delivering this therapy in a combination inhaler is as effective as giving each drug separately, but fixed combination inhalers are more convenient for adolescents with asthma, increasing treatment adherence and ensuring that long-acting β2-agonists are always accompanied by inhaled corticosteroids [1,2]. An extrafine fixed combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) is marketed both as a pressurized metered dose inhaler (pMDI) and as a dry powder inhaler (DPI), as Foster® and Foster® Nexthaler® (Chiesi Farmaceutici S.p.A., Parma, Italy) [3], respectively, at the dose strength of 100/6 μg for patients with asthma ≥18 years of age. The same dose strength is currently being developed in asthmatic adolescents aged 12–17 years. The purpose of this study was to investigate the systemic availability of B17MP (active metabolite of BDP) and formoterol after inhalation of an extrafine fixed combination of BDP/FF 100/6 μg via the NEXThaler® DPI in comparison to the free combination of BDP (Clenil® Pulvinal® 100 μg) and FF (Foradil® Aerolizer® 12 μg) DPIs (Novartis Pharmaceuticals Ltd, Frimley, UK) at a total single dose of 400/24 μg in asthmatic adolescents. Adolescents aged 12–17 years with mild-to-moderate asthma in a stable state participated in this randomized, crossover, single-dose study with two active treatment periods conducted at the Childrens Asthma Clinic, Copenhagen, Denmark (ClinicalTrials.gov Identifier: NCT01191424). On each treatment day, blood was sampled for pharmacokinetic and pharmacodynamic assessments before and 5, 15 and 30 min and 1, 2, 4, 6 and 8 h after actuation of the DPIs [4]. Lung function [forced expiratory volume in 1 s (FEV1)] and heart rate were assessed concomitantly and adverse events recorded (see Appendix S1 for details). Pharmacokinetic end-points were as follows: area under the plasma drug concentration–time curve (AUC0–t), maximal plasma concentration (Cmax) and terminal half-life (t1/2) for B17MP and formoterol. The AUC0–t for B17MP was the primary end-point. Pharmacodynamic end-points were as follows: plasma potassium and plasma cortisol minimum plasma concentration (Cmin) and AUC0–t, plasma glucose Cmax and AUC0–2h, time-averaged FEV1 (AUC0–8h/8h) and heart rate (AUC0–8h/8h). All variables were log-transformed and treatment comparisons made using ANOVA models estimating the ratio of the adjusted geometric means test/reference (fixed/free combination) with the corresponding 90% confidence interval (CI) for the pharmacokinetic variables and 95% CI for the pharmacodynamic variables. Bioequivalence for the variables between treatments was demonstrated if the CIs were within the 0.8–1.25 acceptance region [5]. The study design had 90% power to reject the null hypothesis that the upper limit of the 90% CI for the ratio of test/reference means above 1.25 for B17MP AUC0–t. Twenty-seven adolescents [55% males; mean age (SD), 14 years (1.7)] completed the study. The B17MP AUC0–t was slightly higher following BDP/FF NEXThaler® vs. BDP and FF DPIs: test/reference ratio 1.14 (90% CI, 1.03–1.28; Table 1). The plasma cortisol test/reference ratio lower 90% CI bound was just below 0.8 [AUC0–t ratio, 0.92 (0.79–1.06)], but no plasma cortisol levels were below the lower clinical normal limit (5 ng ml−1) in either treatment group. Formoterol AUC0–t was higher following test vs. reference treatment [ratio, 1.46 (1.36–1.56)] and Cmax significantly increased [ratio, 2.83 (2.56–3.13)], but time to Cmax was the same for both treatments (median, 0.08 h). The plasma potassium [AUC0–t test/reference ratio, 0.98 (0.95–1.00)], plasma glucose [AUC0–2h ratio, 1.02 (0.99–1.05)] and heart rate [AUC0–8h/8h ratio, 1.05 (1.01–1.09)] were all within the predefined bioequivalence limit. The treatment effects on FEV1 were similar, and no notable differences in adverse events were observed (see Appendix S1). Table 1 Pharmacokinetic and pharmacodynamic comparison of BDP/FF 400/24 μg inhaled from the fixed BDP/FF 100/6 μg NEXThaler® DPI vs. BDP (Clenil® Pulvinal® 100 μg) and FF ... In adolescents with asthma, the systemic exposure to B17MP following four actuations of BDP/FF 100/6 μg NEXThaler® DPI compared with four actuations of BDP (Clenil® Pulvinal® 100 μg) and two actuations of FF (Foradil® Aerolizer® 12 μg) DPIs was slightly above the 125% bioequivalence limit, with a minor suppression of plasma cortisol levels. The clinical relevance of such suppression should be assessed after repeated administration according to European Medicines Agency guidelines [5]. Formoterol exposure was higher after administration of the fixed vs. free combination, but with comparable systemic effect in terms of heart rate, plasma glucose and plasma potassium. The FEV1 and safety profiles were also comparable. Potassium AUC0–t and Cmin were not affected by the increased formoterol exposure, which may be due to the transient formoterol peak concentration and the time delay between concentration and response or, alternatively, assay insensitivity. We speculate that the increased systemic exposure to formoterol and the slightly increased exposure to B17MP following the fixed BDP/FF NEXThaler® is caused by device-dependent different lung deposition. The BDP/FF NEXThaler® is an extrafine particle DPI with a low minimal inhalation flow threshold [6] in comparison to the Foradil® Aerolizer®, which requires a flow >60 l min−1, below which deagglomeration may be inefficient, resulting in a reduced emitted dose with larger particles and reduced lung deposition. In conclusion, inhalation from BDP/FF 100/6 μg NEXThaler® DPI resulted in a very similar exposure to B17MP but a greater exposure to formoterol compared with the licensed free combination in asthmatic adolescents. However, the greater bioavailability of formoterol following dosing with NEXThaler® had no systemic impact and did not affect the safety profile. For conduction of future bioequivalence trials, we highly recommend usage of devices with comparable lung deposition characteristics, because systemic absorption in adolescents seems to differ according to the device, which may have safety implications.