Pharmacokinetics of extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide in adolescent and adult patients with asthma.

The single-inhaler extrafine formulation triple combination beclometasone dipropionate (BDP), formoterol fumarate (FF) plus glycopyrronium bromide (GB) is available for asthma management in adults. Its use in adolescents has not yet been evaluated. This study investigated the pharmacokinetic profile of BDP/FF/GB in adults and adolescents, with the aim of ruling out higher plasma exposure in adolescents compared to adults. In this open-label, non-randomized study, patients with asthma aged 12-17 (adolescents) and 18-64 years (adults) self-administered a single dose of BDP/FF/GB 400/24/50 µg via pressurized metered-dose inhaler (pMDI). The primary objective was to rule out higher systemic exposure to beclometasone 17-monopropionate (B17MP; active metabolite of BDP), formoterol, and GB in terms of the area under the plasma concentration-time curve from 0 to the last quantifiable concentration (AUC0-t ) in adolescents versus adults. A total of 40 adolescents and 40 adults entered the study (mean age of 14.8 and 43.6 years, respectively). The primary objective (AUC0-t ) was met, with the upper 90% confidence interval of the geometric mean ratio between adolescents and adults <125% for B17MP (point estimate 79.28 [90% CI 71.19; 88.29]), formoterol (88.68 [77.71; 101.20]) and GB (85.49 [72.96; 100.16]). All secondary pharmacokinetic endpoints supported the primary, with pharmacodynamic (safety) and tolerability results similar in the two populations. In conclusion, systemic exposure to extrafine BDP/FF/GB pMDI in adolescents was not higher than that in adults. Furthermore, there were no safety or tolerability signals to warrant a reduction in the dose of BDP/FF/GB for adolescents with asthma.

A Randomized, Controlled Trial to Investigate the Efficacy of Nebulized Poractant Alfa in Premature Babies with Respiratory Distress Syndrome.

OBJECTIVE: To investigate the efficacy and safety of nebulized poractant alfa (at 200 and 400 mg/kg doses) delivered in combination with nasal continuous positive airway pressure compared with nasal continuous positive airway pressure alone in premature infants with diagnosed respiratory distress syndrome. STUDY DESIGN: This randomized, controlled, multinational study was conducted in infants at 280/7 to 326/7 weeks of gestation. The primary outcome was the incidence of respiratory failure in the first 72 hours of life, defined as needing endotracheal surfactant and/or mechanical ventilation owing to prespecified criteria. Secondary outcomes included the time to respiratory failure in the first 72 hours, duration of ventilation, mortality, incidence of bronchopulmonary dysplasia, and major associated neonatal comorbidities. In addition, the safety and tolerability of the treatments were assessed reporting the number and percentage of infants with treatment-emergent adverse events and adverse drug reactions during nebulization. RESULTS: In total, 129 infants were randomized. No significant differences were observed for the primary outcome: 24 (57%), 20 (49%), and 25 (58%) infants received endotracheal surfactant and/or mechanical ventilation within 72 hours in the poractant alfa 200 mg/kg, poractant alfa 400 mg/kg, and nasal continuous positive airway pressure groups, respectively. Similarly, secondary respiratory outcomes did not differ among groups. Enrollment was halted early owing to a change in the benefit-risk balance of the intervention. Nebulized poractant alfa was well-tolerated and safe, and no serious adverse events were related to the study treatment. CONCLUSIONS: The intervention did not decrease the likelihood of respiratory failure within the first 72 hours of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03235986.

Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in De Novo Kidney Transplant Recipients: A Randomized, Parallel-Group, Open-Label, Multicenter Study.

INTRODUCTION: Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus®) has not been compared with PR-Tac (Advagraf®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations. METHODS: This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations. RESULTS: PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (tmax), lower maximum concentration (Cmax) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar. CONCLUSION: In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac. TRIAL REGISTRATION: Registered at ClinicalTrials.gov; study number NCT02500212. FUNDING: Chiesi Farmaceutici S.p.A.

Acute cardiovascular safety of two formulations of beclometasone dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study.

INTRODUCTION: An extrafine combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) via a pressurised metered-dose inhaler (pMDI) has been commercially available for some years for the management of asthma and chronic obstructive pulmonary disease (COPD). A dry powder inhaler (DPI) formulation of extrafine BDP/FF is now also available. This study evaluated the cardiovascular safety of BDP/FF DPI in comparison to BDP/FF pMDI and placebo. METHODS: Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study. Main inclusion criteria: aged 40-75 years; moderate to severe COPD (post-bronchodilator FEV1 40-80% predicted, FEV1/FVC <0.7). Patients received BDP/FF 200/12, 800/48 µg and placebo via DPI, and BDP/FF 200/12 and 800/48 µg via pMDI. In both devices, 200/12 µg is the therapeutic dose; 800/48 µg is supratherapeutic. PRIMARY OBJECTIVE: to demonstrate non-inferiority between BDP/FF DPI and pMDI in average 4-h heart rate (HR0-4h) at each dose level. Secondary variables included: HR0-12h, HR peak and individual timepoint; QTcF interval; SBP and DBP AUC0-12h; and potassium and glucose AUC0-4h. Adverse events (AEs) were collected. RESULTS: Forty-nine patients were randomised; 45 (92%) received all five treatments. Non-inferiority was demonstrated between the DPI and pMDI formulations at both doses (-0.2 bpm [95% CI -1.3, 0.9] for 200/12 µg and 0.6 bpm [-0.5, 1.7] for 800/48 µg). Although there were statistically significant treatment-placebo differences at both doses and with both devices (thus confirming assay sensitivity), these differences were small and well below 5 bpm for the 200/12 µg dose. The results for the secondary parameters (QTcF, glucose and potassium) further supported the therapeutic equivalence of the two treatments. At the therapeutic dose, there were no clinically relevant treatment-placebo differences in any parameter with either formulation. There was no increase in the proportion of patients reporting AEs whilst receiving therapeutic doses of BDF/FF (either formulation) compared with placebo. CONCLUSIONS: Overall, this study provides reassurance over the cardiovascular safety of extrafine BDP/FF, both in a DPI and a pMDI formulation.

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 ß2-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. In one period, subjects received cimetidine 800 mg twice daily for 6 days; on the fourth day they also received CHF 5993 (BDP/FF/GB 400/24/100 µg). In the other, they received CHF 5993 alone. Primary objective was to compare the area under the plasma concentration-time curve from time 0 to last quantifiable concentration (AUC0-t) of GB, with and without cimetidine. Secondary endpoints included GB AUC0-12h, maximum concentration (C max), time to C max (t max), elimination half-life (t ½) and urinary excretion. Pharmacokinetic parameters of BDP, beclometasone-17-monopropionate (B17MP; active metabolite of BDP) and formoterol were also evaluated. RESULTS: Twenty-six subjects were randomised; 25 completed. Co-administration of CHF 5993 and cimetidine resulted in small, statistically significant increases in GB AUC0-t, AUC0-12h and C max vs CHF 5993 (ratios 1.16, 1.21 and 1.26, respectively); t ½, t max and urinary excretion were unaffected. There were small, statistically significant increases in formoterol AUC0-t, AUC0-24h and t ½ following co-administration of cimetidine and CHF 5993; urinary excretion was unaffected. There were no significant differences for either BDP or B17MP. There were few adverse events (AEs), and no serious AEs. CONCLUSIONS: Overall, this study indicates that there is no clinically relevant drug-drug interaction between CHF 5993 and cimetidine.

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.