Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Cough and cold preparations, Mucolytic. ATC code: R05CB16 
Mechanism of action
Bronchitol is an inhaled hyperosmotic medicinal product. While the exact mechanism of action is unknown, inhaled mannitol may change the viscoelastic properties of mucus, increase the hydration of the periciliary fluid layer and contribute to increased mucus clearance of the retained secretions through mucociliary activity. Productive cough can contribute to sputum clearance.

Pharmacodynamic effects
In the ITT population of an open label dose response study, DPM-CF-202, the mean (SD) percent change in FEV 1 for the 400 mg dose was 8.75 (SD: 12.4) and -1.569 (SD: 9.0) for 40 mg dose (p < 0.0001).

Clinical efficacy and safety
Two Phase 3, 26-week double blind, randomised, parallel arm, controlled, intervention studies (DPM-CF-301 and DPM-CF-302) have been performed in which 324 (DPM-CF-301) and 318 (DPM- CF-302) patients aged 6 years and above were randomised in a 3:2 ratio to inhaled mannitol 400 mg twice daily or to control (inhaled mannitol 50 mg twice daily). Twenty seven (7%) out of 389 patients enrolled in study 301 and 14 (4.1%) out of 342 enrolled in study 302 were not randomised due to a positive mannitol tolerance test (MTT) defined as either 1) a fall in FEV 1 >20% from baseline at midpoint (step 4) or 2) fall from baseline > 20 % at end of test that did not recover to < 20% within 15 minutes or 3) who had a fall in FEV 1 > 50% from baseline at end of test (step 6) or 4) who had a fall in Sp02 to < 89% during the procedure. An additional 4% (n=27) of patients from the two studies had incomplete MTTs and were not randomised.

Mean (SD) baseline FEV 1 percent predicted in study DPM-CF-301 (safety population, N= 295) was 62.4 (SD:16.45) and 61.4 (SD:16.13) in the mannitol and control groups, respectively. These figures for study DPM-CF-302 (N=305) are as follows: 65.24 (SD:13.90) and 64.35 (SD:15.29). In study DPM-CF-301 64.4 % of the patient population were adults while in study DPM-CF-302 this figure was 49.5%. Fifty five % of patients were receiving rhDNase in study DPM-CF-301 while in study DPM-CF-302 this number was 75%. The percentage of patients receiving inhaled antibiotics was 55% in study DPM-CF-301 and 56% in study DPM-CF-302. Concomitant administration with hypertonic saline was not permitted in these trials.

The primary pre-specified endpoint i.e. the change8 from baseline in FEV 1 (ml) in the modified ITT (mITT) population (n=269 and 297 in studies DPM-CF-301 and DPM-CF-302, respectively) compared to control over the 26 weeks period is provided in Table 1 alongside FEV 1 presented as absolute and relative change % predicted.

Table 1 – Change in FEV 1 from baseline over 26 weeks in the mITT and adult populations 


In rhDNase users in study 301 the relative change in FEV 1 % predicted from baseline across 26 weeks of treatment was 2.83 (95% CI -0.62, 6.27). For non-users the relative change was 4.30 (95% CI 0.53, 8.07). In study 302 the relative change (95% CI) for rhDNase users and non-users was 3.21 (- 0.61, 7.03) and 4.73 (-1.93, 11.40), respectively.

The number of subjects with at least one protocol defined pulmonary exacerbation (PDPE, defined by the presence of at least 4 symptoms and signs plus the use of intravenous antibiotics) was 18.1% in the mannitol arm and 28% in the control arm in study 301 (ITT population). In study 302 15.2% subjects in the mannitol arm and 19% in the control had a PDPE.

The estimated effect of treatment (mean change and 95% CI from baseline over 26 weeks, mITT population) on FVC was 108.78 ml (95% CI: 49.21, 168.35) in study 301 and 71.4 ml (95% CI: 10.57, 132.13) in study 302.

Paediatric population
As stated in section 4.2, the safety and efficacy of 9Bronchitol in children and adolescents aged less than 18 years has not been established.

In studies DPM-CF-301 and 302 relative % predicted FEV 1 compared to control in children (6-11 years) was improved by 0.44% (95% CI -5.90, 6.77, N=43) and 6.1% (95% CI -1.28, 13.54, N=59) over 26 weeks (p=0.892 and 0.104) respectively.
In adolescents (12-17 years) relative change in % predicted FEV 1 compared to control improved by 3.31% (95% CI -2.29, 8.90, N=55) and 0.42% (95% CI -5.45, 6.29, N=94) over 26 weeks (p=0.245 and 0.888) respectively.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
In a study of 18 healthy male adult volunteers, the absolute bioavailability of mannitol powder for inhalation by comparison to mannitol administered intravenously was 0.59% ± 0.15.
The rate and extent of absorption of mannitol after inhaled administration was very similar to that observed after oral administration. The T max after inhaled administration was 1.5 ± 0.5 hours.

In a study of 9 cystic fibrosis patients (6 adults, 3 adolescents), using 400 mg inhaled mannitol as a single dose (Day 1) then twice a day for 7 days (Days 2 - 7), pharmacokinetic parameters were similar for adults and adolescents, except for a longer average apparent terminal half life for adolescents (Day 1 = 7.29 hours, Day 7 = 6.52 hours) compared with adults (Day 1 = 6.10 hours, Day 7 = 5.42 hours). Overall, the comparison of AUCs between Day 1 and Day 7 showed a time independence of pharmacokinetics, indicating linearity at the dose level administered in this study.

Biotransformation
A small percentage of systemically absorbed mannitol undergoes hepatic metabolism to glycogen and carbon dioxide. Studies in rats, mice and humans have demonstrated that mannitol has no toxic metabolites. The metabolic pathway of inhaled mannitol was not examined in pharmacokinetic studies.

Distribution
Lung deposition studies have demonstrated a 24.7% deposition of inhaled mannitol confirming its distribution to the target organ. Nonclinical toxicology studies indicate that mannitol inhaled into the lungs is absorbed into the bloodstream, with the maximum serum concentration being achieved occurring at 1 hour. There is no evidence that mannitol is accumulated in the body, therefore distribution of inhaled mannitol was not examined in PK studies.

Elimination
The cumulative amount of mannitol filtered into the urine over the 24 hour collection period was similar for inhaled (55%) and oral (54%) mannitol. When administered intravenously, mannitol is eliminated largely unchanged by glomerular filtration and 87% of the dose is excreted in the urine within 24 hours. The mean terminal half-life in adults was approximately 4 to 5 hours from serum and approximately 3.66 hours from urine.

Paediatric population
The safety and efficacy of Bronchitol in children and adolescents aged 6 to 18 years has not yet been established.

Adolescents aged 12 to 17 years. Limited data available in the population indicate the pharmacokinetic parameters of inhaled mannitol are similar to the adult population. There are no data available for children under 12 years of age.