Chemical formula: C₆H₁₄O₆ Molecular mass: 182.172 g/mol PubChem compound: 6251
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.
Mannitol, a carbohydrate, is confined to the extracellular compartment. It has an osmotic effect which causes fluid to pass from the intracellular to the extracellular compartment.
Mannitol is freely filterable at the kidney glomerulus and less than 10% is reabsorbed back from the kidney tubule. In the kidney tubules, mannitol exerts an osmotic effect which diminishes water reabsorption from the glomerular filtrate and produces diuresis. Mannitol thereby promotes urine flow in oliguria/anuria or in situations where the patient is at risk of onset of acute renal failure. Mannitol also increases electrolyte excretion, especially sodium, potassium and chloride. Excretion of renally excreted substances such as salicylates and barbiturates is also increased.
Mannitol does not penetrate the intact blood-brain barrier under usual circumstances. Confined to the plasma, mannitol exerts an osmotic pressure, causing fluid to leave the brain tissue, and brain volume and intracranial pressure to be reduced.
Mannitol does not penetrate the eye. Mannitol reduces the intraocular pressure due to its osmotic effect.
In the ITT population of an open label dose response study, DPM-CF-202, the mean (SD) percent change in FEV1 for the 400 mg dose was 8.75 (SD: 12.4) and -1.569 (SD: 9.0) for 40 mg dose (p <0.0001).
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 Tmax 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.
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.
When administered intravenously, mannitol is eliminated largely unmetabolised through the glomeruli. Only 10% is reabsorbed back from the kidney tubule.
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.
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.
When administered intravenously, the elimination half-life in adults is approximately 2 hours, longer where renal failure is present. 80% of an intravenous dose is excreted unchanged within 3 hours.
The safety and efficacy of mannitol in children and adolescents aged 6 to 18 years has not yet been established.
The limited data available in adolescents aged 12 to 17 years 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.
In male rats after 13 weeks of inhaled mannitol dosing, elevated circulating lymphocyte numbers and mandibular lymph node plasmacytosis was observed at doses greater than 9.3 fold the maximal dose.
The elevated lymphocyte count was within historical control values, did not progress and was essentially resolved by the end of the in life phase of the study and following withdrawal of treatment. This effect was not noted in any other species and did not result in clinical signs.
In dogs an increased occurrence of coughing was observed both during and immediately post dose for low and high dose inhaled mannitol administration. No treatment-related adverse effect occurred greater than 13 fold the maximal therapeutic dose.
No mutagenic or genotoxic effect has been revealed when mannitol was assayed in a standard battery of genotoxicity tests.
Mannitol was shown not to be an irritant in an isolated bovine eye assay or when introduced into rabbit eyes.
No evidence of carcinogenicity was observed when dietary mannitol (≤5%) was administered to mice and rats for 2 years. Carcinogenicity studies have not been carried out with inhaled mannitol.
Reproduction and developmental toxicity studies have not been carried out with inhaled mannitol. However, studies conducted with mannitol administered via other routes indicated no effect on foetal survival in mice, rats and hamsters and on embryo and foetal development in rats and rabbits.
Animal reproduction studies have not been carried out with inhaled mannitol. However, studies conducted with orally administered mannitol indicated no teratogenic effects in mice or rats, at doses of up to 1.6 g/kg, or in hamsters at 1.2 g/kg.
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