"The U.S. Food and Drug Administration today approved Nucala (mepolizumab) for use with other asthma medicines for the maintenance treatment of asthma in patients age 12 years and older. Nucala is approved for patients who have a history of "...
Mechanism of Action
The precise mechanisms through which inhaled mannitol causes bronchoconstriction are not known.
The response to inhaled mannitol is reported as the delivered dose of mannitol causing a 15% reduction in FEV1 and is expressed as PD15.
The rate and extent of absorption of mannitol after oral inhalation was generally similar to that observed after oral administration. In a study of 18 healthy adult male subjects the absolute bioavailability of mannitol powder following oral inhalation was 59% while the relative bioavailability of inhaled mannitol in comparison to orally administered mannitol was 96%. Following oral inhalation of 635 mg, the mean mannitol peak plasma concentration (Cmax) was 13.71 mcg/mL while the mean extent of systemic exposure (AUC) was 73.15 mcg•hr/mL. The mean time to peak plasma concentration (Tmax) after oral inhalation was 1.5 hour.
Based on intravenous administration, the volume of distribution of mannitol was 34.3 L.
The extent of metabolism of mannitol appears to be small. This is evident from a urinary excretion of about 87% of unchanged drug after an intravenous dose to healthy subjects.
Following oral inhalation, the elimination half-life of mannitol was 4.7 hours. The mean terminal elimination half-life for mannitol in plasma remained unchanged regardless of the route of administration (oral, inhalation, and intravenous). The urinary excretion rate versus time profile for mannitol was consistent for all routes of administration. The total clearance after intravenous administration was 5.1 L/hr while the renal clearance was 4.4 L/hr. Therefore, the clearance of mannitol was predominately via the kidney. Following inhalation of 635 mg of mannitol in 18 healthy subjects, about 55% of the total dose was excreted in the urine as unchanged mannitol. Following oral or intravenous administration of a 500 mg dose, the corresponding values were 54% and 87% of the dose, respectively.
Hepatic and Renal Impairment
Formal pharmacokinetic studies using ARIDOL (mannitol inhalation powder) have not been conducted in patients with hepatic or renal impairment. Since the drug is eliminated primarily via the kidney, an increase in systemic exposure can be expected in renally impaired patients.
Animal Toxicology and/or Pharmacology
Reproductive Toxicology Studies
Mannitol did not cause any embryofetal malformations when given to pregnant rats and mice at oral doses of 1.6 g/kg each (approximately 20 and 10 times the MRHDID in adults, respectively, on a mg/m² basis).
The effectiveness of the ARIDOL (mannitol inhalation powder) bronchial challenge test kit in assessing bronchial hyperresponsiveness in adults and children 6 years of age and older was assessed in two clinical studies. Study 1 was an operator-blinded, open-label crossover trial that assessed the sensitivity and specificity of bronchial challenge testing with ARIDOL (mannitol inhalation powder) compared with a methacholine bronchial challenge test in detecting bronchial hyperresponsiveness in subjects with symptoms suggestive of asthma but without a definite diagnosis of asthma. During the course of the study subjects underwent three types of bronchial challenge tests utilizing exercise, ARIDOL (mannitol inhalation powder) , and methacholine. A positive exercise test was defined as a decrease in FEV1 ≥ 10%, a positive bronchial challenge test with ARIDOL (mannitol inhalation powder) was defined by either a decrease in FEV1 by ≥ 15% from baseline or a between-dose reduction in FEV1 ≥ 10%, and a positive methacholine response was defined as a decrease in FEV1 ≥ 20% after breathing methacholine at a concentration less than or equal to 16 mg/mL. The sensitivity and specificity of bronchial challenge testing with ARIDOL (mannitol inhalation powder) and methacholine were then assessed relative to exercise testing which served as a common comparator. The sensitivity and specificity of ARIDOL (mannitol inhalation powder) and methacholine challenges were also assessed using a blinded study physician's diagnosis of asthma at the end of the study. Five-hundred nine subjects aged 6 to 50 years were screened for enrolment with 419 and 420 subjects receiving at least one dose of mannitol, the active ingredient in ARIDOL, or methacholine, respectively. The maximum cumulative dose of mannitol was 635 mg. Bronchial challenge testing with ARIDOL (mannitol inhalation powder) and methacholine demonstrated similar sensitivity and specificity in predicting bronchial hyperresponsiveness defined by a positive exercise challenge (Table 4).
Table 4 : Comparisons of the sensitivity and specificity
(calculated relative to exercise challenge) for the ARIDOL (mannitol inhalation powder) test and methacholine
in Study 1
|Population||Treatment||Sensitivity % (95% CI)||Specificity % (95% CI)|
|Overall Population (n=419)|
|ARIDOL||58 (50, 65)||63 (57, 69)|
|Methacholine||53 (46, 51)||68 (62, 73)|
|Difference||5 (-4, 13)||-5 (-12, 3)|
|Age 6-11 years old (n=36)|
|ARIDOL||67 (47, 87)||47 (21, 72)|
|Methacholine||71 (52, 91)||33 (9, 57)|
|Difference||-5 (-29, 20)||17 (-29, 62)|
|Age 12-17 years old (n=70)|
|ARIDOL||55 (37, 72)||62 (46, 77)|
|Methacholine||65 (48, 81)||64 (49, 79)|
|Difference||-10 (32, 13)||-3 (-24, 19)|
Bronchial challenge testing with ARIDOL (mannitol inhalation powder) and methacholine also demonstrated similar sensitivity and specificity when calculated relative to a blinded study physician's diagnosis of asthma in subjects at the end of the study.
The sensitivity and specificity of bronchial challenge testing with ARIDOL (mannitol inhalation powder) in children and adolescents 6 to 17 years of age in Study 1 was similar to that in the overall population (Table 4).
Study 2 was a crossover study comparing bronchial challenge testing with ARIDOL (mannitol inhalation powder) to hypertonic (4.5%) saline in identifying bronchial hyperresponsiveness in subjects 6 to 83 years of age with (n=551) and without (n=95) asthma. In this study the efficacy endpoint of interest was an estimation of the sensitivity and specificity of bronchial challenge testing with ARIDOL (mannitol inhalation powder) with respect to a physician's clinical diagnosis of asthma. Following completion of the bronchial challenge tests with ARIDOL (mannitol inhalation powder) and hypertonic saline, a respiratory physician assessed the data and categorized the subjects as having or not having asthma. The sensitivity of the ARIDOL (mannitol inhalation powder) bronchial challenge test in subjects with a physician diagnosis of asthma was 58% [(54%, 62%, 95th CI)] compared to a sensitivity of the physician diagnosis in the same population of 97% [(95%, 98%, 95th CI)]. The specificity of the ARIDOL (mannitol inhalation powder) bronchial challenge test in subjects without asthma was 95% [(90%, 99%, 95th CI)] compared to the specificity of the physician diagnosis of 98% [(95%, 100%, 95th CI)].
Last reviewed on RxList: 10/29/2010
This monograph has been modified to include the generic and brand name in many instances.
Additional Aridol Information
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