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Knorr B et al in 1999 did a comparison of pharmacokinetics in children and adults after single dose oral administration. Based on dose-ranging studies, a once daily 10 mg dose of montelukast (film-coated tablet), was used as the optimal adult dose. The study was performed on children with 6 to 14 year of age by giving the dose of 5mg chewable montelukast tablet and all pharmacokinetics parameters were studied. On the basis of montelukast plasma concentration it was observed that the exposure to dose in children was similar to adult and the drug was well tolerated. Area under the plasma concentration-time curve (AUC) in children of 6 to 14 year was comparable to AUC of adult with 10mg montelukast dose. The observations predicted that the 5mg chewable tablet dose of montelukast is appropriate in 6 to 14 year-old children with asthma ad produce efficacious effects.
Knorr B et al in 2001worked for the study of dose selection in children of 2 - 5 years of age. For this purpose, comparison of population pharmacokinetics of adults and the children in asthmatic patients was done. It was an open, one-period, multicenter population pharmacokinetic study. To estimate single-dose pharmacokinetic profile i.e. area under the plasma concentration-time curve (AUC), 4mg chewable tablet (CT) dose of montelukast for administration to children ages 2 to 5 years with 10 mg film-coated tablet (FCT) dose in adults was compared. Population pharmacokinetic approach was used to estimate population AUC (AUCpop). It was observed that in children dose of montelukast was well tolerated and produced an AUCpop (2721 ng.h/mL) similar to adult AUCpop (2595 ng.h/mL). So the result showed that the selection of a 4 mg once-daily CT dose of montelukast is satisfactory.
Migoya E et al in 2004 carried out a open-label study in 32 patients. The purpose of this study was to investigate the pharmacokinetic comparison of a 4mg dose of montelukast oral granules with the 10 mg already approved dose in adults in patients with age less than or equal 6 months to more than 24 months. Population pharmacokinetic parameters estimated were AUC (pop), C (max), and t (max) and the results were compared with the results of historically study on adult patients receiving 10mg dose of film coated montelukast. The AUC (pop) ratio and the 95% Confidence interval for dosage of children in comparison to adults were between the predefined comparability bounds (0.5, 2.00) and observed plasma concentrations were also similar. It was found on the basis of systemic exposure that 4mg dose of montelukast was appropriate for young children as with 6 months of age.
Friesen CA et al in 2004 planned a double blind, placebo-controlled, cross-over study to see the montelukast therapy effect on children and adolescents (6-18 yr) suffering from dyspepsia and duodenal eosinophilia. Forty subjects were given 10 mg of montelukast or identical placebo for 14 days. On day 14, symptomatic and biochemical responses were evaluated. To evaluate pharmacokinetics of montelukast blood samples were also collected. Post treatment global pain assessments were used and positive pain assessment responses were observed in 84% of patients taking montelukast as compared to 42% patients receiving placebo (p < 0.01). Response rate did not changed by age, gender or histologic findings dis not changed the response rate. Pharmacokinetic parameters including absorption rate constant (Ka), apparent volume of distribution (Vd) and elimination rate constant (Kel) were estimated which respectively resulted in 0.42 h, 0.19 L/kg and 0.26 h. The results obtained by relative extent of systemic drug exposure were parallel to those observed in historical pediatric investigations with similar montelukast doses adjusted according to weight. It was concluded from the data that montelukast have a beneficial role in the treatment of pediatric patients suffering from dyspepsia associated with duodenal eosinophilia.
Knorr B et al in 2005 studied the pharmacokinetics, safety and tolerability of montelukast in children with age of 3 to 6 months. Area under the concentration-time curve from time zero to infinity (AUC0-∞), maximum plasma concentration (Cmax) and time to reach Cmax (tmax) of montelukast in infants with age 3 to 6 months by giving single dose of 4mg granules was investigated. Dose after oral administration was quantified. Population based approach with a nonlinear mixed-effect, one compartment model with first-order absorption and elimination was used for the determination of pharmacokinetic parameters. It was observed that the systemic exposure of 4mg dose of granules is similar in both children aged 3 to 6 months and 6 to 24 months.
Jaakkola Tet al in 2006 performed a double-blind, randomized, crossover study with 3 phases and with 3 weeks washout period. The purpose of this study was to identify that Montelukast and zafirlukast did not increase the pioglitazone plasma concentrations which is a CYP2C8 substrate. 12 healthy volunteers were either administered 10 mg of montelukast once a day and placebo once a day or 20 mg zafirlukast twice a day, or placebo twice a day, for 6 days. On day 3, they took a single oral dose of pioglitazone 15 mg and the plasma concentrations of pioglitazone, the CYP2C8 substrate and its metabolites M-IV, M-III, M-V and M-XI were determined for 96 h. The range defined for area under the plasma concentration-time curve (AUC) of pioglitazone was 71 - 143% for montelukast and 78 - 146% for Zafirlukast. During placebo phase the AUC of pioglitazone for montelukast and zafirlukast was 101% and 103 % respectively, which was within the range. It was also observed that the peak plasma concentration and elimination half-life of pioglitazone was not affected by montelukast and zafirlukast. Any statistically significant differences in pharmacokinetics of any of the metabolites of pioglitazone were not observed.
Kim KA et al in 2007 performed a two-period, randomized crossover study on 10 healthy subjects. The purpose of this study was to study the pharmacokinetics of Rosiglitazone a CYP2C8 substrate in humans with multiple dosing of montelukast. 10 mg oral dose of montelukast or placebo were given daily for 6 days and also the 4 mg dose of Rosiglitazone was administered. Plasma samples were collected for 24 h and analysis of rosiglitazone and N-desmethylrosiglitazone was done using high performance liquid chromatography with fluorescence detection. The total area under the time-concentration curve of rosiglitazone was 102% (90% CI 98, 107%) and peak plasma concentration of rosiglitazone was 98% (90% CI 92, 103%) during montelukast phase and these values were almost similar to values of placebo phase. The AUC ratio and plasma concentration ratios verified that multiple dosing with montelukast did not affect metabolism and clearance of rosiglitazone (90% CI 90, 103%; P = 0.14).
Sripalakit P et al in 2008 developed high-performance liquid chromatographic (HPLC) method for determining the montelukast in human plasma. Mefenamic acid was used as an internal standard. Plasma protein was precipitated with Acetonitrile and Zorbax Eclipse XDB C8 (150 mm x 4.6 mm i.d., 5 microm) with mobile phase consisted of methanol-acetonitrile-0.04M disodium hydrogen orthophosphate (22:22:56, v/v, pH 4.9) was used for chromatographic separation. For excitation and emission wavelengths of fluorescence detection were set at 350nm and 450nm respectively. Concentration range of 5-1000 ng/ml in human plasma was used for linearity. Intra- and inter-day accuracy was determined from quality control samples. The accuracy was 101.50 and 107.24%, and 97.15 and 100.37%, respectively and precision measured as coefficient of variance were < or =4.72 and < or =9.00%, respectively. Extraction recoveries of drug were >48.14% from plasma.These protocol were used for pharmacokinetic study of tablet formulation of montelukast in healthy Thai male volunteers.
Sripalakit P et al in 2008 comparatively studied the the bioavailabilities of two generic brands of montelukast (Tomont® and Montek®) available in Thiland with the original brand (Singulair®) in healthy male volunteers of Thai under fasting condition A randomized, single-dose, crossover study was designed and the study was done on 24 healthy male volunteers with one week wash out period. After administration, blood samples were collected at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 16 and 24 hour for plasma montelukast levels intervals and pharmacokinetic parameters were analyzed by using a validated HPLC method. The result was that the 90% confidence intervals of Cmax and AUC0-t, AUCt-inf 90% lied within the acceptable range of Thailand food and drug administration. It was concluded that Tomont and Montek were bioequivalent to Singulair.
Chauhan B et al in 2008 worked to develop a liquid-liquid extraction based reverse phase liquid chromatography method using HPLC with fluorescence detector for the estimation of montelukast in small volume of human plasma samples. C8 column (150-4.6 mm, 5 micron) and a mobile phase consisting of a mixture of 10 mM ammonium acetate buffer (pH 3.0) and acetonitrile in a ratio of 35:65 v/v was used for separation purpose. Liquid-liquid extraction technique with ter-butylmethylether was used for montelukast extraction from human plasma. The limit of detection was 5 ng/ml and lowest limit of quantification was10 ng/ml. It was observed that method was linear in the range of 10 - 1000 ng/ml and gave a recovery of 53 - 62%. Intraday and interday precision of this method was less than 15% and accuracy was ranging from 96.23 - 108.39%. It was observed from Stability studies that in human plasma montelukast was stable during the short-time period of sample preparation and analysis.
Kearns GL et al in 2008 measured the Pharmacokinetics and safety of 4mg montelukast oral granules in infants and also the tolerability of two different doses of montelukast (4 mg and 8 mg administered once a day for 7 days) versus placebo were also investigated. Twelve infants with 1 to 3 months of age with bronchiolitis or a history of bronchiolitis and asthma-like symptoms were taken for this study and were given the single dose of 4mg montelukast oral granules. The population area under the concentration-time curve determined was 13 195.7 +/- 2309.8 (standard error) ng.hr/mL which was 3.6 times higher than historical determined in infants with 3 to 24 months of age. Despite increased systemic exposure and in comparison to historically determined data of pediatric patients with age of 3 to 24 months, it was concluded that single 4mg oral granules dose of montelukast in infants with age of 1 to 3 months was well tolerated.
Bharathi DV et al in 2009 for the determination of montelukast (MTK) in human plasma, developed and validated a highly sensitive, rapid assay method with liquid chromatography coupled to tandem mass spectrometry with electro spray ionization in the positive-ion mode. Amlodipine was taken as internal standard and liquid-liquid extraction method was used to extract montelukast and amlodipine in human plasma. 10 mM ammonium acetate (pH 6.4) : acetonitrile (15:85 v/v) on a Discovery HS C(18) column at a flow rate of 0.50 mL/min was used for chromatographic separation and total run time was of 3.5 min. The MS/MS ion transitions monitored for montelukast and amlodipine were 586.10 --> 422.10 and 409.20 --> 238.30, respectively. FDA guidelines were followed for method validation and clinical sample analysis. The lower limit of quantitation and linearity achieved were 0.25 ng/mL and 0.25 to 800 ng/mL respectively. The intra-day and inter-day precisions were 5.97-8.33 and 7.09-10.13%, respectively. The results were within the acceptance criteria.
Knorr B et al in 2010 performed a bioequivalence study of 4 mg Oral Granules and Chewable Tablet Formulations of Montelukast in fasted state and with food. 24 healthy adult subjects were used for Formulation Biocomparison Study (Study 1) and 30 subjects for Final Market Image Study (Study 2) and for this 3 period cross over study was designed. For study 1, one group was receiving a single 4 mg dose of the oral granules and chewable tablet fasted, and a single 4-mg dose of the oral granules formulation with food (2 teaspoons of applesauce or after taking a high-fat breakfast as it was the part of study 2). Prespecified comparability bounds for the AUC(0-infinity) and C(max) of montelukast (oral granules/chewable tablet) were (0.80, 1.25). It was also considered that the formulations were to be bioequivalent if the confidence intervals (CIs) for geometric mean ratios (GMRs) of montelukast would 90% lie in these comparability bounds. For study 2, comparability bounds were prespecified as (0.50, 2.00) while study 2 comparability bounds were not prespecified. The result shows that the 90% CIs of the GMRs for AUC(0-infinity) and C(max) lied in the prespecified bound of (0.80, 1.25, respectively). AUC(0-infinity) values obtained from Study 1 and Study 2 were 1.01 (0.92, 1.11) and 0.95 (0.91, 0.99), respectively and for C(max), respective values obtained were 0.99 (0.86, 1.13) and 0.92 (0.84, 1.01). And, when the oral granules formulation and chewable tablet were taken with food the AUC (0-infinity) and C(max) values were within the interval of (0.50, 2.00). It was concluded that the 4-mg oral granules and chewable tablets of montelukast given in the fasted condition were bioequivalent and well tolerated.
Keronen T et al in 2010 evaluated the significance of CYP2C8 in the pharmacokinetics of montelukast with the help of Gemfibrozil, a CYP2C8 inhibitor. It was a randomized, crossover study on 10 healthy volunteers and the parameters like mean area under the plasma concentration-time curve (AUC)(0-infinity), peak plasma concentration (C(max)), and elimination half life (t(1/2)) were measured . In this study, Gemfibrozil 600 mg or placebo was administered twice daily for 3 days and on 3rd day 10mg montelukast was administered. Gemfibrozil increased the (AUC)(0-infinity), C(max) and t(1/2) of montelukast 4.5-fold, 1.5-fold, and 3.0-fold, respectively (P < 0.001). It was concluded that gemfibrozil increased the plasma concentrations of montelukast which showed that CYP2C8 also play important in the elimination of montelukast.
Mougey EB et al in 2010 studied the effect on pharmacokinetics of montelukast with the use of Citrus Juice and SLCO2B1 Genotype. In vitro studies were performed which showed that citrus juice could reduce the permeability of montelukast with inhibition of organic anion-transporting polypeptides. The purpose of this study was to measure clinical significance of c.935G>. A single-dose, pharmacokinetic study of montelukast co-ingested with citrus juice was done. For this study volunteers were given montelukast co-ingested with either orange juice or 4- concentrated grapefruit juice and co-ingestion with Gatorade was taken as control (n = 24). On average, it was observed that coingestion produced a minimal effect on the area under the plasma concentration time curve from time zero extrapolated to infinite time (AUC0→∞) of montelukast relative to co-ingestion with control. However when the data was studied according to genotype at c.935 (G/G n = 21, A/G n = 5), a significant reduction in AUC0→∞ was observed with orange juice in G/G homozygotes (AUC0→∞, G/G, Gatorade = 2560 ± 900 ng·h·mL−1 vs AUC0→∞, G/G, orange juice = 2010 ± 650 ng·h·mL−1, P = .032). A/G heterozygotes showed decreased AUC0→∞ relative to G/G homozygotes, independent of treatment (AUC0→∞, G/G, combined treatments = 2310 ± 820 ng·h·mL−1 vs AUC0→∞, A/G, combined treatments = 1460 ± 340 ng·h·mL−1, P = 2.0 - 10 −5) significantly.This data was replicating previous observations.