A Population Pharmacokinetic Model for Montelukast Disposition in Adults and Children

Ramakrishnan, Rohini; Migoya, Elizabeth; Knorr, Barbara

doi:10.1007/s11095-005-2493-y

Cited by 20 publications

(10 citation statements)

References 29 publications

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“…The PK of montelukast in this study was found to be consistent with a 1st-order absorption and 1-compartment elimination model with CL/F and V/F increasing with body weight and a proportional error structure. These results were similar to those from a previous study [ 20 ] and a previous PPK analysis in non-Japanese paediatric patients. [ 17 ] We observed that montelukast plasma concentrations decreased slightly with age and that the relationship between PK and age is likely explained by the underlying relationship between age and body weight.…”

Section: Discussionsupporting

confidence: 92%

Montelukast in the treatment of perennial allergic rhinitis in paediatric Japanese patients; an open-label clinical trial

Okubo

Inoue

Numaguchi

et al. 2016

Journal of Drug Assessment

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Background: This study was conducted to evaluate the safety and tolerability, and population pharmacokinetics (PPK) of montelukast as well as efficacy in the treatment of perennial allergic rhinitis (PAR) in paediatric Japanese patients aged between 1 and 15 years. Methods: In this multi-centre, open-label trial, 87 paediatric Japanese patients with PAR received montelukast 4 mg oral granules (OG) for 4 weeks (1–5-year-olds, N = 15), 4 mg OG for 12 weeks (1–5-year-olds, N = 36), 5 mg chewable tablets (CT) for 12 weeks (6–9-year-olds, N = 18), or 5 mg CT for12 weeks (10–15-year-olds, N = 18). Clinical exams and laboratory assessments were conducted at study visits, and adverse events (AE) were monitored throughout the study up to 14 days after the last visit. Population pharmacokinetic approach was used to estimate AUC0–∞, Cmax, Tmax and apparent elimination half-life in each age group. Efficacy was assessed based on global evaluations by the subject’s caregiver. Results: There were no serious AEs and one discontinuation due to an AE. The most common AEs in any of the treatment groups were nasopharyngitis, pharyngitis, and acute sinusitis. Montelukast exposure (AUC0–∞) was similar in the 1–5-year-old group and the 6–9-year-old group, but 19% lower in the 10–15-year-old group. Among all patients, the total proportion of patients whose global evaluation was “very much better” was 5.7% (week 2), 11.5% (week 4), and 16.9% (week 12) reflecting improvement in symptoms over time. Conclusion: Montelukast was generally well tolerated in Japanese children with PAR. AUC0–∞was similar in 1–5 and 6–9-year-olds, while a lower exposure was observed in the 10–15-year-old group likely due to differences in bodyweight. The exposure in Japanese paediatric patients was generally consistent with that in non-Japanese paediatric and adult patients. As assessed by the patients’ caregivers, montelukast also demonstrated symptomatic improvement based on global evaluations of PAR.

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Section: Discussionsupporting

confidence: 92%

Montelukast in the treatment of perennial allergic rhinitis in paediatric Japanese patients; an open-label clinical trial

Okubo

Inoue

Numaguchi

et al. 2016

Journal of Drug Assessment

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“…Like oxycodone, milrinone, and voriconazole, midazolam is hepatically metabolized, and the model of midazolam pharmacokinetics in children showed that age was not an important covariate compared to weight. Ramakrishnan et al 26 studied intravenous montelukast in children with asthma and identified total body water as more predictive than weight and both more predictive than age. Taken together, these are interesting findings because the known developmental regulation of the cytochrome C P450 (CYP) system elucidated by de Wildt et al 27 would predict an increasing CL with increasing age in the ages under study.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Oxycodone in Children 6 Months to 7 Years Old

El‐Tahtawy

Kokki

Reidenberg

2006

The Journal of Clinical Pharma

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Young children are often undertreated for pain. One barrier to effective pain treatment is understanding the pharmacokinetic behavior of analgesics in this age group. Oxycodone is a commonly prescribed opioid for severe pain, yet little is known about its pharmacokinetics in young children. This article used population pharmacokinetic modeling to synthesize pharmacokinetic data from several studies into a model. A single population model that described the observed pharmacokinetics was developed. The combined data were best described with a 2-compartment linear model with different first-order absorption rates depending on route of administration. Weight was found to significantly influence both clearance (CL) and volume of distribution (Vd). The following model adequately describes the population pharmacokinetic profile of oxycodone where absolute bioavailability (F) is estimated for each administration route: CL/F=55x(body weight/70)0.87; V/F=86x(body weight/70)1.16. The interindividual coefficients of variation in CL and Vd were 20.2 and 19.7%, respectively. This finding confirms that the allometric scaling using the above model explained most of the variability in exposure observed among children. This model confirms using a weight-based dose for oxycodone without adjustment for age between 6 months and 7 years and is valuable for evaluating dosing schedules and dosing routes.

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“…The impact of weight on montelukast clearance is in agreement with the results of a previous pharmacokinetic study in children. 23 The clearance of montelukast increased allometrically along with body weight.…”

Section: Discussionmentioning

confidence: 99%

“…An external validation of the previously published model in children was performed at the first step; then, the validated model was used to derive individual clearance of montelukast for the following pharmacogenetic analysis. A linear threecompartment pharmacokinetic model 23 with 73% bioavailability of the chewable tablets 7 and a constant absorption rate (Ka) of 0.5L/h 24 was evaluated. The following modeling information was extracted from the published article: interindividual variability for clearance (CL), central compartment volume of distribution (Vc) and peripheral volume of distribution (Vp) (% coefficient of variation [%CV], 24.2%, 14.0% and 45.4%, respectively) by exponential error model, residual variability using a combined additive and proportional model (%CV, 3.7 ng/mL and 10.4%) and a significant influence of current weight (CW) on CL and V c , V P1 , V P2 , Q 1 , Q 2 with the following regression equations (equations 1-6):…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

<p>Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children</p>

Wang

Shi

et al. 2019

DDDT

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Background: Montelukast, a potent oral selective leukotriene-receptor antagonist, inhibits the action of cysteinyl-leukotriene in patients with asthma. Although pharmacokinetic studies of montelukast have been reported in Caucasian adults and children, and showed large interindividual variability on pharmacokinetics, none of these studies has been explored in Chinese children. Given the potential inter-ethnic difference, the purpose of the present study was to evaluate the effects of developmental factors and pharmacogenetics of CYP2C8 and SLCO2B1 on montelukast clearance in Chinese pediatric patients. Methods: After the administration of montelukast, blood samples were collected from children and plasma concentrations were determined using an adapted micro highperformance liquid chromatography coupled with the fluorescence detection (HPLC-FLD) method. A previously published pharmacokinetic model was validated using the opportunistic pharmacokinetic samples, and individual patient's clearance was calculated using the validated model. Population pharmacokinetic analysis was performed using a nonlinear mixed-effects model approach (NONMEM V 7.2.0) and variants of CYP2C8 and SLCO2B1 were genotyped. Results: Fifty patients (age range: 0.7-10.0 years) with asthma were enrolled in this study. The clearance of montelukast was significantly higher in children with the SLCO2B1 c.935GA and c.935AA genotypes compared with that of children with the SLCO2B1 c.935GG genotype (0.94 ± 0.26 versus 0.77 ± 0.21, p = 0.020). The patient's weight was also found to be significantly corrected with montelukast clearance (p <0.0001). Conclusion: The developmental pharmacology of montelukast in Chinese children was evaluated. Weight and SLCO2B1 genotype were found to have independent significant impacts on the clearance of montelukast.

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A Population Pharmacokinetic Model for Montelukast Disposition in Adults and Children

Abstract: The model developed can adequately describe the intravenous pharmacokinetics of montelukast and can be used as a useful tool for dose selection in pediatric subpopulations.

Cited by 20 publications

References 29 publications

Montelukast in the treatment of perennial allergic rhinitis in paediatric Japanese patients; an open-label clinical trial

Montelukast in the treatment of perennial allergic rhinitis in paediatric Japanese patients; an open-label clinical trial

Population Pharmacokinetics of Oxycodone in Children 6 Months to 7 Years Old

<p>Developmental Pharmacogenetics of SLCO2B1 on Montelukast Pharmacokinetics in Chinese Children</p>

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