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Case Study Merck’s Singulair (Montelukast) Tablets

Case Study Merck’s Singulair (Montelukast) Tablets. Tien-Mien Chen, Ph.D. Division of Pharmaceutical Evaluation II Office of Clinical Pharmacology and Biopharmaceutics CDER, FDA. Background. Montelukast: Cysteinyl leukotriene receptor antagonist.

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Case Study Merck’s Singulair (Montelukast) Tablets

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  1. Case StudyMerck’s Singulair (Montelukast) Tablets Tien-Mien Chen, Ph.D. Division of Pharmaceutical Evaluation II Office of Clinical Pharmacology and Biopharmaceutics CDER, FDA

  2. Background • Montelukast: Cysteinyl leukotriene receptor antagonist • Indication: Prophylaxis and chronic treatment of asthma * Two original NDAs approved in 1998 • 10 mg film-coated tablet (FCT) for  15 years old • 5 mg chewable tablet (CT) for 6 to 14 years old • Dosing regimen: One tablet QD given in the evening

  3. Pediatric Study Decision Tree • Reasonable to assume (pediatrics vs adults) • similar disease progression? • similar response to intervention? Yes To Both No Reasonable to assume similar exposure-response (C-R) in pediatrics and adults? • Conduct PK studies • Conduct safety/efficacy trials No No Yes Is there a PD measurement that can be used to predict efficacy? • Conduct PK studies to achieve levels similar to adults • Conduct safety trials Yes • Conduct PK/PD studies to get • Conduct safety study • C-R for PD measurement • Conduct PK studies to achieve target concentrations based on C-R

  4. I. Adult PK: In healthy volunteers only Basic PK Data: • Absolute bioavailability: 70% in healthy adults • Extensively metabolized then excreted in the bile (>86% of an oral dose) and <0.2% in urine • Parent drug is predominant in the systemic circulation • T1/2: 4-5 hrs

  5. Pivotal PK #01: Dose comparison study (2, 5, 10 mg CT vs. 10 mg FCT) 1) Head-to-head comparison between the 10 mg FCT and the 10 mg CT and 2) Dose proportionality information on CT (2, 5, and 10 mg) Objective:  To allow for conversion of the AUC from a 10 mg FCT to a 10 mg CT  To allow for scaling down the AUC of a 10 mg CT to a smaller pediatric CT dose in order to obtain the similar AUC as adults receiving a 10 mg FCT

  6. II. Adult Dose Ranging Study: (subgroups of earlier phase-2 trials) • Dose range studied: • Placebo (n=58), 10 mg QD (n=57), 10 mg BID (n=54), 50 mg BID (n=57), 100 mg QD (n=56), and 200 mg QD (n=61) • Results: 1. The active treatments were all significantly different from placebo group 2. No differences were found among the active treatments

  7. Based on the above observations: • Proposed dose selection for adult patients was: One 10 mg dose QD given in the evening

  8. III. Adult Clinical Efficacy and Safety Trials (# 01 and # 02):  12-week studies in patients with mild-to-moderate persistent asthma at baseline Primary Endpoints: Changes in FEV1 and DSS (daytime asthma symptom scores)

  9. Results: Adult Clinical Trial # 01 (during the 4 visits) • 1. Mean % change in FEV1 (from baseline): • montelukast was significantly different from • placebo (overall mean: 12.8% vs. 4.1% ) • 2. Mean % change in DSS (from baseline): • montelukast was also significantly different from placebo (overall mean: -0.43% vs. -0.20%)

  10. Results: Adult Clinical Trial # 02 (during the 4 visits) • 1. Mean % change in FEV1 (from baseline): • montelukast was significantly different from placebo (overall mean: 7.4% vs. 1.4% ) • 2. Mean % change in DSS (from baseline): • montelukast was also significantly different from placebo (overall mean: -0.50% vs. -0.30%)

  11. Similarsafety profiles between active treatments and placebo Proposed dosing regimen (1 x 10 mg FCT QD) was confirmed by adult clinical efficacy and safety studies

  12. Pediatric Study Decision Tree • Reasonable to assume (pediatrics vs adults) • similar disease progression? • similar response to intervention? Yes To Both No 6-14 yrs old Reasonable to assume similar concentration-response (C-R) in pediatrics and adults? • Conduct PK studies • Conduct safety/efficacy trials

  13. IV. Pediatric PK: In asthmatic pediatric patients only PK # 02: SD PK in early pubertal adolescents 9-14 years old (3 x 2 mg and 10 mg FCT) PK # 03: SD and MD PK in pediatric patients 6-8 years old (5 mg CT)

  14. Subjects (9-14 yrs old) Dosea N AUC0- (ng-hr/ml) Cmax (ng/ml) Tmax (hr) T1/2 (hr) Pediatrics ( 45 kg) 6 mg FCT 9 2929 ± 994 444 ± 97 4.0 ±0.7 3.4 Pediatrics (> 45 kg) 10 mg FCT 9 3528 ± 1883 526 ± 413 4.0 ±0.3 4.2 Adults (PK # 01) 10 mg FCT 16 2690. ± 867 421 ± 145 3.0 ±1.0 5.3 Table 1: Mean PK Parameters: Pediatric (PK # 02) Compared With Adult Historical Data

  15. Table 2: Mean PK Parameters for Pediatric Patients (Day 1; PK # 03) Based on dose-normalization in AUC: • A 5 mg CT dose given QD (9-14 years old; PK # 02) is expected to provide similarsystemic exposure as adults receiving an effective dose (10 mg FCT) • Similar mean AUC in 6-8 year old patients was obtained (PK # 03)

  16. V. Pediatric Efficacy and Safety Trial: • One 5 mg CT of montelukast given QD in the evening was therefore chosen • Since montelukast was a new class of drug, a pivotal clinical efficacy and safety trial was conducted in 6-14 years old group (Clinical Trial #03) Note: Since the adolescents (15 years and older) had similar plasma profiles compared with adults, they were included in the adult Phase III efficacy trials using the adult 10 mg FCT dose

  17.  No pediatric dose-ranging trials conducted For this age group (6-14 years old):  Assumptions: • Similarity of disease progression in asthma between pediatric and adult patients • Comparable efficacy is associated with similar systemic exposure (AUC)

  18. Pivotal Pediatric Clinical Efficacy and Safety Trial # 03: • 8-week treatment study (n=321) • Mean % change in FEV1 from baseline: 8.71% and 4.16% for montelukast (5 mg CT)and placebo groups, respectively (p<0.001) • Original NDA for a 5 mg CT approved for 6-14 years old

  19. VI. Younger pediatric patients(2 to 5 years old): • Based on previous successful experience in dose selection (the same principle: similar mean AUC)  A smaller 4 mg CT dose selected  The 4 mg CT dose tested in a PK study employing sparse sampling technique and population PK approach  Mean AUCpop: 2721 ± 164 ng-hr/ml

  20. Only a 12-week clinical safety trial (n=619) conducted • No dose ranging studies nor formal clinical efficacy studies conducted • The 4 mg CT approved later for 2-5 years old under NDA supplement

  21. Pediatric Study Decision Tree • Reasonable to assume (pediatrics vs adults) • similar disease progression? • similar response to intervention? Yes To Both No 6-14 yrs old Reasonable to assume similar concentration-response (C-R) in pediatrics and adults? • Conduct PK studies • Conduct safety/efficacy trials Yes 2-5 yrs old • Conduct PK studies to achieve levels similar to adults • Conduct safety trials

  22. Acknowledgement • Robert Meyer, M.D. • Peter Honig, M.D. • Anne Trontell, M.D. • Larry Lesko, Ph.D. • Shiew-Mei Huang, Ph.D.

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