Case Study Merck

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Case StudyMercks Singulair (Montelukast) Tablets

• Tien-Mien Chen, Ph.D.
• Division of Pharmaceutical Evaluation II
• Office of Clinical Pharmacology and
  Biopharmaceutics
• CDER, FDA

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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

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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

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I. Adult PK In healthy volunteers only
Basic PK Data

• Absolute bioavailability ?70 in healthy adults
• Extensively metabolized then excreted in the bile
  (gt86 of an oral dose) and lt0.2 in urine
• Parent drug is predominant in the systemic
  circulation
• T1/2 4-5 hrs

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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
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II. Adult Dose Ranging Study (subgroups of
earlier phase-2 trials)

• Dose range studied
• Placebo (n58), 10 mg QD (n57), 10 mg BID
  (n54), 50 mg BID (n57), 100 mg QD (n56), and
  200 mg QD (n61)

• Results

1. The active treatments were all significantly
different from placebo group
2. No differences were found among the active
treatments
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Based on the above observations

• Proposed dose selection for adult patients was

One 10 mg dose QD given in the evening
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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)
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Results Adult Clinical Trial 01 (during the 4
visits)
1. Mean change in FEV1 (from baseline) montel
ukast was significantly different from placebo
(overall mean 12.8 vs. 4.1 )
2. Mean change in DSS (from baseline) montelu
kast was also significantly different from
placebo (overall mean -0.43 vs. -0.20)
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Results Adult Clinical Trial 02 (during the 4
visits)
1. Mean change in FEV1 (from baseline) montel
ukast was significantly different from placebo
(overall mean 7.4 vs. 1.4 )
2. Mean change in DSS (from baseline) montelu
kast was also significantly different from
placebo (overall mean -0.50 vs. -0.30)
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• Similar safety profiles between active
  treatments and placebo

? Proposed dosing regimen (1 x 10 mg FCT QD)
was confirmed by adult clinical efficacy and
safety studies
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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-respons
e (C-R) in pediatrics and adults?

• Conduct PK studies
• Conduct safety/efficacy trials

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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)
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Table 1 Mean PK Parameters Pediatric (PK 02)
Compared With Adult Historical Data
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Table 2 Mean PK Parameters for Pediatric
Patients (Day 1 PK 03)
Subjects (6-8 years old) Dosea N AUC0-? (ng-hr/ml) Cmax (ng/ml) Tmax (hr) T1/2 (hr)
Pediatrics 5 mg CT 19 2928 904 495 129 2.0 1.3 3.7
Based on dose-normalization in AUC

• A 5 mg CT dose given QD (9-14 years old PK
  02) is expected to provide similar systemic
  exposure as adults receiving an effective dose
  (10 mg FCT)

• Similar mean AUC in 6-8 year old patients was
  obtained (PK 03)

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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
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• For this age group (6-14 years old)

? No pediatric dose-ranging trials conducted
? Assumptions

• Similarity of disease progression in asthma
  between pediatric and adult patients

• Comparable efficacy is associated with similar
  systemic exposure (AUC)

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Pivotal Pediatric Clinical Efficacy and Safety
Trial 03

• 8-week treatment study (n321)

• Mean change in FEV1 from baseline 8.71 and
  4.16 for montelukast (5 mg CT) and placebo
  groups, respectively (plt0.001)

• Original NDA for a 5 mg CT approved for 6-14
  years old

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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

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• Only a 12-week clinical safety trial (n619)
  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

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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-respons
e (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

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Acknowledgement

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