Module232025

09/05/2025

Introduction key concepts

PHA022121-C001 / FASTING CONDITIONS (1, 2, 4.5, 12, and 22 mg) Representation of popPK approach Truncated to 24 h post-dose

PO Dose

1 mg 2 mg 4.5 mg 12 mg 22 mg

1 mg 2 mg 4.5 mg 12 mg 22 mg

No.1

Dose-corrected Cp (ng/mL) 0 5 10 15

LOG Dose-corrected Cp (ng/mL) -6 -4 -2 0 2

Ka_fast Ka_fed

Q/F

Central Compartment V2/F

Peripheral distribution compartment V3/F

K = CL/V2

0 2 3 6 8 10 12

24

0 2 3 6 8 10 12

24

Subject specific PK parameters

Time (hours)

Time (hours)

Population parameters

Vc i Ka Vc

VARIABILITY also modelled!!

ത

CL i Q i

Covariates

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Introduction • Several models may be needed to support a given pediatric drug development program depending on the question(s) to be addressed, the credibility of the model, and the emerging data generated. • Example: impact of maturation will be larger when defining doses for neonates than for older children • Staggered approach allows several learn and confirm cycles, usual as data becomes available. • Levelof uncertaintyacceptablefor guiding study designis not acceptable for confirming efficacy by clinical trial simulation • Risks associated with accepting the model depend on the relative contribution of the model in making a decision during product development and its consequences. • When M&S is used for risk/benefit assessment or as basis of approval it has a high regulatory impact, requires low uncertainty

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