Progress in Drug Development–Pediatric Dose Selection: Workshop Summary

Drug dosing in neonates should be based on integrated knowledge concerning the disease to be treated, the physiological characteristics of the neonate, and the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug. It is critically important that all sources of information be leveraged to optimize dose selection for neonates. Sources may include data from adult studies, pediatric studies, non-clinical (juvenile) animal models, in vitro studies, and in silico models. Depending on the drug development program, each of these modalities could be used to varying degrees and with varying levels of confidence to guide dosing. This paper aims to illustrate the variability between neonatal drug development programs for neonatal diseases that are similar to those seen in other populations (meropenem), neonatal diseases related but not similar to pediatric or adult populations (clopidogrel, thyroid hormone), and diseases unique to neonates (caffeine, surfactant). Extrapolation of efficacy from older children or adults to neonates is infrequently used. Even if a disease process is similar between neonates and children or adults, such as with anti-infectives, additional dosing and safety information will be necessary for labeling, recognizing that dosing in neonates is confounded by maturational PK in addition to body size.

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Pediatric Dose Selection and Utility of PBPK in Determining Dose

The AAPS Journal ◽

10.1208/s12248-018-0187-8 ◽

2018 ◽

Vol 20 (2) ◽

Cited By ~ 21

Author(s):

Ian E. Templeton ◽

Nicholas S. Jones ◽

Luna Musib

Keyword(s):

Dose Selection ◽

Pediatric Dose

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Scaling Approaches for Pediatric Dose Selection: The Fremanezumab (AJOVY®) Journey to Select a Phase 3 Dose Using Pharmacokinetic Data from a Phase 1 Study

Pharmaceutics ◽

10.3390/pharmaceutics13060785 ◽

2021 ◽

Vol 13 (6) ◽

pp. 785

Author(s):

Aksana Jones ◽

Orit Cohen-Barak ◽

Andrijana Radivojevic ◽

Jill Fiedler-Kelly

Keyword(s):

Pediatric Population ◽

Phase 1 ◽

Adult Population ◽

Predictive Performance ◽

Pharmacokinetic Data ◽

Dose Selection ◽

Open Label ◽

Phase 3 ◽

Pediatric Dose ◽

Population Pk

Fremanezumab, a fully humanized IgG2Δa/kappa monoclonal antibody, selectively targets the calcitonin-gene-related peptide (CGRP) and prevents it from binding to the CGRP receptor. The safety, tolerability, pharmacokinetics (PK), and efficacy of fremanezumab for treating migraines administered as a once monthly 225 mg dose or a once quarterly 675 mg dose have been well characterized in adults. The fremanezumab exposure and body weight relationship supported the use of the approved 225 mg monthly adult dose for pediatric patients weighing ≥45 kg. In the pediatric Phase 3 program, a 120 mg dose for patients weighing <45 kg was determined using the results of an open-label study and a population PK modeling and simulation strategy. A thorough evaluation was conducted to further characterize the population PK of fremanezumab and assess the predictive performance of the adult population PK model when applied to the Phase 1 pediatric data, the predictive performance of alternative pediatric population PK models, and the predictive performance of the selected pediatric population PK model via a noncompartmental-based approach. This latter comparison to noncompartmental results provided additional evidence that the pediatric population PK model predicts the observed data well and supports the 120 mg monthly dose in patients weighing <45 kg.

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