Dose selection for fremanezumab (AJOVY) phase 3 pediatric migraine studies using pharmacokinetic data from a pediatric phase 1 study and a population pharmacokinetic modeling and simulation approach

Abstract

Background Potential fremanezumab doses for pediatric patients were evaluated using pharmacokinetic modeling and simulation. An open-label phase 1 pharmacokinetic and safety study was conducted in pediatric patients with migraine. This study’s results together with refinement of the adult population pharmacokinetic model were used to determine fremanezumab dose recommendations for phase 3 pediatric studies. Methods Initial application of the adult model suggested that a 75 mg dose in pediatric patients would match exposures determined safe and efficacious in adults; thus, in the phase 1 study, 15 patients, aged 6–11 years and weighing 17–45 kg received a single subcutaneous 75 mg fremanezumab dose. The sparse pharmacokinetic data collected were used to refine the adult model and simulate concentration-time profiles for monthly subcutaneous doses (60 to 225 mg) in a virtual pediatric population. Results In the phase 1 pediatric study, the safety profile was similar to that of adults. A two-compartment model with first-order absorption and elimination and body weight effects on clearance and central volume was found to adequately describe the pediatric pharmacokinetic data. Conclusions Using exposure matching to the effective adult fremanezumab dose (225 mg subcutaneous monthly), modeling and simulations predict recommended dose of 120 mg in pediatric patients weighing < 45 kg. Registration: The phase 1 study of this report is registered at EudraCT with the identifier 2018-000734-35.

Pharmacokinetics and safety of erenumab in pediatric patients with migraine: A phase I, randomized, open‐label, multiple‐dose study

“…The study only included 10 participants who were children (6 to <12 years) and 13 participants who weighed less than 40 kg, limiting the generalizability of these findings. However, the sample size generally aligns with those of other phase I studies in children and adolescents 25–27 . Additionally, the calculation of AUC tau was based on a limited number of PK samples during the dosing interval (4 or 5), and some subjects had different numbers of PK samples after dose 1 (4 or 5 samples) versus dose 3 (4 samples) which were used to calculate AUC, and, therefore, the corresponding AR between dose 1 and dose 3.…”

“…However, the sample size generally aligns with those of other phase I studies in children and adolescents. 25 , 26 , 27 Additionally, the calculation of AUC tau was based on a limited number of PK samples during the dosing interval (4 or 5), and some subjects had different numbers of PK samples after dose 1 (4 or 5 samples) versus dose 3 (4 samples) which were used to calculate AUC, and, therefore, the corresponding AR between dose 1 and dose 3. Given the long half‐life of erenumab, we anticipate that these limitations to the sampling scheme and the PK parameter calculations had a minor impact.…”

Consenso sobre anticuerpos monoclonales en migraña del Grupo de Estudio de Cefaleas de la Asociación Madrileña de Neurología

“…No se dispone de datos de seguridad y eficacia en menores de 18 años, y por lo tanto estos fármacos no están aprobados para dicha población. Existen varios ensayos clínicos en curso para estudiar el efecto del erenumab y del galcanezumab en adolescentes, y una publicación preliminar en pacientes entre 15 y 18 años; también hay datos disponibles de estudios preclínicos y retrospectivos con fremanezumab y eptinezumab [68][69][70] . En el documento de consenso de la AHS se recomienda plantear su uso en jóvenes tras la pubertad, con ME de alta frecuencia y gran repercusión en la calidad de vida (pedMIDAS > 30) en caso de que no existan otras alternativas terapéuticas.…”

From the New Diagnostic Criteria to COVID-19 Pandemic Passing Through the Placebo Effect. What Have We Learned in the Management of Pediatric Migrane Over the Past 5 Years?

“…Phase 1 studies in pediatrics have to date documented a safety profile of CGRP comparable to that of adults ( 47 , 48 ). A retrospective study was recently published on adolescents with chronic migraine who received at least one dose of CGRP mAb.…”