Evaluation of Weight Thresholds for Pediatric Patients to Use Adult Dosage of Therapeutic Monoclonal Antibodies

Abstract

With increasing interest in enrolling adolescent patients in adult trials, a question often arises: when can pediatric patients use adult dosages? For currently approved therapeutic monoclonal antibodies (mAbs) with equivalent adult and pediatric indications, body weight thresholds for pediatric patients to receive adult doses vary from 30 to 75 kg. Our objective is to determine if a consistent weight threshold can be recommended for therapeutic mAbs with wide therapeutic windows. Simulations were run to predict exposure using a population pharmacokinetic model describing the typical PK characteristics of a mAb with linear elimination. Simulated steady‐state areas under the concentration‐time curves (AUCss) were compared between pediatric and adult populations. Exponent values of 0.50, 0.75, and 1.0 for the allometric relationship of weight on clearance were also evaluated. Following administration of the same fixed adult dosage in pediatric subjects above a given threshold, median AUCss in the pediatric subjects increased with decreasing weight thresholds. Pediatrics with a minimum weight of 40 kg had median AUCss within 20% to 30% above adult median AUCss when the reference adult population had a median weight ≤80 kg. Higher relative pediatric exposures were seen in lower‐weight pediatric subjects when the weight exponent on clearance was >0.75. Simulations suggested that a weight threshold of 40 kg could generally be considered for pediatric subjects to receive the adult dosage for therapeutic mAbs with linear pharmacokinetics. Weight threshold selection should be based on considerations of therapeutic index of the drug product, weight distribution of the reference adult population, and magnitude of weight effect on pharmacokinetic parameters.

Model‐Aided Adults‐to‐Children Pharmacokinetic Extrapolation and Empirical Body Size‐Based Dosing Exploration for Therapeutic Monoclonal Antibodies—Is Allometry a Reasonable Choice?

“…23,28 We have conducted simulations to explore the empirical body size-based dosing of therapeutic mAbs in children 2-17 years by matching the exposures in children to those of adults. Consistent with the report by Yang et al, 15 our data support that pediatric subjects ≥ 40 kg can generally receive an adult dose; the simulated exposure difference between adults and children ≥ 40 kg was < ±20%, which is considered clinically insignificant. For children < 40 kg, BSA-based dosing (mg/m 2 ) may provide exposure comparable to that of adults, whereas additional adjustment factor is needed when using weight-based dosing (mg/kg) to avoid underexposure in young children with low body weight.…”

“…In the hybrid dosing approach, older children above certain weight cutoffs often receive adult doses (and thus offer dosing convenience), and younger children may have to use body size‐based dosing (mg/kg or mg/m 2 ) to ensure adequate drug exposure. For mAbs with linear PK, children ≥ 40 kg are generally suggested to receive the adult dose, 15,16 but it becomes less clear about empirical body size‐based dosing in children < 40 kg.…”

Allometric scaling of therapeutic monoclonal antibodies in preclinical and clinical settings

“…The PK of mAbs is primarily affected by body weight, 33,57 but additional age-associated changes in the physiological processes and the receptor system may further affect the disposition and elimination of mAbs. This is especially true for the youngest children, i.e., neonates and infants, whose characteristics, such as body composition, membrane permeability, and plasma protein concentration, are the most different to adult.…”

“…3,4,21,95 It may also be used to waive certain unnecessary pediatric trials, and hence avoid ethical and practical concerns that can occur with pediatric trials. 8,10,57 Allometric scaling approaches are thus regularly used for pediatric PK extrapolation, and are applicable to small-molecule drugs 20,95,134 and also mAbs. 1,7,15,47 Allometric weight scaling of clinical PK data is typically done within a population PK approach, due to the abovementioned advantages, namely the ability to analyze sparse data (common in adult trials beyond Phase 1 and typical for pediatric studies), and possibility to identify and include covariates that affect PK, facilitating (pediatric) dose selection.…”

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

“…Similarly in 2019, Yang et al. (19) conducted an analysis to identify body weight thresholds for therapeutic monoclonal antibodies above which pediatric patients can receive adult dosages, and found that a 40 kg body weight threshold is generally recommended if the reference median adult population is ≤80 kg and the product has a wide therapeutic window. The clinical studies for fremanezumab in adult patients had a median body weight of 71 kg and a large therapeutic window of up to 900 mg sc monthly (1,2).…”