SP06-51: The Pharmacokinetics and Dose Strategy of Monoclonal Antibodies in Pediatrics
Michelle La Nguyen
Doctor of Pharmacy Candidate, Class of 2021
University of Maryland School of Pharmacy United States
The goals are: 1) to identify monoclonal antibodies (mAbs) with pediatric information; 2) to investigate pharmacokinetic (PK) differences between pediatrics and adults; 3) to explore the potential mechanisms for any difference; 4) to evaluate the dose strategy for mAbs in pediatrics.
The product labeling and published literature (by June 2019) were searched for mAbs with pediatric use (sources: Drugs@FDA, PubMed, Google Scholar). Further information was investigated, including age range, PK parameters, dose strategy, PK difference compared to adults, and potential mechanisms.
As of the end of June 2019, 25 mAbs are approved for pediatric indications and 14 unapproved mAbs have pediatric information from literature reports. The 14 unapproved mAbs are either under development, withdrawn or have off-label use for pediatric patients. Among these 39 mAbs with pediatric information, 18 are evaluated in pediatrics less than 2 years of age: basiliximab, bevacizumab, burosumab, cetuximab, daclizumab, dinutuximab, eculizumab, emapalumab, emicizumab, gemtuzumab ozogamicin, infliximab, MEDI8897, motavizumab, pagibaximab, palivizumab, rituximab, SB209763, and urtoxazumab.
The PK parameters in pediatrics, focusing on subjects less than 2 year of age, were summarized and compared to results in adults when data were available for both age groups. The investigation suggests the PK difference between pediatrics and adults is mAb dependent. The body weight (BW) or body-surface area (BSA) normalized clearance (CL) was comparable between pediatrics and adults for several mAbs, including gemtuzumab ozogamicin, MEDI8897, palivizumab. However, the BW-normalized CL was higher in pediatrics for infliximab, pagibaximab, tocilizumab. No mAbs were found to have lower BW-normalized CL in pediatrics so far.
Dose selection of mAbs for evaluation in pediatric trials is often extrapolated from the adult dose according to BW, age, or BSA. While these methods account for the size differences between pediatrics and adults, they do not account for the maturation of processes that may play a key role in PK of mAbs.
The knowledge about factors affecting mAbs exposure in pediatrics is stilling evolving. The data for comparison of PK difference between pediatrics and adults, especially for pediatrics less than 2 years of age, are still limited. Based on available data from several mAbs, current investigation suggests the PK difference between pediatrics and adults is mAb dependent, and the BW-normalized CL could be similar or higher for individual mAb. Thus, the same or higher BW-normalized dose can provide similar exposure in pediatrics compared to adults.
Different potential mechanisms may contribute to the PK differences between pediatrics and adults. Higher transcapillary escape rate (TER) in pediatrics less than 2 years of age may lead to higher CL, and higher extracellular fluid (ECF) volume fraction in pediatrics less than 1 year of age may lead to higher volume of distribution. Lower endogenous IgG level in pediatrics less than 2 years of age (except neonates with higher level from maternal IgG transfer) may result in lower CL. The combination of different mechanisms at different age stages determines the overall effect on mAb exposure.