Initiation of Pediatric Clinical Trials for Coagulation Factors: Application of Pharmacokinetics and Allometry to First‐in‐Pediatric Dose Selection

Abstract

Allometric scaling is a method that can be used for the extrapolation of pharmacokinetic parameters from adults to children. Subsequently, these allometrically predicted PK parameters can be used to project a suitable dose to initiate a pediatric clinical trial. The objective of this study was to predict clearance and in vivo recovery of coagulation factors VIII and IX allometrically in children from 1 year of age to adolescents and then project the first‐in‐children dose. The values for observed clearance, in vivo recovery, and dose for pediatric as well as adult subjects for 7 factor VIII and 3 factor IX products were obtained from the US Food and Drug Administration package insert and the allometrically predicted clearance, in vivo recovery, and dose were compared with the observed values. The clearance of factors VIII and IX were predicted with reasonable accuracy. Of 27 predicted clearance values, all 27 (100%) were predicted with ≤30% prediction error (range, 5%–28%). Of 27 predicted in vivo recovery values, 26 (96%) were predicted with ≤30% prediction error (range, 0%–45%). The projected doses of factor VIII or IX, either by clearance or in vivo recovery, were generally within the recommended dose range indicating an accurate prediction of pediatric dose for both factors. The proposed allometric methods can be used to select first‐in‐children dose in pediatric clinical trials.

Prediction of Clearance of Monoclonal and Polyclonal Antibodies and Non-Antibody Proteins in Children: Application of Allometric Scaling

“…Allometric scaling is a useful tool and can be used to predict PK parameters such as clearance, volume of distribution, and half-life in children from adult data [2][3][4][5][6][7][52][53][54][55]. Allometry has been successfully used for the prediction of clearance in children from adults for small molecules and coagulation factors [2][3][4][5][6][7][53][54][55].…”

“…The exponents selected in the ADE model are based from previous experience, observation, and data analysis. The exponents of the ADE model were previously applied to test the suitability of the exponents in the allometric model across the age group to predict the clearances of small molecule drugs and coagulation factors in children [2][3][4][5][6][7].…”

“…Allometric scaling is regularly used to predict PK parameters such as clearance, volume of distribution {XE "volume of distribution"}, and half-life {XE "half-life"} from animals to humans (interspecies scaling) [8]. From the same token, the allometric principles can also be applied to scale physiological and PK parameters from preterm neonates to adolescents [2][3][4][5][6][7] from adult data. This approach is of practical value during drug development because it can provide some information for first-in-pediatric dose selection.…”

“…As clearance is the most important PK parameter, using allometry, it is possible to predict clearance of drugs in children across the age groups from adult drug clearance values [2][3][4][5][6][7]. From these predicted clearance, one can project first-in-pediatric dose to initiate a clinical trial.…”

Clinical Pharmacology Review of Plasma‐derived and Recombinant Protein Products: CBER Experience and Perspectives on Model‐Informed Drug Development

“…For example, the FDA package insert for COAGADEX (Coagulation Factor X) provides clearance data only for >12 years old subjects . In the absence of PK data in young children, the knowledge of age or bodyweight dependent clearance scaling across a wide age range for FVIII and FIX can be applied for designing clinical trial for other coagulation factors used for treatment of rare hereditary bleeding disorders . Clinical pharmacology experience gained from FVIII and FIX products can also be leveraged and assist in dose optimization of rare coagulation disorders.…”