Prediction of Drug Clearance in Premature and Mature Neonates, Infants, and Children ≤2 Years of Age: A Comparison of the Predictive Performance of 4 Allometric Models

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The objective of this study was to evaluate the predictive performances of allometric models and a physiologically based pharmacokinetic model (PBPK) to predict clearance of glucuronidated drugs in neonates (≤ 3 months of age). From the literature, clearance values for 9 drugs (glucuronidated) for neonates and adults were obtained. Three allometric models were used to predict clearances of these glucuronidated drugs. A PBPK model was developed using the physicochemical, biopharmaceutical, and metabolic properties together with known pediatric physiology and enzymatic ontogeny. The model was first developed for adult subjects and then verified using external data and then applied to simulations in neonates. The predictive performances of allometric and PBPK models were evaluated by comparing the predicted values of clearance with the observed clearance values in the neonates. For 9 drugs, there were 13 age groups (preterm and term neonates) for which prediction error in mean clearance values within 0.5- to 1.5-fold was observed in 10 and 11 age groups by 2 allometric models and a PBPK model, respectively. The proposed allometric methods can predict mean clearances of glucuronidated drugs in preterm and term neonates (≤ 3 months of age) with reasonable accuracy (within 0.5- to 1.5-fold or 50% error) and are of practical value during neonatal drug development. The predicted mean clearance values of glucuronidated drugs in neonates ≤ 3 months of age by 2 allometric methods were comparable with the PBPK model.

\begin{matrix} true \\ right CL in neonates \\ left = Adult CL * {(Weight of the child / 70)}^{1.2 or 1.1} \end{matrix}

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Section: Methodsmentioning

confidence: 97%

Prediction of Clearance in Neonates and Infants (≤ 3 Months of Age) for Drugs That Are Glucuronidated: A Comparative Study Between Allometric Scaling and Physiologically Based Pharmacokinetic Modeling

Mahmood

Ahmad²,

Mansoor

et al. 2016

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“…Below the age of 2 years there is more uncertainty. Allometric scaling with age‐dependent exponents can match PBPK modeling in pediatric PK prediction for very young children, but the age‐dependent exponents have to be learned with similar compounds as prior information …”

mentioning

confidence: 99%

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

Malik

Edginton

2019

An understanding of pediatric pharmacokinetics (PK) is essential for first‐in‐pediatric dose selection and clinical trial design. At present, there is no reliable way to scale the PK of monoclonal antibodies and immunoglobulin G drug products from adults to young children or to premature infants—a vulnerable population with a rapidly growing drug development pipeline. In this work, pediatric physiologically based PK models are constructed in PK‐Sim and Mobi to explore the PK of pagibaximab, palivizumab, MEDI8897, and intravenous immunoglobulin in preterm infants. In addition to considering ontogeny in pediatric organ volumes, organ composition, blood flow rates, and hematocrit, advanced ontogeny is applied for 3 key parameters: capillary surface area, hematopoietic cell concentration, and lymph flow rate. The role and importance of each parameter for determining pediatric clearance (CL) and volume of distribution at steady state (VSS) are quantitatively assessed with a local sensitivity analysis. In addition, the uncertainty around parameters with limited information in pediatrics is addressed (eg, free neonatal Fc receptor concentration). The full ontogeny parameterization yields pediatric PK predictions that are within 1.5‐fold prediction error >90% of the time for preterm infants, with an absolute average fold error of 1.05. This result suggests that many of the key factors related to ontogeny are appropriately addressed. Overall, this study makes a first step toward developing a platform pediatric physiologically based PK model for monoclonal antibodies and immunoglobulin G drug products by solidifying existing parameterizations, integrating new concepts, and drawing attention to unmet needs for physiologic knowledge in children.

“…Most physiologic parameters of living organisms are allometrically related with body weights. When the exponents of allometry for CL were determined across the age groups (neonates to adults), it was noted that the exponents of allometry change with body weight or age . This change in allometric exponents as a function of weight or age may explain the allometric relationship with ontogeny or maturation for that particular age or body weight.…”

Section: Discussionmentioning

confidence: 99%

“…The allometric exponents widely vary and are data dependent . The rapid physiologic changes in children are nonlinear, and a single exponent cannot describe the CL vs body weight data across all age groups (neonates to adults).…”

Section: Discussionmentioning

confidence: 99%

“…The rapid physiologic changes in children are nonlinear, and a single exponent cannot describe the CL vs body weight data across all age groups (neonates to adults). This observation led Mahmood to introduce the concept of the age‐dependent exponent model for small molecules. With the introduction of the age‐dependent exponent model, a substantial improvement in the prediction of drug CL in children from neonates to adolescents was noted .…”

Section: Discussionmentioning

confidence: 99%

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

Mahmood

2019

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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.