A Model-Based Approach to Dose Selection in Early Pediatric Development

Cella, Massimo; Vries, F. Gorter de; Burger, David M.; Danhof, Meindert; Pasqua, Oscar Della

doi:10.1038/clpt.2009.234

Cited by 56 publications

(75 citation statements)

References 16 publications

(18 reference statements)

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“…Given the mechanism of action of abacavir, the exposure-effect relationship can be assumed to be independent of age. The adult AUC0-12 target value of 6.02 mg h ml -1 can be set as the target exposure for effective and safe treatment in children [10]. These findings provide the rationale for AUC guided abacavir dosing adjustment, but implementation in clinical practice is missing.…”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV‐infected infants and toddlers

Zhao

Cella

Pasqua

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Abacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8 mg kg−1 twice daily up to a maximum of 300 mg twice daily. • Weight was identified as the central covariate influencing pharmacokinetics of abacavir in children. WHAT THIS STUDY ADDS • A population pharmacokinetic model was developed to describe both once and twice daily pharmacokinetic profiles of abacavir in infants and toddlers. • Standard dosage regimen is associated with large interindividual variability in abacavir concentrations. • A maximum a posteriori probability Bayesian estimator of AUC0–t based on three time points (0, 1 or 2, and 3 h) is proposed to support area under the concentration–time curve (AUC) targeted individualized therapy in infants and toddlers. AIMS To develop a population pharmacokinetic model for abacavir in HIV‐infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration–time curve (AUC) targeted dosage and individualize therapy. METHODS The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed‐effects modelling (NONMEM) software. A two‐compartment model with first‐order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross‐validation and simulation–estimation method. RESULTS The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 l h−1 (RSE 6.3%), apparent central volume of distribution 4.94 l (RSE 28.7%), apparent peripheral volume of distribution 8.12 l (RSE14.2%), apparent intercompartment clearance 1.25 l h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0–t. CONCLUSIONS The population pharmacokinetic model developed for abacavir in HIV‐infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC0–t was developed from the final model and can be used routinely to optimize individual dosing.

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Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV‐infected infants and toddlers

Zhao

Cella

Pasqua

et al. 2012

Brit J Clinical Pharma

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“…Despite the potential of innovative research methods in collecting data on drug effects in children and/or developing clinical trials, it seems that their benefits as tools in pharmaceutical R&D has remained undervalued and sometimes ignored by key stakeholders (Cella et al, 2010;Abernethy & Burckart,2010). This attitude appears to contradict those ethical and scientific beliefs that emphasize the need for evaluation of the risk-benefit ratio in special populations, such as the paediatric one.…”

Section: Research Aim and Results (What Have We Done)mentioning

confidence: 99%

Changes in Research and Development of Medicinal Products since the Paediatric Regulation

Ceci¹,

Catapano²,

Manfredi³

et al. 2011

Drug Development - A Case Study Based Insight Into Modern Strategies

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“…Pediatric developmental changes must be taken into account, as they also play a key role in pharmacokinetics. For example, obvious maturation changes are related to the volume increase of luminal fluids, intestinal surface area, and intestinal permeability (12)(13)(14)(15). Administered dose is also fundamentally important, and therefore, there may be a need for a more quantitative, dose-dependent approach to pediatric BCS (16,17).…”

Section: Challenges In the Development Of Pediatric Dosage Forms Frommentioning

confidence: 99%

A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms

Zajicek

Fossler

Barrett

et al. 2013

AAPS J

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Abstract. Despite the fact that a significant percentage of the population is unable to swallow tablets and capsules, these dosage forms continue to be the default standard. These oral formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. The American Association of Pharmaceutical Scientists formed a Pediatric Formulations Task Force, consisting of members with various areas of expertise including pediatrics, formulation development, clinical pharmacology, and regulatory science, in order to identify pediatric, manufacturing, and regulatory issues and areas of needed research and regulatory guidance. Dosage form and palatability standards for all pediatric ages, relative bioavailability requirements, and small batch manufacturing capabilities and creation of a viable economic model were identified as particular needs. This assessment is considered an important first step for a task force seeking creative approaches to providing more appropriate oral formulations for children.

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A Model-Based Approach to Dose Selection in Early Pediatric Development

Cited by 56 publications

References 16 publications

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV‐infected infants and toddlers

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV‐infected infants and toddlers

Changes in Research and Development of Medicinal Products since the Paediatric Regulation

A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms

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