Monoclonal antibodies (mAbs) constitute a therapeutically and economically important drug class with increasing use in both adult and paediatric patients. The rather complex pharmacokinetic and pharmacodynamic properties of mAbs have been extensively reviewed in adults. In children, however, limited information is currently available. This paper aims to comprehensively review published pharmacokinetic and pharmacokinetic-pharmacodynamic studies of mAbs in children. The current status of mAbs in the USA and in Europe is outlined, including a critical discussion of the dosing strategies of approved mAbs. The pharmacokinetic properties of mAbs in children are exhaustively summarised along with comparisons to reports in adults: for each pharmacokinetic process, we discuss the general principles and mechanisms of the pharmacokinetic/pharmacodynamic characteristics of mAbs, as well as key growth and maturational processes in children that might impact these characteristics. Throughout this review, considerable knowledge gaps are identified, especially regarding children-specific properties that influence pharmacokinetics, pharmacodynamics and immunogenicity. Furthermore, the large heterogeneity in the presentation of pharmacokinetic/pharmacodynamic data limited clinical inferences in many aspects of paediatric mAb therapy. Overall, further studies are needed to fully understand the impact of body size and maturational changes on drug exposure and response. To maximise future knowledge gain, we propose a 'Guideline for Best Practice' on how to report pharmacokinetic and pharmacokinetic-pharmacodynamic results from mAb studies in children which also facilitates comparisons. Finally, we advocate the use of more sophisticated modelling strategies (population analysis, physiology-based approaches) to appropriately characterise pharmacokinetic-pharmacodynamic relationships of mAbs and, thus, allow for a more rational use of mAb in the paediatric population.
aBMD decreased at the hip but increased at the spine and radius, in which the increment was explained by continued mineralization and augmented cortical thickness due to endosteal contraction in men between ages 19 and 24 yr.
Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing <20 kg. EudraCT number: 2013-000260-28, 2013-000259-42.
AZD5423 is a non-steroidal glucocorticoid receptor modulator, with low aqueous solubility, developed for treatment of asthma and COPD. In this work, we aim to evaluate and compare the absorption pharmacokinetics (PK) of AZD5423 after inhalation via four devices, (Spira®, I-neb®, Turbuhaler® and a new dry powder inhaler (new DPI)) with two formulations using differently sized primary particles, and to compare the pulmonary bioavailability with the predicted lung deposited dose. Plasma concentration-time data after intravenous, oral and inhaled administration via four devices were available from two clinical studies in healthy and asthmatic subjects. A population PK modelling approach was taken to sequentially incorporate each route of administration, assuming parallel absorption compartments for inhaled AZD5423. A non-compartmental analysis for derivation of PK parameters was performed for comparison. Pulmonary bioavailability varied between devices, with the lowest estimates for I-neb (27%) and Turbuhaler (30%) and the highest for the new DPI (46%) and Spira (35-49%). The pulmonary bioavailability was substantially lower than the predicted lung deposited dose (range 59-90%). Lung absorption was separated into a faster and a slower process in the model. The half-life of the faster absorption appeared formulation-dependent, while the slower absorption (half-life of 0.59-0.78 h) appeared independent of formulation. The large difference in the estimated pulmonary bioavailability and the predicted lung deposited dose for AZD5423 implies an impact of mucociliary clearance. The lung absorption half-life indicates that AZD5423 is retained in the lung for a relatively short time.
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