Clin Pharmacokinet
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Antimicrobials and antivirals are widely used in young infants and neonates. These patients have historically been largely excluded from clinical trials and, as a consequence, the pharmacokinetics and pharmacodynamics of commonly used antibacterials, antifungals, and antivirals are incompletely understood in this population. This review summarizes the current literature specific to neonates and infants regarding pharmacokinetic parameters and changes in neonatal development that affect antimicrobial and antiviral pharmacodynamics. ⋯ Though ganciclovir and valganciclovir demonstrate excellent activity against cytomegalovirus, they are associated with significant neutropenia. In summary, many pharmacokinetic and pharmacodynamic studies have been conducted in this vulnerable population; however, there are also substantial gaps in our knowledge that require further investigation. These studies will be invaluable in determining optimal neonatal dosing regimens that have the potential to improve clinical outcomes and decrease adverse effects associated with antimicrobial and antiviral treatments.
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Randomized Controlled Trial
Evidence-based morphine dosing for postoperative neonates and infants.
From a previously validated paediatric population pharmacokinetic model, it was derived that non-linear morphine maintenance doses of 5 μg/kg(1.5)/h, with a 50 % dose reduction in neonates with a postnatal age (PNA) <10 days, yield similar morphine and metabolite concentrations across patients younger than 3 years. Compared with traditional dosing, this model-derived dosing regimen yields significantly reduced doses in neonates aged <10 days. ⋯ Morphine paediatric dosing algorithms corrected for pharmacokinetic differences alone yield effective doses that prevent over-dosing for neonates with a PNA <10 days. The fact that many neonates and infants with a PNA ≥10 days still required rescue medication warrants pharmacodynamic studies to further optimize the dosing algorithm for these patients.
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Randomized Controlled Trial Multicenter Study
Population pharmacokinetic modeling of veliparib (ABT-888) in patients with non-hematologic malignancies.
Veliparib (ABT-888) is a potent oral inhibitor of Poly(ADP-ribose) polymerase enzyme that is currently in development for the treatment of non-hematologic and hematologic malignancies. This analysis characterizes the population pharmacokinetics of veliparib, including developing a structural pharmacokinetic model and testing patient demographics and covariates for potential influence on veliparib pharmacokinetics in patients with non-hematologic malignancies. ⋯ Only LBM and CLCR were found to be determinants of veliparib V d/F and CL/F, respectively. Dosage adjustments of veliparib on the basis of body size, age, sex, race, liver function, and temozolomide coadministration are not necessary in patients with non-hematologic malignancies. This is the first study to characterize the population pharmacokinetics of veliparib, and the developed model will be used to conduct simulations and evaluate veliparib exposure-response relationships.
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Linifanib is a multi-targeted receptor tyrosine kinase inhibitor, which can inhibit members of the vascular endothelial growth factor and platelet-derived growth factor receptor families. The objective of this analysis was to characterize the population pharmacokinetics of linifanib in cancer patients. ⋯ The use of mixed-effects modelling allowed robust assessment of the impact of the concomitant effects of body size, different cancer types, formulation, diurnal variation, sex and food on linifanib pharmacokinetics. The developed population pharmacokinetic model describes linifanib concentrations adequately and can be used to conduct simulations or to evaluate the linifanib exposure-response relationship.
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Randomized Controlled Trial
Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban.
Venous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population. ⋯ The paediatric PBPK model developed here allowed an exploratory analysis of the pharmacokinetics of rivaroxaban in children to inform the dosing regimen for a clinical study in paediatric patients.