Quantitative Systems Pharmacology Model to Predict the Effects of Commonly Used Anticoagulants on the Human Coagulation Network.

Warfarin is the anticoagulant of choice for venous thromboembolism (VTE) treatment, although its suppression of the endogenous clot-dissolution complex APC:PS may ultimately lead to longer time-to-clot dissolution profiles, resulting in increased risk of re-thrombosis. This detrimental effect might not occur during VTE treatment using other anticoagulants, such as rivaroxaban or enoxaparin, given their different mechanisms of action within the coagulation network. A quantitative systems pharmacology model was developed describing the coagulation network to monitor clotting factor levels under warfarin, enoxaparin, and rivaroxaban treatment. The model allowed for estimation of all factor rate constants and production rates. Predictions of individual coagulation factor time courses under steady-state warfarin, enoxaparin, and rivaroxaban treatment reflected the suppression of protein C and protein S under warfarin compared to rivaroxaban and enoxaparin. The model may be used as a tool during clinical practice to predict effects of anticoagulants on individual clotting factor time courses and optimize antithrombotic therapy.

MatVPC: A User-Friendly MATLAB-Based Tool for the Simulation and Evaluation of Systems Pharmacology Models.

Quantitative systems pharmacology (QSP) models are progressively entering the arena of contemporary pharmacology. The efficient implementation and evaluation of complex QSP models necessitates the development of flexible computational tools that are built into QSP mainstream software. To this end, we present MatVPC, a versatile MATLAB-based tool that accommodates QSP models of any complexity level. MatVPC executes Monte Carlo simulations as well as automatic construction of visual predictive checks (VPCs) and quantified VPCs (QVPCs).

Sobol Sensitivity Analysis: A Tool to Guide the Development and Evaluation of Systems Pharmacology Models.

A systems pharmacology model typically integrates pharmacokinetic, biochemical network, and systems biology concepts into a unifying approach. It typically consists of a large number of parameters and reaction species that are interlinked based upon the underlying (patho)physiology and the mechanism of drug action. The more complex these models are, the greater the challenge of reliably identifying and estimating respective model parameters. Global sensitivity analysis provides an innovative tool that can meet this challenge. CPT Pharmacometrics Syst. Pharmacol. (2015) 4, 69-79; doi:10.1002/psp4.6; published online 25 February 2015.

The management of hypertensive emergencies in children after stem cell transplantation.

AIM OF THE REVIEW: This work presents a short overview on the available data about drugs that are currently used to treat hypertensive emergencies in children with a focus on incidents after stem cell transplantation. It shows that the pediatric use of all hypotensive agents appears to be mainly based on personal experience of the attending physicians rather than on convincing clinical trials. METHOD: A literature search was performed in MEDLINE, through PubMed, using the medical subject headings (MeSH) hypertensive emergencies, nifedipine, nicardipine, and children. Further articles were identified by checking cross-references of articles and books. RESULTS: Hypertensive emergencies in children after stem cell transplantation usually have a renal etiology, because of the treatment with the calcineurin inhibitors cyclosporine and tacrolimus. In these severe cases an immediate action is necessary to avoid possible appearance or exacerbation of endorgan damage. Because of their mechanism of action and a potential nephroprotective effect calcium channel blockers may be particularly suitable in cases of hypertensive emergencies. An intravenous application of nifedipine may compensate the difficulties of accurate dosing, but keeping in mind possible severe side effects and the lack of published experience its use in children is at least questionable. Nicardipine appears to be the hypotensive agent of first choice. In adults, the treatment of hypertensive emergencies with intravenous nicardipine is well-documented, but for an evaluation of safety in pediatric use, the published studies and case reports appear to be barely adequate. CONCLUSION: The actual treatment approaches vary widely, demonstrating the lack of hard science on which current treatment of hypertensive emergencies in children is based. The hypotensive agent for the individual situation should be chosen considering the properties, side effects, the limited experiences with its use and the patient's anamnesis.

Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study.

BACKGROUND: Enoxaparin has been extensively studied in adults on its safety and efficacy during prevention of symptomatic thromboembolism when acute anticoagulation or secondary prevention is required as a result of venous thrombosis or stroke. In children, it is still used off-label and little is known about the pharmacokinetics in children. OBJECTIVES: The aim of the present study was to evaluate whether a once- or twice-daily dosing regimen would be feasible in children to achieve appropriate plasma levels of enoxaparin. PATIENTS/METHODS: A population pharmacokinetic model was developed using anti-factor (F)Xa activity data from 126 children (median age: 5.9 years) receiving enoxaparin either as a once- or twice-daily dosing regimen. RESULTS: A two-compartment model was adequate for describing the enoxaparin kinetics. Body weight proved to be the most predictive covariate for clearance and central volume of distribution: clearance 15 mL h⁻¹ kg⁻¹, central volume of distribution 169 mL kg⁻¹, intercompartmental clearance 58 mL h⁻¹, peripheral volume of distribution 10 L and absorption rate 0.414 h⁻¹. Interindividual variability was found to be 54% for clearance and 42% for volume of distribution. CONCLUSION: The model is capable of describing all age groups and dosing levels of our population and predicts 12 h and 24 h enoxaparin activities sufficiently. According to our results, a once-daily enoxaparin dosing regimen with frequent monitoring is feasible. In 53.2% of the patients the median 24 h trough level was above the desired range of 0.1 IU mL⁻¹ anti-FXa activity for prophylaxis therapy.