prevention of low cardiac output syndrome in paediatric patients after open heart
surgery
Winnie Vogt
Dept. of Clinical Pharmacy and Pharmacotherapy, Heinrich-Heine-Universität Düsseldorf, Germany Objectives: There is an undisputable need for improving paediatrics’ access to safe and effective drug therapy. Thus, regulatory agencies have fostered the increased use of modelling and simulation to minimise the burden of clinical trials and maximise the use of existing information [1,2]. In this scope, physiology-based pharmacokinetic (PBPK) modelling and simulation could be an appropriate tool, especially for treatment indications where bridging of pharmacokinetics from adults to paediatrics is limited due to differences in disease and outcome. This is the case for low cardiac output syndrome (LCOS), which determines morbidity and mortality after open heart surgery for congenital cardiac lesion in paediatric patients [3]. Although drugs are an essential component to treat and prevent paediatric LCOS, limited prescribing guidance hampers the appropriate use of drugs with the inherent risk of increased patient harm and/or lack of efficacy. This also applies to milrinone, the drug of choice for paediatric LCOS treatment and prevention across Europe [4,5].
Therefore, the objective of the study was to employ a PBPK drug-disease modelling and simulation approach towards the evaluation and optimisation of current milrinone dosing for LCOS treatment and prevention in paediatric patients after open heart surgery. This approach should provide insight into the capabilities of system-biology modelling as exploratory tool for improving paediatric drug dosing.
Methods: Model development was based on existing workflows for PBPK drug-disease modelling in adults [6–9] and retrograde drug clearance scaling from healthy adults to paediatrics [10–13] but extended by a link between them. This was necessary because retrograde drug clearance scaling from adult to paediatric patients is limited when age- and disease related differences in drug exposure exist. Thus, a bridge was established to link healthy adult volunteers with aged adult patients and paediatric patients by quantifying and attributing the impact of the normal age-related decline of renal and hepatic clearance pathways and disease on drug exposure. Model development and evaluation was done in PK-Sim® and Mobi®,
respectively.
The first step of model building involved the development of the adult PBPK drug model for intravenously administered milrinone by incorporating physico-chemical input parameters (logP, fu, Mw, pKA/B) as well as hepatic and renal clearance values for milrinone from healthy male adult volunteers taken from literature.
In addition, urinary excretion data of milrinone in patients with renal impairment and healthy adult volunteers were merged to quantify the effect of renal impairment on milrinone’s fraction excreted unchanged in urine. This regulator component was also introduced into the model together with a dose-response relationship of milrinone on blood flow. The second step of model development proceeded with a literature search on pre- and postoperative organ function values in adult patients with (treatment) or without (prevention) LCOS after open heart surgery, which were integrated in a disease model as factorial changes from the reference values in young healthy adults. The disease model was integrated in the drug model to describe the altered pharmacokinetics in diseased adults. At last, the PBPK drug-disease model for
parametric sensitivity analysis.
Following successful model evaluation, the PBPK drug-disease model was used to evaluate current milrinone dosing for LCOS treatment [14] and prevention [4,15] in paediatrics towards achieving the therapeutic target range of 100-300 ng/ml milrinone in plasma. For this, virtual paediatric patient populations were created each with 1000 subjects and reflecting the average paediatric patient characteristics with regard to gender and degree of malnutrition from neonatal to adolescent age. The populations were integrated in Mobi and used to run the PBPK drug-disease model. Optimised dosing regimens were subsequently developed.
Results: A population based PBPK drug model for milrinone was developed and linked with a LCOS disease model for adult and paediatric patients, which constituted disease characteristic key parameter changes, such as haematocrit, albumin abundance, cardiac output and organ blood flows as well as hepatic and renal drug clearances. The model accurately described the pharmacokinetics of milrinone for healthy and diseased, different dosing regimens, ethnicities and age groups: observed versus predicted plasma concentration profiles of milrinone were compared with an average fold error of 1.1±0.1 (mean±SD) and mean relative deviation of 1.5±0.3 as measures of bias and precision, respectively. In addition, observed versus predicted total plasma clearance and volume of distribution deviated by 1.1±0.1 and 1.2±0.2 fold errors, respectively. Normalised maximum sensitivity coefficients for model input parameters ranged from -0.84 to 0.71 indicating the robustness of the model.
The evaluation of milrinone dosing across different paediatric age groups showed that none of the currently used dosing regimens for milrinone achieved the therapeutic target range across all paediatric age groups.
Optimised dosing regimens were subsequently developed that considered the age-dependent and (patho-)physiological differences.
Conclusions: The herein presented approach demonstrates the feasibility and transferability of paediatric PBPK drug-disease modelling and provides evidence on its capabilities as exploratory tool for improving paediatric drug dosing. The selected disease, LCOS, presents an example with marked differences in drug exposure due to age and disease, which is also commonly observed for other cardiovascular, hepatic and renal diseases. PBPK drug-disease modelling helped attributing these differences and optimising dosing strategies for paediatric patients. Nonetheless, model development also highlighted current weaknesses of PBPK drug-disease modelling, driven by the incomplete understanding of disease on body function and drug exposure. Future research needs to narrow these gaps, which may ultimately lead to improved a-priori prediction of drug exposure in paediatric patients and limit the burden of clinical trials.
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Poster: New Modelling Approaches