Model Informed Precision Dosing of Oral Ibuprofen for Treatment of Persistent Patent Ductus Arteriosus: A Pilot Randomized Controlled Feasibility Trial
Maternal, Child & Mental Health
Patent Ductus Arteriosus (PDA) is a common and serious morbidity of preterm birth. Oral ibuprofen, although recognized as the preferred pharmacotherapeutic option for treatment of PDA, remains limited in its effectiveness with failure to close the PDA in more than 50% of extremely preterm neonates. Studies have shown that standard dosing regimens of ibuprofen result in significantly variable exposures, with responders to ibuprofen having higher degree of exposure. Individualized dosing approach (Model-informed precision dosing-MIPD), can therefore be a key factor in improving the rate of response. To make the individual dosing adjustments feasible, our team at the University of Waterloo has developed a Bayesian forecasting tool (WAPPS-PDA), which makes the timely and individual MIPD of oral ibuprofen possible and practical. In this study, we hypothesize that a large, definitive trial comparing effectiveness and safety of MIPD versus standard dosing of oral ibuprofen for treatment of persistent PDA is feasible. Our approach is unique and innovative in development of WAPPS tool and facilitating the individualized dosing of oral ibuprofen for treatment of a persistent PDA, both transferable and scalable to other national and international institutions.
Introduction: Persistent Patent Ductus Arteriosus (PDA) is one of the most common and serious morbidities of preterm birth. Oral ibuprofen, as the preferred pharmacotherapeutic option for treatment of PDA, remains limited in its effectiveness with failure to close the PDA in more than 50% of extremely preterm neonates. Studies have shown that standard dosing regimens of ibuprofen result in significantly variable exposures, with responders to ibuprofen having higher degree of exposure. Model-informed precision dosing (MIPD) is a precision dosing approach and is essential when PK variability of a drug surpasses the limits of an effective or safe range of drug exposure such as the case of oral ibuprofen therapy in preterm neonates with a PDA.
Objective: The feasibility of conducting a large and definitive clinical trial comparing the effectiveness and safety of MIPD as compared to standard dosing of oral ibuprofen therapy.
Methodlogy: A single-center pilot, randomized controlled triple-blind trial (feasibility study) of inpatient neonates ≤27+6 WGA and diagnosed with a PDA in need for treatment.
Enrolled neonates will be randomized to standard dosing (control arm) or MIPD of oral ibuprofen (intervention arm). Patients randomized to standard therapy will receive oral ibuprofen as per the local standard of care. Patients randomized to the MIPD oral ibuprofen therapy will receive dosing regimen that will be informed and adjusted by daily PK samples and TnEcho results to meet predefined exposure targets associated with successful closure of PDA, using WAPPS-PDA tool.
Primary outcome: Feasibility of the conduct of a larger definitive trial assessed as per our primary outcome measures.
Outcome evaluation: As per the result of our primary outcomes, if the hypothesis of feasibility of the conduct of a RCT is confirmed, this study will lay the groundwork for a large-scale definitive trial, providing data on MIPD of ibuprofen therapy for closure of a persistent PDA in preterm neonates. In the event of failure of the feasibility, or evidence of adverse events in the MIPD ibuprofen therapy arm, this study provides important information on the potential barriers for personalized oral ibuprofen therapy in neonatal patients and possible adverse drug reactions.
Possible challenges and strategies: To accomplish a pilot feasibility clinical trial that provides reliable and accurate results, we have established and validated infrastructures that support the optimal and rigorous implementation of the study. A few examples are: The measurement of ibuprofen concentration will be performed at the McMaster Research Center using a method that was locally developed, validated and published. The principle investigator of this study developed the design and strategy of this trial in close collaboration with a team of national and international pharmacology experts that she has established partnership with. The pharmacokinetics Research Group at the University of Waterloo, has developed the Bayesian forecasting WAPPS-PDA tool, informed by our published PK model and has validated its accuracy and reliability through multiple simulation exercises.
N/A to the current project but related to this research program and it’s infrastructural work:
Samiee-Zafarghandy S, van Donge T, Fusch G, et al. Novel strategy to personalise use of ibuprofen for closure of patent ductus arteriosus in preterm neonates. Arch Dis Child. 2022;107(1):86-91. doi:10.1136/archdischild-2020-321381
Smit C, Engbers AGJ, Samiee-Zafarghandy S, et al. Oral Ibuprofen Is More Effective than Intravenous Ibuprofen for Closure of a Patent Ductus Arteriosus: Can Pharmacokinetic Modeling Help Us to Understand Why?. Neonatology. 2023;120(1):81-89. doi:10.1159/000526210