(S-043) Near Real-Time Apixaban Clinical Dose Decision-Making in Treating a Neonatal Venous Thromboembolism Population Using the InsightRX Nova™ Platform
Clinical Pharmacology Lead Pfizer Inc., United States
Disclosure(s):
Puneet Gaitonde, PhD: No relevant disclosure to display
Objectives: Here, we describe a pharmacokinetic (PK) analysis from the safety and descriptive efficacy study of apixaban in neonate patients (aged < 28 days old) with venous thromboembolism (VTE) requiring anticoagulation (NTC02464969).1 A careful approach was required in dosing these patients due to their risk of adverse events while attempting to maintain efficacy in this vulnerable population. To mitigate the risks, a near real-time model-informed precision dosing (MIPD) approach using the InsightRX Nova™ Pfizer platform was utilized.2 The platform leveraged PK data from individual patients to provide precise apixaban dose-adjustment recommendations during the study to maintain exposures within a prespecified target apixaban exposure range, allowing for effective treatment of this population.
Methods: The MIPD approach used an apixaban pediatric population PK model as its base and was developed using data from two pediatric PK studies and Phase 1 studies in healthy adults.3 The final model used was a 2-compartment model with first-order absorption and elimination and dose-dependent bioavailability and covariates for age, weight, and formulation. Neonates randomized to apixaban treatment received a starting dose of 0.1 mg of apixaban twice daily (BID); blood samples for PK analysis were collected on Day 1 at 3, 12, and 24 hours following the first dose. The target area under the curve (AUC) range was 1293–4807 ng/mL*hr (i.e. 90% prediction interval based on exposure results from adults treated with 5 mg apixaban BID).
For each neonate, a maximum a posteriori fit using the PK model estimated individual drug exposures over 24 hours at steady state (AUC24,ss), with Bayesian priors weighted at 25% to mitigate model misspecification in this new patient population. Dosing recommendations were based on the InsightRX Nova™ platform’s PK model-predicted drug exposures using patient covariates. If apixaban exposures were within the target range, the dose remained 0.1 mg BID; if > 4807 and ≤ 9614 ng*hr/mL, the dose was reduced to 0.1 mg once daily (QD); if ≥ 646.5 and < 1293 ng*hr/mL, the dose was increased to 0.2 mg BID; if the 90% prediction interval could not be achieved with either 0.1 mg QD or 0.2 mg BID, the patient was discontinued from apixaban.
Results: Eleven patients were dosed with a starting dose of 0.1 mg apixaban BID, of which 9 patients had evaluable Day 1 apixaban PK data. Following initial apixaban dosing, InsightRX Nova™ platform-based PK analysis predicted 3 patients’ drug exposures to be within the target AUC24,ss range and thus recommended staying on the initial dose. Six neonates had predicted exposures lower than the target range and a dose increase to 0.2 mg BID was recommended. PK analysis of patient blood samples confirmed predicted exposures were within < 1% of actual exposures. There were no efficacy (VTE) or safety (major bleeding or clinically relevant non-major bleeding) events in this population.
Conclusions: The novel MIPD approach using the InsightRX Nova™ platform’s ability to deliver near real-time PK analyses allowed for informed dosing decisions to be made without compromising the efficacy/safety of VTE treatment with apixaban in vulnerable neonatal patients.
Citations: 1. Driscoll J, et al. Blood 2024;144(suppl 1):295 2. Shukla P, et al. Front Pharmacol 2020;11:888 3. Byon W, et al. CPT Pharmacometrics Syst Pharmacol. 2017;6(5):340–349
