(T-095) Pharmacokinetic Modeling of Prophylactic Dose Rivaroxaban Transfer into Human Milk

Kathleen Job, PhD, DABCP – Pediatrics – The University of Utah; Ware Branch, MD – Obstetrics and Gynecology – The University of Utah; Ming Lim, MBBCh, MS – Hematology – The University of Utah; Julie Shakib, DO, MS, MPH – General Pediatrics – The University of Utah; Erin Zinkhan, MD – Pediatric Neonatology – The University of Utah; Intermountain Health; Torri Metz, MD – Obstetrics and Gynecology – The University of Utah; Kevin Watt, MD, PHD – Pediatrics – The University of Utah; Ann Bruno, MD – Obstetrics and Gynecology – The University of Utah

Objectives: Rivaroxaban is a direct oral anticoagulant used for the treatment and prevention of venous thromboembolism. There is a paucity of data on rivaroxaban excretion into human milk, and due to the concern for neonatal exposure, current guidelines recommend against use while breastfeeding. We aimed to evaluate the excretion of prophylactic dose rivaroxaban into human milk through: 1) measurement of relative infant dose (RID) and daily infant dose (DID), and 2) development of a preliminary population pharmacokinetic (popPK) model to predict rivaroxaban transfer into human milk.

Methods: Data were collected in a single-center, 2-day, open-label pilot study of participants who received prophylactic dose rivaroxaban (10 mg every 24 hours) and collected milk without an intent to breastfeed. Maternal plasma and human milk samples were collected immediately before, and 2, 4, and 6 hours after the second dose. Salivary samples were collected for CYP3A4, CYP3A5, and ABCB1 characterization. PKAnalix was used for non-compartmental analyses, including area under the curve (AUC), maximum concentration, and time to maximum concentration. Milk-to-plasma (M/P) ratio was calculated as the ratio between milk and maternal plasma AUC. DID was calculated as a function of the average maternal plasma concentration multiplied by the M/P ratio and the average fully expressed milk intake per infant weight (150 mL/kg/day). RID was calculated as the weight-adjusted percent of maternal dose that an infant was estimated to receive, assuming a 75 kg maternal weight and a 10 mg dose. A popPK model was developed using nonlinear mixed effects modeling with 1-and 2-compartment models tested (NONMEM (v7.5) and Finch Studio (v1.5.2). A forward inclusion (p < 0.05) and backward elimination (p < 0.01) approach was used to identify covariates (e.g., BMI, CYP3A4/5 genotype, and ABCB1 genotype, time after delivery) and explore inter-individual variability in PK parameters. Visual predictive checks and bootstrap methods were performed.

Results: Overall, 20 participants were enrolled. The mean M/P ratio, DID, and RID were 0.45, 0.0039 mg/kg/day, and 2.92%, respectively. A 2-compartment popPK model with linear absorption and elimination best described the data. Final model parameters and relative standard error were estimated for apparent clearance (CL/F), apparent volume of distribution for the central compartment (V2/F), apparent volume of distribution for the milk compartment (V3/F), distribution to the milk compartment (Q), and absorption rate (Ka): CL/F, 10 L/h (9.11%); V2/F, 24.1 L (23.3%), V3/F, 42.1 L (14.3%), Q, 11.1 L/h (22.1%), and Ka, 0.82/h (fixed). Interindividual variability for CL/F and V2/F were 0.10 (42.7%) and 0.10 (33.2%), respectively. Time after delivery (CL/F, V2/F, and Q) and CYP3A5 (V2/F) were significant covariates.

Conclusions: Non-compartmental analyses indicate the DID from a maternal prophylactic rivaroxaban dose is less than 10% of a typical infant therapeutic dose. The developed popPK model estimates similar CL/F and a decrease in V2/F compared to adult models [1, 2]. Larger studies are needed to further evaluate safety of rivaroxaban use while breastfeeding.

Citations: [1] Willmann, S., et al., Integrated Population Pharmacokinetic Analysis of Rivaroxaban Across Multiple Patient Populations. CPT Pharmacometrics Syst Pharmacol, 2018. 7(5): p. 309-320.
[2] Mueck, W., et al., Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban--an oral, direct factor xa inhibitor--in healthy subjects. Int J Clin Pharmacol Ther, 2007. 45(6): p. 335-44.

Keywords: rivaroxaban, lactation, population pharmacokinetic modeling