(T-113) Model-informed Evidence Generation to Optimize Warfarin Dosing for Hepatic Impairment

Gledys Reynaldo Fernandez, Posdoctoral Associate – Department of Pharmaceutics – University of Florida; Leyanis Rodriguez Vera, Senior Research Scientist – Model Informed Development – CTI Clinical Trial & Consulting; Karine Rodriguez Fernandez, PhD student – Department of Pharmacy and Pharmaceutical Technology and Parasitology – University of Valencia; Victor Mangas Sanjuan, Associate Professor – Department of Pharmacy and Pharmaceutical Technology and Parasitology – University of Valencia; Francine Johansson Azeredo, Research Assistant Professor – Department of Pharmaceutics – University of Florida; Jorge Duconge, Assistant Dean for Research & Graduate Programs – Department of Pharmaceutical Sciences – University of Puerto Rico; Valvanera Vozmediano, Senior Director Model Informed Development – Model Informed Development – CTI Clinical Trial & Consulting

Objectives: Although warfarin is the only oral anticoagulant recommended for patients with severe hepatic impairment, specific dosing guidelines are lacking [1]. This study aimed to evaluate warfarin dose adjustments in patients with liver dysfunction and different CYP2C9 and VKORC1 polymorphisms, considering the impact of reduced warfarin clearance (CL) on response, measured as the International Normalized Ratio (INR). Since warfarin is eliminated through hepatic metabolism, liver dysfunction is likely to affect drug exposure, potentially necessitating dose modifications.

Methods: Based on a previously published population PK/PD model [2], we performed simulations to evaluate warfarin dosing according to CYP2C9 and VKORC1 genotypes under 30%, 50%, and 70% reductions in CL. Simulations assessed the time required for patients to exceed the therapeutic INR range (INR > 3) and compared them to those with normal hepatic functions. A 21-day treatment period was used to evaluate the need for dose adjustments based on INR responses. Simulations were performed in NONMEM v7.5 and data handling and graphics were done with R-software version 4.3.1 (www.r-project.org).

Results: In poor metabolizers (∗2/∗3, ∗2/∗5) with VKORC1 resistance (G/G) and a 70% CL reduction, INR exceeded the therapeutic range by day 10 with a 3 mg/day dose. For 50% and 30% reductions, INR exceeded the range on days 12 and 17, respectively. However, VKORC1 sensitive (A/A) individuals maintained therapeutic INR at 1 mg/day across all CL reductions, though those with 70% reduction required closer monitoring.

Intermediate metabolizers (∗2/∗2, ∗1/∗3, ∗1/∗5, ∗1/∗8) with VKORC1 resistance required a 5 mg/day dose to maintain a therapeutic INR. However, individuals with a 70% CL reduction exceeded the therapeutic range by day 10, while those with 50% and 30% reductions exceeded it by days 12 and 17, respectively. Additionally, intermediate metabolizers with VKORC1 sensitivity required a 1 mg/day dose to maintain therapeutic INR levels. Intermediate-to-normal metabolizers (∗1/∗2, ∗1/∗1) with VKORC1 resistance exhibited similar patterns at 5 mg/day, with rapid excursions beyond the therapeutic range, particularly with 50% and 70% CL reductions. VKORC1 sensitive individuals showed similar trends at a 3 mg/day, exceeding the therapeutic range by day 10 in cases of 50% and 70% CL reduction.

Conclusions: Our results indicate that patients with liver dysfunction may need dose adjustments based on their VKORC1 genotype. VKORC1 resistant patients might benefit from starting warfarin therapy at 2 mg/day, while VKORC1 sensitive patients could begin with 1 mg/day to maintain a therapeutic INR and reduce the risk of exceeding the therapeutic range. Due to the challenges in predicting hepatic impairment and the absence of validation data, further clinical studies are needed to confirm these findings.

Citations: [1] Arman Qamar, MD,a Muthiah Vaduganathan, MD, MPH,b Norton J. Greenberger, MD,c Robert P. Giugliano, MD, SMa. Oral Anticoagulation in Patients with Liver Disease. JACC VOL. 71, NO. 19, 2018. MAY 1 5, 2018: 2162–75.
[2] Karine Rodríguez-Fernández, Gledys Reynaldo-Fernández, Stephanie Reyes-González, Camila de las Barreras, Leyanis Rodríguez-Vera, Cornelis Vlaar, Jean-Christophe M. Monbaliu, Torsten Stelzer, Jorge Duconge, Victor Mangas-Sanjuan. New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model. Biomedicine & Pharmacotherapy. 2024 Jan; 170: 115977.

Keywords: Model-Informed Drug Development, Hepatic Impairment, Specific Populations