Physiologically‐Based Pharmacokinetic Modeling‐Guided Dose Management of Oral Anticoagulants when Initiating Nirmatrelvir/Ritonavir (Paxlovid) for COVID‐19 Treatment

Abstract

Patients with coronavirus disease 2019 (COVID‐19) with cardiovascular diseases who are at higher risk of progressing to critical illness should be treated with nirmatrelvir/ritonavir (Paxlovid). Ritonavir, the booster in nirmatrelvir/ritonavir, modulates multiple drug metabolizing enzymes and transporters, complicating its use in real‐world clinics. We aimed to apply physiologically‐based pharmacokinetic (PBPK) modeling to simulate the complex drug–drug interactions (DDIs) of ritonavir with two anticoagulants, rivaroxaban and racemic warfarin, to address this important clinical conundrum. Simulations were implemented within Simcyp Simulator. Compound and population models were adopted from Simcyp and our previous studies. Upon verification and validation of the PBPK model of ritonavir, prospective DDI simulations with the anticoagulants were performed in both the general population (20–65 years) and geriatric subjects (65–85 years) with or without moderate renal impairment. Elevated rivaroxaban concentrations were simulated with nirmatrelvir/ritonavir treatment, where the impact was more profound among geriatric subjects with renal impairment. The overexposure of rivaroxaban was restored to normal range on day 4 post‐discontinuation of nirmatrelvir/ritonavir, corroborating with the recovery of enzyme activity. A lower 10 mg daily dose of rivaroxaban could effectively maintain acceptable systemic exposure of rivaroxaban during nirmatrelvir/ritonavir treatment. Treatment of ritonavir marginally declined simulated S‐warfarin concentrations, but substantially elevated that of R‐warfarin, resulting in a decrease in the international normalized ratio (INR). As INR only recovered 2 weeks post‐nirmatrelvir/ritonavir treatment, a longer surveillance INR for warfarin becomes important. Our PBPK‐guided simulations evaluated clinically important yet untested DDIs and supports clinical studies to ensure proper anticoagulation management of patients with COVID‐19 with chronic coagulative abnormalities when initiating nirmatrelvir/ritonavir therapy.

Adverse Events of SARS-CoV-2 Therapy: A Pharmacovigilance Study of the FAERS Database

“…Although no significant events in the FAERS database were noted for cross-reactivity with direct oral anticoagulants and corticosteroids, they are still medications clinicians should be aware of as they have known to have interactions with ritonavir. This was noted in Wang and Chan 23 pharmacokinetic modeling-based study noting the need for possible dose adjustment of direct oral anticoagulants due to drug-drug interactions in patients requiring antiviral therapy. Our study was limited by the events documented in the FAERS database being reported voluntarily, potentially missing AEs that were not reported.…”

A physiologically‐based pharmacokinetic/pharmacodynamic modeling approach for drug–drug‐gene interaction evaluation of S‐warfarin with fluconazole

“…PBPK modeling of warfarin has previously been applied to investigate specific scenarios, such as studying bioequivalence, 57 determining the role of OAT2, 35 predicting in vivo target occupancy, 38 and DDI. 59,66,69 Two studies of PBPK/PD modeling are applied to dose management when warfarin and sorafenib or nirmatrelvir/ ritonavir are administered in combination. 66,69 Compared to our model, the TMDD process was incorporated, the fraction of CYP2C9 enzyme metabolism was considered, and a different PD model was used.…”

Cardiovascular Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19

“…However, the risk of bleeding was noted to be higher in elderly patients and those with at least moderate renal impairment. 14 …”