SUMMARY  

• There are no formal drug-drug interaction (DDI) studies evaluating the concomitant use of XARELTO and ritonavir-boosted nirmatrelvir. Janssen does not provide any individual treatment recommendations for patients on XARELTO who are initiating treatment with ritonavir-boosted nirmatrelvir.
• Paxlovid is nirmatrelvir tablets co-packaged with ritonavir tablets, to be taken twice daily (BID) for a full 5-day treatment course.¹
• Ritonavir-boosted nirmatrelvir prescribing information and several guidance resources recommend avoiding coadministration of XARELTO and ritonavir-boosted nirmatrelvir and using an alternative COVID 19 medicine. If both medications are needed, some guidance resources provide suggestions for how to exercise clinical judgement on a case-by-case basis.^1-6
• In the EPIC-HR study, XARELTO was included under the categorization of prohibited medications that are dependent on cytochrome P450 (CYP) 3A4 for clearance or with other notable interactions. XARELTO was not permitted during dosing of ritonavir-boosted nirmatrelvir from the first dose of study drug, through 4 days after the last dose of study drug.⁷
• Two pharmacokinetic studies and 1 physiologically based pharmacokinetic and pharmacodynamic modeling study reporting the effects of ritonavir on XARELTO concentrations are summarized below.^8-11
• Several review articles^12-15 and additional citations^16-20 are included in the REFERENCES section for your review.

PHARMACOKINETIC EFFECTS

Potential Effect of Ritonavir-Boosted Nirmatrelvir on Rivaroxaban

Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-glycoprotein (P-gp; also known as multidrug resistance protein 1 [MDR1]) and ATP-binding cassette G2 (ABCG2) transporters.²¹

Ritonavir is a strong inhibitor of CYP3A and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A.¹ Nirmatrelvir does not induce any CYPs at clinically relevant concentrations. Nirmatrelvir has the potential to reversibly and time-dependently inhibit CYP3A4 and inhibit MDR1. ^1,22 When taken together, ritonavir and nirmatrelvir are a combination of a strong CYP3A inhibitor and P-gp inhibitor. ^1,22

The concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors should be avoided due to increased exposure to XARELTO and potential increased bleeding risk.²¹

Potential Effect of Rivaroxaban on Ritonavir-Boosted Nirmatrelvir

In vitro data indicates that nirmatrelvir is a substrate for human MDR1 and CYP3A4.^1,22 In vitro studies indicate that ritonavir is a major CYP3A4 substrate, and a minor substrate for CYP2D6.¹

In vitro studies indicate that rivaroxaban does not inhibit CYP3A or CYP2D6 nor does it induce CYP3A. In vitro data indicates low rivaroxaban inhibitory potential for P-gp transporters.²¹ CYP2D6 is not known to be an inducible enzyme and therefore in vitro induction studies are not conducted.^23,24

Phase 1 clinical studies have shown that rivaroxaban does not exhibit a clinically relevant effect on the pharmacokinetic parameters of agents that are substrates of CYP3A4 or P-gp.^10,25

GUIDANCE DOCUMENTS

• Ritonavir-boosted nirmatrelvir prescribing information and several guidance resources recommend avoiding coadministration of XARELTO and ritonavir-boosted nirmatrelvir and using an alternative COVID-19 medication due to increased XARELTO concentrations and increased bleeding risk.^1-6
• If both medicines are needed, some guidance resources suggest evaluating if XARELTO can be held and restarted 2-3 days after the last ritonavir-boosted nirmatrelvir dose, but this is based on patient risk and other anticoagulants may need to be used temporarily while XARELTO is held.^2-5

CLINICAL study

EPIC-HR Study

EPIC-HR (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) was a phase 2-3 study to determine whether ritonavir-boosted nirmatrelvir was safe and effective for the treatment of adults who are symptomatic with COVID-19 and do not need to be hospitalized but are at increased risk of developing severe illness. XARELTO was included under the categorization of prohibited medications that are dependent on CYP3A4 for clearance or with other notable interactions. XARELTO was not permitted during dosing of ritonavir-boosted nirmatrelvir from the first dose of the study drug, through 4 days after the last dose of study drug. If a participant could not temporarily hold XARELTO during this period, they were considered ineligible for the study.^7,26

Pharmacokinetic/pharmacodynamic studies

Physiologically-Based Pharmacokinetic/Pharmacodynamic Modeling Study

Wang et al (2022)^8,9 applied physiologically-based pharmacokinetic and pharmacodynamic modeling and simulations to investigate disease-DDIs between ritonavir-boosted nirmatrelvir and XARELTO and recommend dosage adjustment.

• Models and simulations were implemented within the population based Simcyp Simulator (version 19, Sheffield, UK).
• The ritonavir model was utilized based on previous studies while XARELTO models were constructed for the simulation. Nirmatrelvir was not incorporated into the simulation due to low DDI potential.
• The populations utilized in this simulation were healthy population, general white population, geriatric population (65 to 85 years), and moderate renal impairment (creatinine clearance [CrCl] 30 to 49 mL/min) population.
• The ritonavir dose was set at 100 mg BID for 5 days. In patients with moderate renal impairment, the XARELTO dose was decreased from 20 mg to 15 mg daily. A lower dose of XARELTO 10 mg daily was prospectively simulated as a dose adjustment strategy.
• The DDI potential with XARELTO was based on simulated plasma concentrations of XARELTO and the fold-change of area under the plasma concentration-time curve (AUC) on the fifth day of ritonavir treatment and was further calculated for risk of major bleeding.
• An AUC fold-change range of 0.7 to 1.43 was pre-defined to be appropriate as equivalent to the in vivo exposure of XARELTO.
• In the presence of ritonavir 100 mg and normal XARELTO doses (20 mg or 15 mg), the fold change in AUC was 1.91 in the general population with normal renal function, 2 in the general population with moderate renal impairment, 2.08 in the geriatric population with normal renal function, and 2.12 in the geriatric population with moderate renal impairment. The overexposure of XARELTO normalized on day 4 post discontinuation of ritonavir.
• In the presence of ritonavir 100 mg and adjusted XARELTO dose (10 mg), the fold change in AUC was 1.03, 1.21, 1.26, and 1.44 in the respective populations.

Pharmacokinetic Studies

Rohr et al (2024)¹¹ through a phase 1, single-center, open-label, fixed-sequence clinical trial evaluated the effect of 5-day low-dose ritonavir therapy (100 mg BID) on the pharmacokinetics of 3 factor Xa inhibitors (FXaI) and the activity of CYP2D6, CYP2C19, and CYP3A4 in healthy volunteers.

• Eight healthy subjects (7 females) with a median age of 25.5 years (range,
  21-58 years) and a body mass index of 24.2 kg/m² (range, 18.0-28.1 kg/m²) were included in the study.
• Subjects received a microdosed cocktail of FXaI consisting of apixaban 25 μg, edoxaban 50 μg, and XARELTO 25 μg on the baseline day (before ritonavir administration) and on the last day of ritonavir administration.
• Coadministration of ritonavir with FXaI elevated plasma concentrations of all 3 FXaI but to different extents. To test the differences of each FXaI between their baseline and on the fifth day of ritonavir administration, the geometric mean ratios (GMRs) and their 90% CIs were calculated. When the 90% CIs for systemic exposure (AUC) ratios are entirely within the equivalence range of 0.85–1.25, according to the standard practice of the FDA, it is concluded that no clinically relevant interaction is present.
  • XARELTO GMR area under the concentration-time curve from 0 to 24 hours (AUC_0-24) was 1.87 (90% confidence interval [CI]: 1.54-2.28)
  • Apixaban GMR AUC_0-24 was 1.29 (90% CI: 1.04-1.61)
  • Edoxaban GMR AUC_0-24 was 1.46 (90% CI: 1.23-1.73)
• The details of changes in pharmacokinetic parameters of XARELTO from before ritonavir administration to after 5 days of ritonavir are presented in Table: Pharmacokinetic Changes of XARELTO from Baseline to Ritonavir Day 5

Mueck et al (2013)¹⁰ assessed the pharmacokinetic effects of CYP3A4, P-gp, and breast cancer resistant protein (BCRP) substrates and inhibitors on XARELTO in healthy volunteers.

• Seven single-center studies were assessed to determine the extent of potential interactions with single doses of XARELTO (10 mg or 20 mg) and steady-state ketoconazole, ritonavir, clarithromycin, erythromycin, fluconazole, and midazolam.
• Interaction between a single dose of XARELTO and steady-state ritonavir was evaluated in a nonrandomized, open-label study in which patients received a single dose of XARELTO 10 mg on day 1, ritonavir 600 mg BID on days 3-7, and ritonavir 600 mg BID plus a single dose of XARELTO on day 8. All study drugs were administered with food.
• Eighteen patients were enrolled, with a mean age of 33.2 years (range, 18-44 years) and mean weight of 84.3 ± 11.1 kg.
• A total of 16 patients were included in the safety analysis. All patients received a single dose of XARELTO 10 mg on day 1 and at least 1 dose of ritonavir (600 mg). Twelve patients received the combination of XARELTO and ritonavir on day 8; however, none of the patients received the second dose of ritonavir on day 8 due to tolerability issues, which were likely related to ritonavir.
• Four patients withdrew from the study secondary to ritonavir-related adverse events, leaving 12 patients eligible for the pharmacokinetic analyses.
• Steady-state ritonavir significantly increased the AUC and peak concentration (C_max) of XARELTO. Mean AUC increased by 153% (90% CI: 134-174%) and mean C_max increased by 55% (90% CI: 41-69%) compared with XARELTO alone. Mean plasma concentrations of XARELTO were shown to increase with concomitant use.
• The combination of XARELTO with ritonavir significantly decreased total body clearance of rivaroxaban from plasma from 10.0 L/h to 4.0 L/h (60% reduction; 90% CI: -63 to
  -57%) without affecting the fraction of free (unbound) drug in plasma (f_u) of XARELTO; clearance by active renal secretion (CL_RS) was also significantly reduced (82% reduction; 90% CI: -86% to -76%).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 09 July 2024.