Pharmacokinetics Profile and Genetics of Double Antiviral Therapy with Remdesivir and Nirmatrelvir/Ritonavir for Prolonged COVID-19 in Patients Treated with Rituximab: A Real-Life Study and Literature Review

Author:

De Benedetto Ilaria1ORCID,Corcione Silvia12,Giambra Carlotta3,Ferrante Matteo3,Mornese Pinna Simone1ORCID,Zanotto Elisa4,Palermiti Alice5ORCID,Sidoti Francesca4,Scaglione Luca3,Grosso Cecilia15,Billi Martina5,Lupia Tommaso1ORCID,Soloperto Sara5,Cusato Jessica5ORCID,Costa Cristina4ORCID,D’Avolio Antonio5ORCID,De Rosa Francesco Giuseppe1ORCID

Affiliation:

1. Department of Medical Sciences, Infectious Diseases, University of Turin, 10139 Turin, Italy

2. School of Medicine, Tufts University, Boston, MA 02111, USA

3. Internal Medicine Unit, Department of Medical Sciences, University Hospital Città della Salute e della Scienza di Torino, 10139 Turin, Italy

4. Microbiology and Virology Unit, Department of Paediatrics and Public Health, University Hospital Città della Salute e della Scienza di Torino, 10139 Turin, Italy

5. Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Amedeo di Savoia Hospital, University of Turin, 10149 Turin, Italy

Abstract

Introduction: Patients with hematologic malignancies are more likely to develop severe and prolonged SARS-CoV-2 infection, often showing viral persistence despite the use of authorized antivirals. Herein, we report the cases of four patients who received rituximab for different conditions and developed persistent COVID-19 treated with an extended course of dual antivirals, Nirmatrelvir/Ritonavir and Remdesivir. Moreover, we describe the pharmacokinetics and pharmacogenetics (PK/PG) characteristics of Nirmatrelvir/Ritonavir and Remdesivir treatment in two of these patients. Methods: Plasma specimens for evaluation of trough concentrations (Ctrough) were collected 10 min before the daily dose administration, in addition to 3 h (Cmax), 4 h (C4h), 6 h (C6h) and 1 h (Cmax) after the administration of Nirmatrelvir/Ritonavir and Remdesivir, respectively. The following gene single-nucleotide polymorphisms (SNPs) were investigated: ABCB1 3435 (rs1045642) C > T, ABCB1 1236 (rs1128503) C > T, PXR 63396 (rs2472667) T > C, CYP2D6 (rs1135840) G > C, and CYP3A4*1B (rs2740574) G > A. Results: Double antiviral treatment was successful in terms of symptoms resolution, whereas three out of four patients achieved microbiological eradication. Based on our results, concentrations of Nirmatrelvir ranging from 50 to 5000 ng/mL were effective, whereas a higher concentration (range 1068–3377 ng/mL), compared to that previously reported in patients with similar weight and BMI, was evidenced for Ritonavir. Considering the genetic variant analysis, ABCB1 3435 CT and 1236 CT genotypes were found in patient 1; and ABCB1 3435 CC and 1236 CC in patient 2. In conclusion, this real-life study supports the usefulness of TDM and genetics in immunocompromised patients with persistent SARS-CoV-2 infection, a challenging setting for clinicians in which personalized medicine may improve outcome.

Funder

EU

Publisher

MDPI AG

Subject

General Medicine

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