Home Clinical characteristics and pharmacokinetics of PAXLOVID in COVID-19 patients with hematological tumor
Article Open Access

Clinical characteristics and pharmacokinetics of PAXLOVID in COVID-19 patients with hematological tumor

  • Wei Liu ORCID logo , Ping Yang , Ping Yang ORCID logo , Li Yang , Hongmei Jing , Libo Zhao ORCID logo EMAIL logo and Rongsheng Zhao ORCID logo EMAIL logo
Published/Copyright: March 4, 2024
Download Article (PDF)
Medical Review
From the journal Medical Review Volume 4 Issue 2

To the editor: Since the onset of COVID-19, several new treatments have been studied, but only a few have received approval for clinical use. However, a challenge we still face is that in real-world medical practice, the patient population may differ from those in clinical trials. For instance, prolonged viral elimination has become an issue in immunocompromised patients [1, 2].

The described patients are part of a retrospective cohort study on COVID-19 approved by the ethics committee of Peking University Third Hospital (No. 2023-007-02). Blood samples were collected as part of routine clinical procedures, and the concentration of nirmatrelvir/ritonavir (PAXLOVID) was measured in the pharmacy laboratory using a previously published LC-MS/MS method [3].

Clinical characteristics

Twelve patients were included in the study, with 10 of whom were male. The average age was 59.3 years, and the mean BMI was 24.1. Patient information is presented in Table 1.

Table 1:

Patient demographics and clinical characteristics.

ID Sex Age, year Weight, kg BMI Hematological comorbidity Lymphocytea before Paxlovid use, ×109/La COVID-19 severity Initiation of Paxlovid, days Viral elimination after 1st cycle Paxlovid use, days Time to rebound, days Viral elimination after 2nd cycle Paxlovid use, days Time from symptom to viral elimination, days Cmin of nirmatrelvir, ng/mLc Other COVID treatmentd Survival state (3 months)
1 M 64 74 23.9 MCLe 0.16 Severe 30b Prolonged positive / Prolonged positive 75+ 3,530; 4,094 AZV, BAR Death
2 M 60 78 24.6 MCLe 0.17 Severe 18b Negative 10 Negative 53 3,110; 2,963 AZV, BAR Live
3 M 46 67 22.6 MPAL 0.6 Non-severe 3 Negative / / 19 1,240 / Live
4 M 67 76.5 24.7 MCL 0.49 Severe 22b Negative 11 Negative 46 4,730 AZV, BAR, TOC Live
5 F 70 49 25.0 MZL 0.33 Severe 26 Negative 7 Negative 39 7,200 BAR Live
6 M 41 75 26.0 MCLf 0.46 Non-severe 16b Negative 12 Negative 36 5,810; 4,760 (C25) AZV Live
7 M 40 87 26.3 DLBCLf 0.54 Non-severe 18 Negative 8 Negative 53 2,670 BAR Live
8 M 58 77 24.3 CLL 89.36 Severe 11 Negative 8 Negative 42 12,100; 3,265 BAR Live
9 F 65 58 22.1 FL 0.82 Severe 22 Negative 7 Negative 47 6,442 (1st dose) BAR Live
10 M 89 53 18.3 CLL 139.93 Severe 28b Prolonged positive / / 62+ 6,143 AZV, BAR, TOC Live
11 M 69 74 26.2 DLBCL 0.47 Severe 22 Negative 6 Prolonged positive 46+ 10,378 (C8) AZV, BAR Death
12 M 42 75.5 25.5 FL 2.32 Severe 47b Negative 7 Negative 53 2,277 AZV, BAR Live

  1. aReference range: 1.1–3.2 ×109/L. Record the nearest result before the Paxlovid treatment.bAzvudine was used before Paxlovid. cSteady-state trough concentration unless otherwise noted. Two Cmin means collected from different cycle of Paxlovid use. dAll patients were treated with corticosteroid. eReceived CAR-T treatment. fReceived ASCT treatment. BMI, body mass index; MCL, mantle cell lymphoma; MPAL, mixed phenotype acute leukemia; MZL, marginal zone lymphoma; DLBCL, diffuse large B cell lymphoma; CLL, chronic lymphocytic leukemia; FL, follicle lymphoma. CAR-T, chimeric antigen receptor (CAR)-T cell therapy; ASCT, autologous stem cell transplantation; AZV, azivudine; BAR, baricitinib; TOC, toclizumab.

Eleven patients were diagnosed with non-Hodgkin’s lymphoma (NHL), and one had mixed phenotype acute leukemia (AML and T-ALL). Except for the two chronic lymphocytic leukemia (CLL) patients with abnormally high lymphocyte counts, the average lymphocyte counts for the other NHL patients was 0.64×109/L (reference range: 1.1–3.2×109/L). Eight patients (67 %) experienced a rebound, with a median of 7 days. One patient passed away after 31 days of hospitalization.

Nirmatrelvir concentration and safety

A total of 45 samples from the 12 patients were collected for therapeutic drug monitoring. The mean concentration after 3 h (Cmax) was found to be 6,440.4±3,208.7 ng/mL, and the mean trough concentration (Cmin) was measured at 4,684.0±2,754.8 ng/mL.

Two patients experienced liver injury, with their ALT levels increased to 2.2 and 7.5 times the baseline after starting PAXLOVID. In the case of patient 8, ALT levels rose to 194 U/L three days after taking Paxlovid, and their Cmin reached 12,100.0 ng/mL. This suggests the need for caution regarding safety issues that may arise from the excessive concentration.

According to the drug label, the geometric mean Cmax of nirmatrelvir, when administered as a single 300 mg dose (with ritonavir) is 2,210 ng/mL, and approximately 2-fold accumulation was observed in the phase I clinical trials, despite the EC90 being only 292 ng/mL [4]. A similar concentration was observed in Chinese healthy volunteers (Cmax 2,620 ng/mL, single dose) [5]. Therefore, we speculate that in patients, the absorption process of nirmatrelvir may be altered. Studies have indicated that the intestine could also be a target organ of SARS-CoV-2 [6]. Increased intestinal permeability due to the infection could enhance the absorption of nirmatrelvir, leading to higher plasma concentrations in these patients.

Our study’s patients exhibited significantly higher nirmatrelvir concentrations compared to clinical trials, with substantial variability among individuals. To better understand the characteristics of the target population and ensure rational drug use, we need further investigation into the pharmacokinetic profiles of these medications. Additionally, no correlation was observed between nirmatrelvir concentration and the duration of viral shedding. Therefore, it is essential to explore the appropriate dosage and dosing regimen in more detail.

Corresponding authors: Libo Zhao and Rongsheng Zhao, Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China; Therapeutic Drug Monitoring and Clinical Toxicology Center of Peking University, Beijing 100191, China; Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China; and NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing 100191, China, E-mail: (L. Zhao), (R. Zhao)
Wei Liu and Ping Yang (Department of Hematology) contributed equally to this work.

Funding source: Peking University Third Hospital

Award Identifier / Grant number: BMU2023XY019

Award Identifier / Grant number: BYSYDL2023001-05

Award Identifier / Grant number: BYSYDL2023001-08

Acknowledgments

We extend our gratitude to all those who supported us throughout the study. Specifically, we are grateful to Yinchu Cheng for offering valuable methodological guidance for the clinical studies. Our thanks to Xin Xiong, Xianhua Zhang, Congya Zhou and Yuanyuan Zhang for their contributions in sample analysis and method validation. We further acknowledge Xiaona Li and Jiamin Xu for managing the clinical samples, facilitating data input, and assisting with information consolidation.

  1. Research ethics: The study was approved by the ethics committee of Peking University Third Hospital (No. 2023-007-02).

  2. Informed consent: Informed consent was obtained from all individuals included in this study.

  3. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Competing interests: Authors state no conflict of interest.

  5. Research funding: Peking University Third Hospital, BYSYDL2023001-05, BYSYDL2023001-08, BMU2023XY019.

  6. Data availability: Data are available from the corresponding author under reasonable request.

References

1. Sun, F, Lin, Y, Wang, X, Gao, Y, Ye, S. Paxlovid in patients who are immunocompromised and hospitalised with SARS-CoV-2 infection. Lancet Infect Dis 2022;22:1279. https://doi.org/10.1016/S1473-3099(22)00430-3.Search in Google Scholar PubMed PubMed Central

2. Mikulska, M, Sepulcri, C, Dentone, C, Magne, F, Balletto, E, Baldi, F, et al.. Triple combination therapy with 2 antivirals and monoclonal antibodies for persistent or relapsed severe acute respiratory syndrome coronavirus 2 infection in immunocompromised patients. Clin Infect Dis 2023;77:280–6. https://doi.org/10.1093/cid/ciad181.Search in Google Scholar PubMed

3. Xiong, X, Ying, Y, Zhang, X, Liu, W, Lu, M, Chen, J, et al.. Simultaneous determination of nirmatrelvir, ritonavir and baricitinib concentrations in human plasma by LC-MS/MS (in Chinese). Chinese Pharm J 2023;11:1015–9.Search in Google Scholar

4. Singh, RSP, Toussi, SS, Hackman, F, Chan, PL, Rao, R, Allen, R, et al.. Innovative randomized Phase I study and dosing regimen selection to accelerate and inform pivotal COVID-19 trial of nirmatrelvir. Clin Pharmacol Ther 2022;112:101–11. https://doi.org/10.1002/cpt.2603.Search in Google Scholar PubMed PubMed Central

5. Liu, C, Zhu, M, Cao, L, Boucetta, H, Song, M, Hang, T, et al.. Simultaneous determination of nirmatrelvir and ritonavir in human plasma using LC-MS/MS and its pharmacokinetic application in healthy Chinese volunteers. Biomed Chromatogr 2022;36:e5456. https://doi.org/10.1002/bmc.5456.Search in Google Scholar PubMed

6. Lamers, MM, Beumer, J, van der Vaart, J, Knoops, K, Puschhof, J, Breugem, TI, et al.. SARS-CoV-2 productively infects human gut enterocytes. Science 2020;369:50–4. https://doi.org/10.1126/science.abc1669.Search in Google Scholar PubMed PubMed Central

Received: 2023-12-12
Accepted: 2024-02-06
Published Online: 2024-03-04
Published in Print: 2024-04-25

© 2024 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Opportunity and challenge of rehabilitation medicine in China
  4. Reviews
  5. Engineering pluripotent stem cells with synthetic biology for regenerative medicine
  6. Assembling the RNA therapeutics toolbox
  7. Organoids as preclinical models of human disease: progress and applications
  8. Perspectives
  9. The role of bile acids in human aging
  10. Hormone-based pharmacotherapy for metabolic dysfunction-associated fatty liver disease
  11. Letter
  12. Clinical characteristics and pharmacokinetics of PAXLOVID in COVID-19 patients with hematological tumor
https://doi.org/10.1515/mr-2023-0068
Creative Commons
BY-NC-ND 4.0

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Opportunity and challenge of rehabilitation medicine in China
  4. Reviews
  5. Engineering pluripotent stem cells with synthetic biology for regenerative medicine
  6. Assembling the RNA therapeutics toolbox
  7. Organoids as preclinical models of human disease: progress and applications
  8. Perspectives
  9. The role of bile acids in human aging
  10. Hormone-based pharmacotherapy for metabolic dysfunction-associated fatty liver disease
  11. Letter
  12. Clinical characteristics and pharmacokinetics of PAXLOVID in COVID-19 patients with hematological tumor
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 12.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/mr-2023-0068/html
Scroll to top button