Pharmacokinetics of Oral Nirmatrelvir/Ritonavir, a Protease Inhibitor for Treatment of COVID-19, in Subjects With Renal Impairment

Sima S Toussi, Joel Michael Neutel, Jesus Navarro, Richard Alfred Preston, Haihong Shi, Olga Kavetska, Robert R LaBadie, Michael Binks, Phylinda L S Chan, Neil Demers, Brian Corrigan, Bharat Damle, Sima S Toussi, Joel Michael Neutel, Jesus Navarro, Richard Alfred Preston, Haihong Shi, Olga Kavetska, Robert R LaBadie, Michael Binks, Phylinda L S Chan, Neil Demers, Brian Corrigan, Bharat Damle

Abstract

Nirmatrelvir coadministered with ritonavir is highly efficacious in reducing the risk of coronavirus disease 2019 (COVID-19) adverse outcomes among patients at increased risk of progression to severe disease, including patients with chronic kidney disease. Because nirmatrelvir is eliminated by the kidneys when given with ritonavir, this phase I study evaluated the effects of renal impairment on pharmacokinetics, safety, and tolerability of nirmatrelvir/ritonavir. Participants with normal renal function (n = 10) or mild, moderate, or severe renal impairment (n = 8 each) were administered a single 100-mg nirmatrelvir dose with 100 mg ritonavir given 12 hours before, together with and 12 and 24 hours after the nirmatrelvir dose. Systemic nirmatrelvir exposure increased with increasing renal impairment, with mild, moderate, and severe renal impairment groups having respective adjusted geometric mean ratio areas under the plasma concentration-time profile from time 0 extrapolated to infinite time of 124%, 187%, and 304% vs. the normal renal function group. Corresponding ratios for maximum plasma concentration were 130%, 138%, and 148%. Apparent clearance was positively correlated with estimated glomerular filtration rate, and geometric mean renal clearance values were particularly lower for the moderate (47% decrease) and severe (80% decrease) renal impairment groups vs. the normal renal function group. Nirmatrelvir/ritonavir exhibited an acceptable safety profile; treatment-related adverse events were mild in severity, and there were no significant findings regarding laboratory measurements, vital signs, or electrocardiogram assessments. These findings led to a dose reduction recommendation for nirmatrelvir/ritonavir in patients with moderate renal impairment (150/100 mg nirmatrelvir/ritonavir instead of 300/100 mg twice daily for 5 days). NCT04909853.

Conflict of interest statement

S.S.T., M.B., H.S., O.K., P.L.S.C., N.D., R.R.L., B.C., and B.D. are employees of Pfizer and may hold stock or stock options. J.N., J.M.N. and R.P. declared no conflicts of interest.

© 2022 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Median plasma nirmatrelvir concentrations over time by renal function group. Participants were given a single dose of 100 mg nirmatrelvir with 100 mg ritonavir. Ritonavir was also administered at 12 hours before dosing, and 12 and 24 hours post dosing to achieve and maintain CYP3A inhibition. CYP3A, cytochrome P450 3A.
Figure 2
Figure 2
Linear regression plots of plasma nirmatrelvir CL/F. The bold line is the predicted regression line; the shaded area represents the 90% confidence region. The vertical lines represent the boundary criteria of the renal function groups. CL/F, apparent clearance of drug from plasma; eGFR, estimated glomerular filtration rate.
Figure 3
Figure 3
Predicted nirmatrelvir Ctrough plasma concentrations by dosing regimen and clearance. Open circles represent predicted Ctrough; red symbols represent group means; blue lines represent 10th and 90th percentiles; red dashed line is EC90 of 292 ng/mL for SARS‐CoV‐2. (a) 150/100 mg nirmatrelvir/ritonavir every 12 hours, with clearance reduced by one‐half (i.e., moderate renal impairment); (b) 300/100 mg nirmatrelvir/ritonavir every 12 hours, with clearance reduced by one‐third (i.e., mild renal impairment); (c) 300/100 mg nirmatrelvir/ritonavir every 12 hours, with no reduction in clearance (reference group). Ctrough, trough concentration; EC90, 90% effective concentration; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.

References

    1. World Health Organization . WHO coronavirus (COVID‐19) dashboard <> (2021). Accessed December 9, 2021.
    1. Docherty, A.B. et al. Features of 20,133 UK patients in hospital with covid‐19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ 369, m1985 (2020).
    1. Kim, L. et al. Risk factors for intensive care unit admission and in‐hospital mortality among hospitalized adults identified through the US coronavirus disease 2019 (COVID‐19)‐associated hospitalization surveillance network (COVID‐NET). Clin. Infect. Dis. 72, e206–e214 (2021).
    1. Thakur, B. et al. A systematic review and meta‐analysis of geographic differences in comorbidities and associated severity and mortality among individuals with COVID‐19. Sci. Rep. 11, 8562 (2021).
    1. US Food and Drug Administration . Emergency use authorization 091 (Casirivimab and Imdevimab) <> (2022). Accessed June 30, 2022.
    1. US Food and Drug Administration . Emergency use authorization 094 (Bamlanivimab and Etesevimab) <> (2022). Accessed June 30, 2022.
    1. US Food and Drug Administration . Emergency use authorization 100 (Sotrovimab) <> (2022). Accessed June 30, 2022.
    1. Hu, B. , Guo, H. , Zhou, P. & Shi, Z.L. Characteristics of SARS‐CoV‐2 and COVID‐19. Nat. Rev. Microbiol. 19, 141–154 (2021).
    1. Merck & Co Inc . Merck and Ridgeback Biotherapeutics provide update on results from MOVe‐OUT study of molnupiravir, an investigational oral antiviral medicine, in at risk adults with mild‐to‐moderate COVID‐19 <> (2021). Accessed June 30, 2022.
    1. Owen, D.R. et al. An oral SARS‐CoV‐2 Mpro inhibitor clinical candidate for the treatment of COVID‐19. Science 374, 1586–1593 (2021).
    1. Yang, H. et al. Design of wide‐spectrum inhibitors targeting coronavirus main proteases. PLoS Biol. 3, e324 (2005).
    1. Zhang, L. et al. Crystal structure of SARS‐CoV‐2 main protease provides a basis for design of improved alpha‐ketoamide inhibitors. Science 368, 409–412 (2020).
    1. Hilgenfeld, R. From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design. FEBS J. 281, 4085–4096 (2014).
    1. Anand, K. , Ziebuhr, J. , Wadhwani, P. , Mesters, J.R. & Hilgenfeld, R. Coronavirus main proteinase (3CLpro) structure: basis for design of anti‐SARS drugs. Science 300, 1763–1767 (2003).
    1. US Food and Drug Administration . Highlights of prescribing information, NORVIR (ritonavir) <> (2017). Accessed June 30, 2022.
    1. Hammond, J. et al. Oral Nirmatrelvir for high‐risk, nonhospitalized adults with Covid‐19. N. Engl. J. Med. 386, 1397–1408 (2022).
    1. US Food and Drug Administration . FDA to hold advisory committee meeting to discuss Merck and Ridgeback's EUA application for COVID‐19 oral treatment <> (2021). Accessed June 30, 2022.
    1. Pfizer Inc . Fact sheet for healthcare providers: emergency use authorization for Paxlovid <> (2021). Accessed February 8, 2022.
    1. ERA‐EDTA Council & ERACODA Working Group Chronic kidney disease is a key risk factor for severe COVID‐19: a call to action by the ERA‐EDTA. Nephrol. Dial. Transplant. 36, 87–94 (2021).
    1. Clark, A. et al. Global, regional, and national estimates of the population at increased risk of severe COVID‐19 due to underlying health conditions in 2020: a modelling study. Lancet Glob. Health 8, e1003–e1017 (2020).
    1. Orskov, B. et al. Estimating glomerular filtration rate using the new CKD‐EPI equation and other equations in patients with autosomal dominant polycystic kidney disease. Am. J. Nephrol. 31, 53–57 (2010).
    1. US Food and Drug Administration . Guidance for industry: bioanalytical method validation <> (2018). Accessed June 30, 2022.
    1. European Medicines Agency . Guideline on bioanalytical method validation <> (2011). Accessed June 30, 2022.
    1. US Food and Drug Administration Pharmacokinetics in patients with impaired renal function — study design, data analysis, and impact on dosing and labeling <> (2020). Accessed June 30, 2022.
    1. Hsu, A. et al. Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob. Agents Chemother. 42, 2784–2791 (1998).

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