Caution required with the use of ritonavir-boosted PF-07321332 in the management of COVID-19


We read with interest the news that the UK government has announced deals to purchase oral antivirals for SARS-CoV-2, molnupiravir (Lagevrio, Merck [Branchburg, NJ, USA]) and ritonavir in combination with PF-07321332 (Paxlovid, Pfizer [New York, NY, USA]).
1
UK Department of Health and Welfare
British government obtains groundbreaking COVID-19 antivirals.

While we welcome a new partnership between the government and the pharmaceutical industry in providing effective agents to manage the COVID-19 pandemic, we call for caution with the large-scale use of ritonavir, being given its propensity to cause clinically significant drug interactions with commonly prescribed and over-the-counter drugs.

PF-07321332 is a SARS-CoV-2 protease inhibitor currently being evaluated in phase 3 trials for its safety and efficacy in treating outpatient adult patients with COVID-19 who are not at increased risk to develop serious illness. The drug is also being explored as a post-exposure prophylaxis in patients who have been exposed to SARS-CoV-2. The duration of treatment is 5-10 days and PF-07321332 is co-administered with low dose ritonavir to increase and maintain plasma concentrations of the new agent.

Ritonavir is a potent inhibitor of the CYP3A4 isoenzyme and is widely used in antiretroviral therapy for HIV to increase drug plasma concentrations and prolong the half-life of CYP3A substrates. Originally launched in the mid-1990s as a protease inhibitor designed to treat HIV infection, the use of ritonavir was complicated by high pill load, poor tolerability, and drug interactions. At doses of 100 mg once or twice daily, ritonavir is well tolerated and effective in improving the pharmacokinetic profile of combination agents (eg, resulting in increases in area under the curve, peak concentration and half-life.
2
Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients.

This strategy reduced the frequency of antiretroviral therapy for HIV, the pill load, the impact of food on the bioavailability and variability of systemic drug exposure, and improved the effectiveness of treatment.

3
  • Renjifo B
  • van Wyk J
  • Salem
  • Arc D
  • Ng J
  • Norton M
Improving pharmacokinetics in HIV antiretroviral therapy: a comparison of ritonavir and cobicistat.

It is imperative that clinicians know the pharmacokinetics of ritonavir. In addition to the drug’s potent inhibition of the CYP3A4 isoenzyme, ritonavir exhibits other inhibitory effects on CYP2D6, CYP2C19, CYP2C8 and CYP2C9. In addition, ritonavir inhibits ABCB5 P-gp and the cell transport mechanism via the efflux pump, which may contribute to the pharmacokinetic stimulant effect by disrupting the active transport of concomitant agents out of cells of the intestinal tract, liver. and kidneys. In addition, ritonavir is a known inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19 and of the UGT family.
4
  • Foisy M
  • Yakiwchuk E
  • Hugues C
Ritonavir induction effects: implications for drug interactions.

Other drug transporters inhibited by ritonavir include breast cancer resistance protein (ABCG2), organic anion transporting polypeptides (hOCT1) in the liver, and MATE1, which is important in renal manipulation of drugs.

5
  • Kis O
  • Robillard K
  • Chan GN
  • Bendayan R
The complexities of antiretroviral drug interactions: role of ABC and SLC transporters.

Although ritonavir has been expertly managed in the context of combination antiretroviral therapy for HIV, the strong stimulatory and inducing effects of the drug have led to a variety of co-drug interaction issues, including prescribed, over-the-counter and recreational agents. Concomitant use of ritonavir with certain medicinal products is absolutely contraindicated due to the risk of clinically significant interactions which may lead to life-threatening adverse events. These agents include statins, steroids, sedative hypnotics, anticoagulants, and antiarrhythmic drugs, many of which are prescribed separately in older populations (aged ≥ 70 years) at higher risk for complications from SARS-CoV- 2.

Despite how the treatment of patients with COVID-19 with antiviral agents boosted by ritonavir is likely to be a short-term measure, the potential for clinically significant drug interactions remains. For example, the inhibitory effects are apparent in a short time. We recommend that all prescribing clinicians familiarize themselves with potential interactions using dedicated reference guides, such as the University of Liverpool’s Antiretroviral Drug Interaction Checker and existing antiretroviral therapy guidelines,
6
  • Waters L
  • Ahmed N
  • Angus B
  • et al.
British HIV Association guidelines for treating HIV-1 positive adults with antiretroviral therapy 2015 (interim update 2016).

and liaising closely with colleagues experienced in the treatment of HIV infection, in order to reduce the potential for clinically significant iatrogenic or life-threatening adverse events

JH received research grant funding from the CW + charity and the Westminster Medical School Research Trust; and received honoraria from Gilead unrelated to this correspondence. SJCP received a research grant from the Scientific Exploration Society-Viscount Gough unrelated to this correspondence. NM received speaker fees from Beyer and Pfizer; and received educational support from Eumedica and Baxter. GWD received consulting fees from DNA Nudge. LSPM has consulted and received speaker fees from bioMérieux, Pfizer, Eumedica, Shionogi, Pulmocide, Umovis Labs, DNA Electronics, Profile Pharma and Dairy Crest; and has received research grants from the UK National Institute for Health Research (NIHR), LifeArc and the CW + charity. RJ has received honoraria, speaker fees, travel assistance, or research grants from Gilead, ViiV Healthcare, Bristol Myers Squibb, Abbvie, Janssen, and Merck. All other authors declare no competing interests. JH acknowledges the support of the CW + charity and the Westminster Medical School Research Trust. LSPM thanks NIHR, Imperial Biomedical Research Center and NIHR Health Protection Research Unit for Healthcare Associated Infections and Antimicrobial Resistance at Imperial College London, in partnership with Public Health England. The opinions expressed in this correspondence are those of the authors, and not necessarily those of the National Health Service, NIHR or the UK Department of Health.

The references

  1. 1.
    • UK Department of Health and Welfare

    British government obtains groundbreaking COVID-19 antivirals.

  2. 2.

    Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients.

    J Antimicrobial chemotherapy. 2004 ; 53: 4-9

  3. 3.
    • Renjifo B
    • van Wyk J
    • Salem
    • Arc D
    • Ng J
    • Norton M

    Improving pharmacokinetics in HIV antiretroviral therapy: a comparison of ritonavir and cobicistat.

    AIDS Rev. 2015 ; 17: 37-46

  4. 4.
    • Foisy M
    • Yakiwchuk E
    • Hugues C

    Ritonavir induction effects: implications for drug interactions.

    Ann Pharmacother. 2008; 42: 1048-1059

  5. 5.
    • Kis O
    • Robillard K
    • Chan GN
    • Bendayan R

    The complexities of antiretroviral drug interactions: role of ABC and SLC transporters.

    Pharmacol Sci Trends. 2010; 31: 22-35

  6. 6.
    • Waters L
    • Ahmed N
    • Angus B
    • et al.

    British HIV Association guidelines for treating HIV-1 positive adults with antiretroviral therapy 2015 (interim update 2016).

About Bradley J. Bridges

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