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Paxlovid (nirmatrelvir/ritonavir) is an oral medication indicated for patients recently diagnosed with COVID-19 and who are at high risk of deterioration. This drug received an emergency use authorization (EUA) from the FDA on December 2021. The official EUA reads [1]:

The U.S. Food and Drug Administration has issued an EUA for the emergency use of the unapproved PAXLOVID which includes nirmatrelvir, a SARS-CoV-2 main protease (Mpro: also referred to as 3CLpro or nsp5 protease) inhibitor, and ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor, for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

According to the fact sheet for healthcare providers cited above, Paxlovid is to be taken twice daily for 5 days:

Ritonavir is administered with nirmatrelvir as a pharmacokinetic enhancer resulting in higher systemic concentrations and longer half-life of nirmatrelvir, thereby supporting a twice daily administration regimen.

The reported elimination half-life of Nirmatrelvir in the presence of ritonavir is ~6 hours [1].

A healthcare professional colleague inquired about a Muslim patient who asked if it is possible to adjust administration times according to meal times during Ramadan. Specifically, they asked whether it would be possible to take the medicine at 4:30 and 19:00, i.e. at the beginning and the end of the daily fast. In essence this means that the dosing intervals would alternate between 14.5 hours and 9.5 hours, instead of 12 hours. How would this adjustment impact the drug's efficacy, if at all?

  1. FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR PAXLOVID

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This is a pharmacokinetic question, as it refers to the effect of changes in the prescribed dosage regimen on the amount of drug in the body, which is usually related to the magnitude of effect the drug has (when the effect is said to be dose-dependent).

Now, it should be noted that the limited pharmacodynamic information available about Paxlovid from the manufacturer only says that "the increase in systemic exposure appears to be less than dose proportional up to 750 mg as a single dose and up to 500 mg twice daily as multiple doses". No quantitative information is available, but it seems this piece of information has no clinical significance in the following case.

Under the assumption of first-order pharmacokinetics (as most drugs display), and of short and intravenous-like absorption to simplify (Tmax is ~3 hours, so it can be neglected for the purpose of demonstration), the amount of drug in the body can be plotted as a function of time, as it is dependent on the dose and the elimination half-life, which is provided (6 hours). Thus, the following plot is obtained:

Paxlovid dosage regimen

The blue plot depicts the usual dosage regimen (300 mg twice daily for 5 days (120 hours)) and the red plot depicts the modified dosage regimen as described (alternating dosage intervals of 14.5 hours and 9.5 hours - time 0 is considered to be 4:30).

It is evident from the figure that the trough level and the peak level of the modified dosage regimen are slightly lower at 19:00 compared to the usual dosage regimen, and are slightly higher at 4:30. This behavior is plausible, as the drug continues to be eliminated at the 12-hour point, so by the time of the next dose, the amount in the body is lower than in the usual dosage regimen. By the same token, shorter interval (9.5 hours) means less amount eliminated, which makes for higher amounts in the body following the next dose at 4:30.

However, the difference between the troughs and the peaks seems negligible, and since the manufacturer states that the systemic exposure is 'less than dose proportional' it is safe to assume that these small differences in the amount of the drug in the body do not have any clinical significance.

In addition, the fact sheet states the following:

If the patient misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the patient should take it as soon as possible and resume the normal dosing schedule. If the patient misses a dose by more than 8 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time.

That is, potential extension of the dosage interval up to 8 hours more is not expected to have any clinical significance. A 2.5 hours shift in administration times is well within the allowed 8 hours, thus no clinical consequences are expected.

Reference:
FACT SHEET FOR HEALTHCARE PROVIDERS: EMERGENCY USE AUTHORIZATION FOR PAXLOVID and any basic pharmacokinetic textbook

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    Nice answer. I interpret the missing dose by >8h to be essentially double-dosing, which possibly could put the person into an toxicity situation, rather than a kinetic thing. The 8h limit would put peak absorption of the second dose (@12h) well after peak of the "missed, but taken later" dose, thereby limiting the toxicity situation.
    – bob1
    Apr 5, 2022 at 21:36

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