Oral Drugs Against COVID-19

Management of Drug Interactions With the Use of Nirmatrelvir/Ritonavir

Background: Five-day oral therapies against early COVID-19 infection have recently been conditionally approved in Europe. In the drug combination nirmatrelvir + ritonavir (nirmatrelvir/r), the active agent, nirmatrelvir, is made bioavailable in clinically adequate amounts by the additional administration of a potent inhibitor of its first-pass metabolism by way of cytochrome P450 [CYP] 3A in the gut and liver. In view of the central role of CYP3A in the clearance of many different kinds of drugs, and the fact that many patients with COVID-19 are taking multiple drugs to treat other conditions, it is important to assess the potential for drug interactions when nirmatrelvir/r is given, and to minimize the risks associated with such interactions.

Methods: We defined the interaction profile of ritonavir on the basis of information derived from two databases (Medline, GoogleScholar), three standard electronic texts on drug interactions, and manufacturer-supplied drug information. We compiled a list of drugs and their potentially relevant interactions, developed a risk minimization algorithm, and applied it to the substances in question. We also compiled a list of commonly prescribed drugs for which there is no risk of interaction with nirmatrelvir/r.

Results: Out of 190 drugs and drug combinations, 57 do not need any special measures when given in combination with brief, low-dose ritonavir treatment, while 15 require dose modification or a therapeutic alternative, 8 can be temporarily discontinued, 9 contraindicate ritonavir use, and 102 should preferably be combined with a different treatment.

Conclusion: We have proposed measures that are simple to carry out for the main types of drug that can interact with ritonavir. These measures can be implemented under quarantine conditions before starting a 5-day treatment with nirmatrelvir/r.

Following the recommendation of the European Medicines Agency (EMA), the European Commission granted conditional marketing authorization for nirmatrelvir, the first peptidomimetic, submicromolar reversible inhibitor of SARS-CoV-2-like protease (= Nsp5 protease, 3C-like protease [3CLpro], or main protease [Mpro]), on 28 January 2022 (e1). Due to the inhibition of Nsp5 protease, polyprotein precursor molecules can no longer be processed and SARS-CoV-2 replication is halted (e2). To ensure adequate bioavailability of nirmatrelvir, its exposure is pharmacokinetically enhanced by simultaneously administering low doses of ritonavir (2 × 100  mg/d as a cytochrome P450 [CYP] 3A inhibitor) (1). Using this approach, oral bioavailability is increased by several times (1) and elimination half-life is extended to 6.1  h (e2) so that high antiviral target concentrations are achieved and maintained over a 12h period (1).

In a randomized comparison with placebo, this combination therapy (nirmatrelvir/r; Paxlovid) prevented hospitalization of patients with early COVID-19 in 89% of cases (relative risk reduction; absolute risk reduction: −5.6%) when treatment was initiated within 5 days of symptom onset and the drug was administered for 5 days (2, e1). In addition, no deaths were observed in the treatment group, while in the comparison group 1.1% of patients died within a period of 28 days (3, e2).

Nirmatrelvir/r is indicated in adult patients with evidence of SARS-CoV-2 infection without additional oxygen requirement at high risk for progression to severe COVID-19 (e2). In the pivotal studies, the latter group of patients comprised (3, e2):

• Smokers
• Comorbid patients with, among others,

– Diabetes mellitus

– Active malignancies

– Chronic lung or kidney disease

– Cardiovascular disease

– Overweight (BMI>25)

– Patients with immunocompromising conditions or treatment

• Patients >60 years of age.

CYP3A is not only a key enzyme in the intestinal and hepatic metabolism of nirmatrelvir but also of many other drugs. With its significant pharmacokinetic drug-drug interaction potential, ritonavir, a HIV protease inhibitor, thus significantly increases not only exposure to nirmatrelvir but also exposure to a variety of other (victim) substances (4)—an effect that has long been exploited in the treatment of HIV infection (e.g., in combinations containing lopinavir or darunavir). Substances with very few other drug metabolism and elimination pathways and high first-pass effect are particularly affected by this interaction. With such drugs, the increase in exposure can be so large (e.g., by factor 25 [5]) that it renders it impossible to precisely adjust the dose of oral fixed combinations. Thus, combining these drugs with ritonavir is contraindicated. If the increase in exposure is more moderate, adverse overdosing can be prevented by reducing the doses as appropriate. Whether this approach is clinically feasible also depends on how narrow the therapeutic index of the drug is.

The inhibition of CYP3A by ritonavir is dose-dependent and irreversible (mechanism-based [6, 7]). Based on measurements obtained with the CYP3A marker substrate midazolam, maximum inhibition is achieved with ritonavir doses of 2  × 100  mg/d (8), i.e. doses also intended for nirmatrelvir/r. Given the fact that CYP3A inhibition is irreversible and nirmatrelvir/r should be taken every 12 hours for 5 days, these interactions cannot be reduced by staggering the administration of the victim drug and ritonavir (9). Once the course of nirmatrelvir/r treatment has been completed, a quantitatively relevant effect of ritonavir is maintained only for 2 to 3 days, despite irreversible inhibition (10, 11). One reason for this is that new enterocytes with active CYP3A system are continuously produced as the result of the high regenerative turnover of intestinal villi (12).

In addition, ritonavir inhibits other CYP isoenzymes; however, exposure changes of substrates of other CYPs (such as CYP2D6) are minor and virtually never of clinical relevance (13). Finally, the efflux transporter P-glycoprotein is also inhibited by ritonavir (14). But the effect on transported substrates is much smaller than on CYP3A substrate exposure (change in exposure by less than factor 2) and can be even further reduced by administering the transported victim drug as late as possible after ritonavir administration (15) (e.g., in the case of digoxin, 2  h before the next administration of ritonavir). In addition, prolonged administration (>5 days) of ritonavir has enzyme-inducing effects (on CYP2C19, among others), but it takes many days for these to develop and they are relatively small in regimes with low pharmacokinetic boosting doses (16). The duration of Nirmatrelvir/r treatment for COVID-19 is too short for such effects to develop.

Given the very large number of drug combinations that are presumably present in a vulnerable COVID-19 population (17), the question commonly arises in routine clinical practice as to whether any risks are to be expected with such a combination and which mitigation strategies could be used. Thus, the aim of this study is to compile the currently available scientific evidence on drug interactions which should be considered in the short-term treatment with ritonavir boosting doses.

Methods

We compiled a list of drugs with a narrow therapeutic index whose clearance is largely determined by CYP3A4 and/or CYP3A5. This list is based on:

• Searches in North American databases (e3)
• The list of the U.S. Food & Drug Administration (FDA) on sensitive CYP3A substrates whose exposure increases ≥ 5-times in combination with strong CYP3A inhibitors (e4)
• The list of highly and moderately sensitive CYP3A substrates from a drug interaction textbook (e5).

In addition, we conducted a search for further drugs known to significantly interact with ritonavir (in the interaction module of the ABDA database [e6] and in the AiDKlinik Drug Information system [e7]). Studies on oncological therapies were generally omitted, since these therapies must be highly individualized and thus general recommendations cannot do full justice to the situation of individual patients.

We conducted searches for all of these substances in the FDA’s drug approval documents (e8) as well as in Medline/PubMed, GoogleScholar, AiDKlinik (e7), and Stockley’s Drug Interactions (e5). We searched for studies on drug interactions with ritonavir and extracted their pharmacokinetic data from the original sources and compiled them in a table. If no studies explicitly investigating ritonavir could be identified, studies on ketoconazole or itraconazole were extracted, as both drugs are potent CYP3A inhibitors with very similar potential interactions (13).

In parallel, we developed an algorithm (eFigure, eBox) with 6 categories of recommendations for the management of comedication which may be impacted by nirmatrelvir/r:

eFigure

Algorithm to determine risk mitigation measures for potential drug interactions with nirmatrelvir/ritonavir (Paxlovid)

eBox

Development of an algorithm to assess the relevance of drug interactions with nirmatrelvir/ritonavir

• No relevant interaction is expected and therefore neither special measures nor dose adjustments are required.
• Interaction is expected and thus the maintenance dose of the corresponding victim drug should be reduced by half for the time the victim drug is administered in combination with nirmatrelvir/r.
• Interaction is expected and for this situation the prescription information/summary of product characteristics (SmPC) specifies a certain maintenance dose of the corresponding victim drug which should be chosen for the time the victim drug is administered in combination with nirmatrelvir/r. Furthermore, substances were assigned to the same category (e.g., eletriptan) for which equivalent alternatives are commercially available to which patients could be switched.
• Interaction is expected and the victim drug can be temporarily discontinued for the duration of treatment with nirmatrelvir/r. Reasons for this include:

– that the substance has a very long half-life compared to the duration of nirmatrelvir/r treatment (e.g., amiodarone, cabergoline) and thus a short interruption of treatment will not result in a relevant change in exposure

– that no acute effects/withdrawal syndromes are to be expected (e.g., felodipine)

– that the substances are lifestyle treatments (e.g., PDE5 inhibitors exclusively approved for erectile dysfunction) for activities which, from an infectiological point of view, should anyway be avoided in this situation.

• A clinically relevant interaction is expected with a substance:

– which is not expected with other oral (molnupiravir [e9], remdesivir [e10]) or parenteral (casirivimab/imdevimab [e11], sotrovimab [e12], regdanvimab [e13]) treatment options; and

– whose continuous presence is crucial for the treatment of a comorbidity (immunosuppressants, oncological treatments); and/or

– showing high pharmacokinetic variability in the individual patient (e.g. cyclosporine), as this would require therapeutic drug monitoring which would be difficult to carry out in a quarantine setting; and/or

– which requires complex titration procedures after dose adjustment (e.g., risperidone, phenprocoumon).

Perpetrator drugs which would limit the effectiveness of pharmacokinetic enhancement (inductors of the metabolism of ritonavir and/or nirmatrelvir) were assigned to the same category.

• In case a treatment regimen already contains a pharmacokinetic enhancer (ritonavir, cobicistat), we recommend to omit the ritonavir component contained in the nirmatrelvir/r combination. The rationale is that the desired effect on the pharmacokinetics of nirmatrelvir is already achieved with the existing comedication and increasing the existing pharmacokinetic-enhancing doses of ritonavir could lead to induction phenomena. Furthermore, the combination of cobicistat with ritonavir is considered a relative contraindication.

Besides nirmatrelvir/r, parenteral monoclonal antibodies or antibody combinations, remdesivir and other oral treatments have already been approved or are currently undergoing the European approval process (e14). These differ, among other aspects, in

• when they should be used in the course of the disease;
• whether pulmonary symptoms and additional oxygen requirement need to be present;
• age groups for which they have been studied;
• how well they are suited for outpatient treatment in quarantined patients.

Moreover, the sensitivity of various SARS-CoV-2 variants has to be taken into account. For example, the omicron BA.1 variant is sensitive to nirmatrelvir, remdesivir and molnupiravir (18), but the effectiveness of some monoclonal antibodies is reduced (19). Thus, the final decision on which treatment option to pursue must be made with due consideration of the individual patient‘s overall situation.

Results

A total of 190 substances or substance combinations were included in our list (Table). A decision algorithm (eFigure, eBox) was used to categorize them as follows:

• Category 1 (no dose adjustment; monitoring, where appropriate): n = 57
• Category 2 (half the dose): n = 6
• Category 3 (other dose reduction or a good therapeutic alternative): n = 9
• Category 4 (discontinue temporarily): n = 8
• Category 5 (preferably use another treatment): n = 102
• Category 6 (if possible, omit ritonavir): n = 9.

Table

Substance list and guidance for a planned nirmatrelvir/r treatment

Since maraviroc falls into 2 categories (category 3 and 6), this list exceeds the total by 1.

The recommendations made here differ from the recommendations of the European regulatory authority (European Medicines Agency [EMA]) in five cases (*5 in the Table) and in nine cases from those of the U.S. Food and Drug Administration (FDA) (*6 in the Table), but in no case from both.

Discussion

The approval of nirmatrelvir/r, a ritonavir-containing oral combination therapy to treat COVID-19 in an early stage of the disease, is likely to result in a large number of patients being exposed to a very potent perpetrator drug in the near future which otherwise is only used by HIV specialists and only in combinations that are evaluated in clinical trials. It is therefore important to have tools at hand when prescribing and dispensing this drug that help to identify risk situations and make suggestions for risk minimization without jeopardizing the COVID-19 treatment.

To date, there are no drug interaction data available on nirmatrelvir/r and currently only few studies are being conducted to evaluate such interactions (with the CYP3A inductor carbamazepine [NCT04962230], the CYP inhibitor itraconazole [NCT04962022], the CYP3A substrate midazolam [NCT05032950], and the P-glycoprotein substrate dabigatran etexilate [NCT05064800]). Therefore, we had to rely on evidence on ritonavir alone or in other combinations to assess the risk potential.

Since the patients receive their nirmatrelvir/r treatment in a home quarantine setting, therapeutic drug monitoring is challenging. For this reason, combinations that could have been manageable with intensified monitoring were also rejected. Thus, the recommendations listed here are reflective of this conservative approach and have led to pointing out alternatives which are largely free of interactions (e.g. molnupiravir, monoclonal antibodies). This is true even in situations in which a sound pharmacokinetic approach could be identified on a case-by-case basis that would allow the use of nirmatrelvir/r. For example, this may be the case when patients have to spend their quarantine period in a medical care setting (hospital) where galenic alternatives (e.g., parenteral formulations), on-site healthcare staff trained in dosing and capabilities for intensified monitoring would be available.

Our assessment is almost identical with the corresponding lists of the European Medicines Agency (e15), the UK Medicines and Healthcare products Regulatory Agency (e16) and the U.S. Food and Drug Administration FDA (e17). However, as previous analyses have shown, the assessments of two regulatory authorities rarely fully align (20, 21). In comparison to one or both of the international lists, our assessment is more conservative with regard to statins, because acute discontinuation of statins during acute vascular episodes may be risky (22, 23, 24, 25, 26) and increasing evidence suggests that statins may have a beneficial effect on the often hyperinflammatory course of COVID-19 (27) and significantly reduce 30-day mortality (28).

Our recommendations also deviate with regard to therapies pharmacokinetically-enhanced with cobicistat. In Europe, combinations of such therapies with ritonavir are contraindicated. In addition, we proposed—based on drug interactions studies and physiology-based pharmacokinetic (PBPK) modelling for intensified monitoring—preemptive dose reductions for alprazolam (29), amitriptyline (minimal exposure changes with ketoconazole [30]) and nifedipine (31). Our recommendations apply without restriction to fusidic acid (in Germany only for topical application) and more liberal to

• Bupropion (because several studies did not report relevant interactions [32, 33])
• Digoxin (no change in exposure with staggered dosing [15])
• Codeine (similar to desipramine [34], no relevant change is to be expected)
• Methadone (no change with pharmacokinetically enhanced indinavir [35])
• Fentanyl (no clinically relevant change in exposure with ketoconazole [36])
• Desipramine (no clinically relevant increase in exposure with low-dose ritonavir) (34)
• Ethinyl estradiol for which no relevant changes were identified with pharmacokinetically enhancing ritonavir doses (37).

We also arrived at a different conclusion than the FDA for amiodarone, which we believe can simply be temporarily discontinued. A different COVID-19 treatment is not necessarily required, because the feared accumulation of amiodarone only occurs if administration of amiodarone is continued. Consistent with the EMA recommendations and contrary to the FDA recommendations, we believe that long-term immunosuppressive therapies (cyclosporine, everolimus, tacrolimus) cannot be paused in most cases and thus the switch to an alternative treatment without this interaction potential (e.g. molnupiravir) appears to be more appropriate.

Furthermore, we have largely avoided referring to other prescription information to make direct recommendations whenever possible. Nevertheless, there will be situations where it is preferable to continue critical long-term therapies (e.g. tyrosine kinase inhibitors, rifabutin) despite CYP3A inhibition by nirmatrelvir/r (for example, treatment with afatinib or ceritinib). In such cases, dose adjustments of the victim substance are conceivable and commonly mentioned in the specific prescription information. Finally, our assessment differs from other compilations whenever induction phenomena associated with nirmatrelvir/r are concerned (e.g., atovaquone, bupropion, methadone, morphine), because no clinically relevant induction is to be expected given the briefness of exposure (period of 5 days) and the fact that induction phenomena are typically observed with the use of higher ritonavir maintenance doses (13).

Strengths and limitations

The approach taken in compiling the Table and the eFigure is such that the vast majority of drugs with a high risk potential are likely to be included in the list. On the one hand, there are decades of experience of using therapies which are pharmacokinetically enhanced by ritonavir —albeit based on long-term application. On the other hand—due to surprisingly sparse data despite decades of use—we also tapped into the vast body of interaction information available for ketoconazole and itraconazole. Nevertheless, when using this list, it should be noted that only drug pairs were taken into account. In the population at risk of COVID-19, patients taking multiple drugs to treat other conditions are common (17). Among these patients, comorbidities, such as chronic kidney disease, and adjuvant treatment with additional perpetrator drugs can put further strain on other clearance pathways. While this is irrelevant for exclusive CYP3A substrates, significant exposure increases may occur in substances with mixed clearance pathways—but these increases may appear moderate if testing is limited to only one clearance pathway (38).

Conclusion

As a source of evidence-based information, our compilation is intended to highlight the risk of potential drug-drug interactions when dispensing nirmatrelvir/r and thereby make this treatment safer in the special setting of its use (quarantine).

Conflict of interest statement

Prof. Haefeli received financial support from Gilead Sciences and GlaxoSmithKline. He received consultancy fees from Dr. Wilmar Schwabe, Chiesi GmbH, and Daiichi Sankyo.

Prof. Schulz received consulting fees from MSD. He is Chairman of the Drug Commission of German Pharmacists (AMK).

The remaining authors declare no conflict of interest.

Manuscript received on 5 January 2022, revised version accepted on 16 February 2022

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Prof. Dr. med. Walter E. Haefeli, FBPhS
Abteilung Klinische Pharmakologie und Pharmakoepidemiologie
Universitätsklinikum Heidelberg
Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

Cite this as:
Mikus G, Foerster KI, Terstegen T, Vogt C, Said A, Schulz M, Haefeli WE: Oral drugs against COVID-19—management of drug interactions with the use of nirmatrelvir/ritonavir. Dtsch Arztebl Int 2022; 119: 263–9. DOI: 10.3238/arztebl.m2022.0152

►Supplementary material

eReferences, eBox, eFigure:
www.aerzteblatt-international.de/m2022.0152

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