Additional Points

Letters to the Editor Oral Drugs Against COVID-19 Management of Drug Interactions With the Use of Nirmatrelvir/Ritonavir by Prof. Dr. med. Dipl. Phys. Gerd Mikus, Dr. rer. nat. Kathrin I. Foerster, Theresa Terstegen, Cathrin Vogt, Dr. rer. nat. André Said, Prof. Dr. rer. nat. Martin Schulz, and Prof. Dr. med. Walter E. Haefeli, FBPhS in issue 15/2022

The authors deserve thanks for this highly topical and relevant article. On the background of my 18 years of daily drug level and interaction monitoring of immunosuppressants in transplantation medicine as well as more than 52 000 medication analyses of my own, I would like to add the following aspects to the article (1). 

1. Transplant patients are significantly less immunizable due to their therapeutic immunosuppression, both in terms of their humoral and their cellular vaccine response. In my opinion, they should be clinically supervised in case of confirmed infection because of their increased risk of severe COVID-19. Inpatient care enables antibody treatment and, under conditions of careful adaptation (2, 3) with close therapeutic drug monitoring of the calcineurin or mTOR inhibitors—if necessary with a temporary pause under cortisone bridging—therapy with nirmatrelvir/ritonavir before they develop severe disease courses of COVID-19. Individually, experience and medical expertise are required here. I would prefer this approach to outpatient quarantine with continuation of intensive immunosuppression (caution is indicated regarding mycophenolate-mofetil [MMF]) and application of a currently proven less effective antiviral drug—as recommended alternatively by the authors—and would not completely withhold nirmatrelvir/ritonavir from the patients.

2. The list of problematic interactions with increased drug levels should be supplemented regarding the CYP3A4-/P-glycoprotein substrates/in part the CYP3A4-/P-glycoprotein inhibitors aliskiren, aprepitant, carvedilol, posaconazol, and verapamil, according to valid product information. I consider CYP3A4-inhibited continued use without adjustment of fentanyl (4) and buprenorphrine highly critical, especially with respect to the often cumulative risk of respiratory depression from concomitant psychotropic medication. Fruit juices, such as grapefruit juice, can increase the exposure and risk of adverse drug reactions of nirmatrelvir/ritonavir and should not be consumed at the same time. By contrast, co-administration of metamizole with a potentially 2.9-fold hepatocytic CYP3A4 induction may result in a reduction or loss of nirmatrelvir/ritonavir effectiveness.

3. Accurate dose adjustment requires updated measurement of glomerular filtration rate, particularly in elderly patients with moderate renal impairment and, if possible, transient elimination of concurrent potentially nephrotoxic agents during the five-day treatment period.

DOI: 10.3238/arztebl.m2022.0260

Dr. med. Ursula Wolf

Universitätsklinikum Halle (Saale)

Conflict of interest statement

The author received fees for lectures on the risks of polypharmacy from Bristol-Myers Squibb and Pfizer.

References

1. 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

2. Lange NW, Salerno DM, Jennings DL, et al.: Nirmatrelvir/ritonavir use: managing clinically significant drug-drug interactions with transplant immunosuppressants. Am J Transplant 2022; 11

3. Wang AX, Koff A, Hao D, Tuznik NM, Huang Y: Effect of nirmatrelvir/ritonavir on calcineurin inhibitor levels: early experience in four SARS-CoV-2 infected kidney transplant recipients. Am J Transplant 2022; 14: 10.1111

4. Betapharm: Fachinformation Fentanyl beta 12 /-25/-50/-75/-100 Mikrogramm/Stunde Matrixpflaster transdermales Pflaster. https://s3.eu-central-1.amazonaws.com/prod-cerebro-ifap/media_all/77630.pdf (last accessed on 9 May 2022).