In Reply

We thank the correspondent for her comment on the interaction management of nirmatrelvir/r under conditions of domestic quarantine (1). Watchful medical monitoring of treatments with a narrow therapeutic range is of major importance when starting/stopping potentially interacting co-medications. First peer-reviewed publications of medium-sized retrospective case studies now show that immunosuppressed (calcineurin inhibitors, mTOR inhibitors) transplant patients can indeed be treated with nirmatrelvir/r (2, 3) or molnupiravir (2). This requires established dose reduction protocols, however, and intensive therapeutic drug monitoring after nirmatrelvir/r therapy (1). Even under these conditions, however, tacrolimus concentrations became non-measurable in two studies (2, 3). Thirty-day hospital admission rates (16%) and mortality rates (0%) were identical in both studies, which means that the question remains unanswered whether really relevant differences in effectiveness of the two therapies actually exist. To this end, comparative studies would be desirable, or at least substantially larger study populations that would enable considering the relevant co-factors.

With our comprehensive literature search we aimed to capture experimental evidence for interactions with ritonavir. For reasons of clarity and relevance we restricted our search to substances with a relatively narrow therapeutic range, whose exposure change can be expected to lead to the biggest potential risk (see Method [1]) and to this end we extracted quantitative information from clinical studies. We therefore did not aim to list all CYP3A and P-glycoprotein substrates (see Method [1]|), and we intentionally avoided speculation (buprenorphine exposure changes under ritonavir are, for example, irrelevant [4]).

We agree with Dr. Wolf that limitations of several clearance pathways (for example, moderate renal functional impairment ± P-glycoprotein inhibition ± CYP3A inhibition) can be particularly accentuated in substances that substantially use these elimination pathways. Therefore, when selecting adequate repetitive doses, the activity of all relevant clearance pathways of a drug must always be considered (see Limitations [1]).