ritonavir and Epilepsy

Ritonavir-boosted nirmatrelvir (RBN) has been authorized recently in several countries as an orally active anti-SARS-CoV-2 treatment for patients at high risk of progressing to severe COVID-19 disease. Nirmatrelvir is the active component against the SARS-CoV-2 virus, whereas ritonavir, a potent CYP3A inhibitor, is intended to boost the activity of nirmatrelvir by increasing its concentration in plasma to ensure persistence of antiviral concentrations during the 12-hour dosing interval. RBN is involved in many clinically important drug-drug interactions both as perpetrator and as victim, which can complicate its use in patients treated with antiseizure medications (ASMs). Interactions between RBN and ASMs are bidirectional. As perpetrator, RBN may increase the plasma concentration of a number of ASMs that are CYP3A4 substrates, possibly leading to toxicity. As victims, both nirmatrelvir and ritonavir are subject to metabolic induction by concomitant treatment with potent enzyme-inducing ASMs (carbamazepine, phenytoin, phenobarbital and primidone). According to US and European prescribing information, treatment with these ASMs is a contraindication to the use of RBN. Although remdesivir is a valuable alternative to RBN, it may not be readily accessible in some settings due to cost and/or need for intravenous administration. If remdesivir is not an appropriate option, either bebtelovimab or molnupiravir may be considered. However, evidence about the clinical efficacy of bebtelovimab is still limited, and molnupiravir, the only orally active alternative, is deemed to have appreciably lower efficacy than RBN and remdesivir.

Topics: Antibodies, Neutralizing; Antiviral Agents; COVID-19 Drug Treatment; Epilepsy; Humans; Ritonavir; SARS-CoV-2

In regard to the global pandemic of COVID-19, it seems that persons with epilepsy (PWE) are not more vulnerable to get infected by SARS-CoV-2, nor are they more susceptible to a critical course of the disease. However, management of acute seizures in patients with COVID-19 as well as management of PWE and COVID-19 needs to consider potential drug-drug interactions between antiseizure drugs and candidate drugs currently assessed as therapeutic options for COVID-19. Repurposing of several licensed and investigational drugs is discussed for therapeutic management of COVID-19. While for none of these approaches, efficacy and tolerability has been confirmed yet in sufficiently powered and controlled clinical studies, testing is ongoing with multiple clinical trials worldwide. Here, we have summarized the possible mechanisms of action of drugs currently considered as potential therapeutic options for COVID-19 management along with possible and confirmed drug-drug interactions that should be considered for a combination of antiseizure drugs and COVID-19 candidate drugs. Our review suggests that potential drug-drug interactions should be taken into account with drugs such as chloroquine/hydroxychloroquine and lopinavir/ritonavir while remdesivir and tocilizumab may be less prone to clinically relevant interactions with ASMs.

Topics: Adenosine Monophosphate; Alanine; Amides; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Anticonvulsants; Antiviral Agents; Chloroquine; COVID-19; COVID-19 Drug Treatment; Cytochrome P-450 CYP3A Inducers; Dexamethasone; Drug Combinations; Drug Interactions; Enzyme Inhibitors; Epilepsy; Glucocorticoids; Humans; Hydroxychloroquine; Interleukin 1 Receptor Antagonist Protein; Ivermectin; Lopinavir; Pyrazines; Ritonavir; SARS-CoV-2

Topics: Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Epilepsy; Humans; Retrospective Studies; Ritonavir; Seizures

Presented herein are recommendations for use of nirmatrelvir/ritonavir in patients with epilepsy, as issued by the Steering Committee of the Israeli chapter of the International League Against Epilepsy. The recommendations suggest that patients on moderate-to-strong enzyme-inducing antiseizure medications (ASMs) and everolimus should not be treated with nirmatrelvir/ritonavir; rectal diazepam may be used as an alternative to buccal midazolam; doses of ASMs that are cytochrome P450 (CYP3A4) substrates might be adjusted; and patients treated with combinations of nirmatrelvir/ritonavir and ASMs that are CYP3A4 substrates or lamotrigine should be monitored for drug efficacy and adverse drug reactions.

Topics: Anticonvulsants; Cytochrome P-450 CYP3A; Epilepsy; Humans; Israel; Ritonavir

Topics: Anticonvulsants; Antiviral Agents; Atazanavir Sulfate; Carbamazepine; Cytochrome P-450 CYP3A; Drug Dosage Calculations; Drug Interactions; Drug Monitoring; Enzyme Activation; Epilepsy; Hepatitis C; HIV Infections; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Treatment Outcome