High rate of major drug–drug interactions of lopinavir–ritonavir for COVID-19 treatment

Abstract

The impact of drug–drug interactions (DDI) between ritonavir-boosted lopinavir (LPV-r) to treat patients with coronavirus disease 2019 (COVID-19) and commonly used drugs in clinical practice is not well-known. Thus, we evaluated the rate and severity of DDI between LPV-r for COVID-19 treatment and concomitant medications. This was a cross-sectional study including all individuals diagnosed of SARS-CoV-2 infection treated with LPV-r and attended at a single center in Southern Spain (March 1st to April 30th, 2020). The frequency [95% confidence interval (95% CI)] of potential and major DDI were calculated. Overall, 469 patients were diagnosed of COVID-19, 125 (27%) of them were prescribed LPV-r. LPV-r had potential DDI with concomitant medications in 97 (78%, 95% CI 69–85%) patients, and in 33 (26%, 95% CI 19–35%) individuals showed major DDI. Twelve (36%) patients with major DDI and 14 (15%) individuals without major DDI died (p = 0.010). After adjustment, only the Charlson index was independently associated with death [adjusted OR (95% CI) for Charlson index ≥ 5: 85 (10–731), p < 0.001]. LPV-r was discontinued due to side effects in 31 (25%) patients. Management by the Infectious Diseases Unit was associated with a lower likelihood of major DDI [adjusted odds ratio (95% CI): 0.14 (0.04–0.53), p = 0.003). In conclusion, a high frequency of DDI between LPV-r for treating COVID-19 and concomitant medications was found, including major DDI. Patients with major DDI showed worse outcomes, but this association was explained by the older age and comorbidities. Patients managed by the Infectious Diseases Unit had lower risk of major DDI.

Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics

“…For example the transport of OATP1B substrate drugs, including statins, repaglinide, olmesartan and valsartan 28,49,50 , or the OCT1-and MATE1-mediated metformin transport 51 could also potentially be affected by LOP and/or RIT. Consistently with in vitro findings of transporter inhibition studies, Macias et al found in a cross-sectional study a high overall frequency of DDI between ritonavir-boosted lopinavir for treating COVID-19 and other relevant medications such as statins, antibiotics, corticosteroids, or antiarrhythmic drugs 52 .…”

“…Consistently with in vitro findings of transporter inhibition studies, Macias et al . found in a cross-sectional study a high overall frequency of DDI between ritonavir-boosted lopinavir for treating COVID-19 and other relevant medications such as statins, antibiotics, corticosteroids, or antiarrhythmic drugs 52 .…”

Drug-drug Interactions between COVID-19 Treatments and Antidepressants, Mood Stabilizers/Anticonvulsants, and Benzodiazepines: Integrated Evidence from 3 Databases

“…Consequently, the dose of CY3A4 substrates should be administered with caution when given in combination with lopinavir/ritonavir. The reported effects of ritonavir on enzymes (CYP 3A, 1A2, 2B6, 2C9, 2C19, and glucuronosyltransferase) may result in lower plasma concentrations of coadministered drugs (respective substrate) or may increase the concentrations of their metabolites (in the case of prodrugs) [27][28][29].…”

Remote ischemic conditioning for acute respiratory distress syndrome in COVID-19

“…Furthermore, lopinavir/ritonavir alters serum lipids to increase the risk of atherosclerosis ( 58 ), which may exacerbate thrombotic events. However, recent reports of arrhythmogenic effects from lopinavir/ritonavir ( 59 , 60 ) and remdesivir ( 61 ) as well as other adverse side effects ( 62 ) may prevent further application in COVID-19 clinical settings. RIC accelerates thrombolysis and decreases platelet-mediated thrombosis in a range of animal models and human patients, while proving safe in a variety of clinical settings ( 63 , 64 ), although the mechanisms underlying the protective effects are not yet determined ( 65 ).…”