Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

Abstract

<jats:p><jats:italic>Background:</jats:italic> Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the values of acute phase inflammation marker C-reactive protein (CRP).</jats:p> <jats:p><jats:italic>Methods:</jats:italic> LPV plasma concentrations were prospectively collected in 92 patients hospitalized at our institution. Lopinavir/ritonavir was administered 12-hourly, 800/200 mg on day 1, and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24 and 48 hours. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination.</jats:p> <jats:p><jats:italic>Results:</jats:italic> The median age of study participants was 59 (range 24–85) years, and 71% were male. The median duration from symptom onset to hospitalization and treatment initiation was 7 days (IQR 4–10) and 8 days (IQR 5–10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/mL (IQR 18.9–31.5). LPV plasma concentrations positively correlated with CRP values (r=0.37, p&lt;0.001), and were significantly lower when tocilizumab was preadministrated. No correlation was found between HCQ concentrations and CRP values.</jats:p> <jats:p><jats:italic>Conclusions:</jats:italic> High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 EC50 values indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.</jats:p>

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“…On the contrary, it has been described that the chronic use of this type of NSAIDs could even protect against the occurrence and severity of COVID-19 [26,27]. Therefore, deepening theoretical and experimental in this direction is necessary and is especially justified, because it has been reported that NSAIDs can have a positive effect against ARDS [28] and because the inflammatory process described during SARS-CoV-2 infection has greatly limited the use of other potential drugs [29].…”

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“…The unbound fraction that represents the active part of the drug seems unchanged despite increased overall concentrations [ 40 ]. If part of the discrepancy originates in the undervalued normal range, inflammation has been recently shown to potently augment lopinavir bioavailability through inhibition of CYP450 3A4 [ 41 ]. Indeed, the augmented lopinavir concentrations correlate with those of CRP, mediated by Interleukin-6 (IL-6), in COVID-19 patients, and are prevented by the administration of the IL-6 inhibitor tocilizumab [ 42 ].…”

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“…Initial reports from clinical studies evaluating the use of lopinavir in COVID-19 patients showed that the unbound lopinavir concentrations in the lungs were calculated to be subtherapeutic against SARS-CoV-2 (42,43). Another study found that the unbound drug concentrations of lopinavir are far from reaching the EC50 of SARS-CoV-2 (16.4 μg/mL), although they clearly suffice to inhibit HIV-1 (44).…”