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

Abstract

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 levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 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 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P < 0.001) and were significantly lower when tocilizumab was preadministered. No correlation was found between HCQ concentrations and CRP values. High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 50% effective concentrations (EC₅₀) 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.

Keywords: COVID-19; hydroxychloroquine; inflammation; levels; lopinavir-ritonavir.

FIG 1

Lopinavir (n = 92) and hydroxychloroquine (n = 59) plasma concentrations in COVID-19 patients. The medial lopinavir plasma concentration was 26.5 (IQR, 18.9 to 31.5) μg/ml. The median hydroxychloroquine plasma concentration was 171 (IQR, 128 to 207) ng/ml. The dashed line represents the historical lopinavir trough level observed in HIV-infected individuals treated with lopinavir-ritonavir at 400/100 mg twice daily (i.e., 7.1 μg/ml) (15).

FIG 2

Box plots (showing the 5th, 25th, 50th, 75th, and 95th percentiles) of lopinavir trough concentrations by CRP values in all patients and by age group (A) and box plots of hydroxychloroquine concentrations by CRP values for COVID-19 patients with trough levels (B). CRP, C-reactive protein. The dashed line represents the historical lopinavir trough level observed in HIV-infected individuals treated with lopinavir-ritonavir at 400/100 mg twice daily (i.e., 7.1 μg/ml) (15).

FIG 3

Box plots (showing the 5th, 25th, 50th, 75th, and 95th percentiles) of lopinavir plasma trough concentrations in COVID-19 patients by administration of tocilizumab. The left box depicts LPV plasma levels in COVID-19 patients with no TCZ administration (n = 57) or TCZ administration <12 h prior to LPV measurement (n = 19) (median, 28.8 μg/ml). The right box represents LPV samples from COVID-19 patients with TCZ administration >12 h prior to LPV measurement (median, 18.7 μg/ml).