Cytokine levels in COVID-19 patients
Elevated cytokine levels alter the PK, and thus exposure, of small molecules. A few clinical studies have compared drug exposure before and after treatment with cytokines. The use of Interferon (IFN)-α in chronic hepatitis B has been found to decrease theophylline (metabolized mainly by CYP1A2) clearance by 50% and prolong the half-life of the drug by 70% [18]. Alternatively, blocking IL-6 receptor activity with drugs such as sarilumab and tocilizumab reduces the AUC and Cmax of simvastatin (CYP3A4 substrate) by 40-57% [19, 20].
As clinical studies addressing the impact of different drug metabolizing enzymes and transporters are not always feasible, in vitro models of hepatic and intestinal cell lines can be used. Exposure of hepaRG hepatic cells to IL-6 (10 ng/mL) for 72 h has been found to decrease CYP3A4 mRNA expression and activity by more than 80%, CYP1A2 activity by 60%, and CYP2B6 and 2C19 activity by 80% [21]. In EpiIntestinal cells the expression of Phase I enzymes CYP2C19, CYP2C9, and CYP3A4 was reduced by 40-50% (MAO A, 35%; MAO B, 42%), whilst activities of CYP2C19, CYP2C9, and CYP3A4 were suppressed by 20-75% following exposure to IL-6. However, it is worth noting that extrapolation ofin vitro results to in vivo models is challenging due to the complexity of biological systems, disease pathophysiology, changes in cytokines levels, and interactions among cytokines and DME targets. One difficulty, for example, is making sure that IL-6 is added to cells in concentrations that mimic physiological levels in healthy and diseased states. In healthy individuals, serum IL-6 concentrations range from 1.3 to 10.3 pg/ml, rising to 2.6 to 123 pg/ml in some patient groups with inflammatory diseases including: obesity [22] rheumatoid arthritis [23], psoriasis [24], and cirrhosis [25]. A recent meta-analysis reported IL-6 levels in COVID-19 patients with complex clinical complications to be nearly three-fold higher than in patients with few complications [8]. The average serum level of IL-6 across the 6 studies reported in this review was 65.5 pg/ml in patients with SARDS; severe acute respiratory distress syndrome, which is significantly higher than in non-severe cases of disease (21.4 pg/ml). Mortality rates correlated with higher levels of IL-6, and the addition of IL-6 inhibitors such as tocilizumab improved clinical outcomes with no deaths in a total number of 21 patients receiving treatment [8]. Similar results have been observed for acalabrutinib in COVID-19 patients; elevated IL-6 levels [median (range) of 44 (25-89.8) pg/mL] were noted in COVID-19 patients with a significant (p=6.5E-4) decline observed during acalabrutinib treatment. [3]