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]