Discussion
We report a DDI between crizotinib and sofosbuvir/velpatasvir associated
with severe cardiac toxic effects leading to crizotinib discontinuation.
Overexposure to crizotinib could have accounted for these effects, which
was confirmed by the clinical improvement with crizotinib dose reduction
(3). Drug causality was probable according to the Naranjo scale (score =
8) (9). Factors that could explain the variability in crizotinib
overexposure could be the patient being slightly non-compliant (Girerd
score) and pharmacogenetic analyses showing no cytochrome 3A5 (CYP3A5)
and CYP3A4 functional polymorphism (10,11). The pharmacokinetics
mechanism of this DDI may have been a reciprocal interaction between
crizotinib and velpatasvir (Figure 2). C rizotinib is a CYP3A4/5
and P-glycoprotein (P-gp) moderate inhibitor in vitro and could
lead to a supratherapeutic plasma level of velpatasvir, a substrate of
CYP3A4 and P-gp (Table I) (3,12). Furthermore, velpatasvir is a P-gp
weak inhibitor (Table I) (12). Velpatasvir may have increased the plasma
concentration of crizotinib, a P-gp substrate (Table I) (3). We tested
this hypothesis with a disproportionality analysis using VigiBase (the
World Health Organization global database of individual case safety
reports
(https://www.who-umc.org/vigibase/vigibase/))
and observed a significant association between the concomitant use of
crizotinib and P-gp inhibitors and cardiac arrhythmia (odds ratio of
reporting 2.5, 95% confidence interval 1.2-5.2) as compared with the
use of crizotinib without a P-gp inhibitor (13). This pharmacovigilance
statistical approach supports a DDI between crizotinib and P-gp
inhibitors resulting in higher cardiac adverse-drug-reaction reporting.