Alpha 1-acid glycoprotein is upregulated in severe COVID-19 patients and decreases neutrophil NETs in SARS-CoV-2 infection

PBPK‐led assessment of antimalarial drugs as candidates for Covid‐19: Simulating concentrations at the site of action to inform repurposing strategies

“…Three additional analyses were conducted using the permeability‐limited model to estimate the effect on pyronaridine and amodiaquine concentrations of key parameters known to be modified during COVID‐19 infection. 27 , 33 , 34 With a decreased pH in the lung (pH 6), as observed in COVID‐19 infection, there was enhanced accumulation in the lung tissue with pyronaridine versus blood, and amodiaquine relative to plasma compared with the healthy lung (Table S1 , Figures S1 and S2 ). The effect of modifying AAG and HSA was minor (data not shown).…”

“…This provides further support for these drugs as candidates for repurposing in COVID‐19. Clinical observations indicate that serum concentrations of AAG are elevated in COVID‐19 patients, 33 whereas HSA levels have been shown to decline. 34 Incorporating these modifications into the PBPK model using a virtual population with AAG and HSA levels corresponding to those reported in the literature showed increased lung exposures of both pyronaridine and amodiaquine versus the healthy population but with some attenuation versus the simulations using a pH of 6.…”

“…Thus, an analysis was conducted using both the decreased pH of 6 and plasma levels of 1.695 g/dL and 40 g/dL for AAG and HSA, respectively, consistent with the values reported from COVID‐19 patients. 33 , 34 These two modified analyses could not be done for DEAQ, because as a metabolite, these parameters cannot be varied in the perfusion‐limited PBPK model, though DEAQ is mainly bound to AAG.…”

“… 27 Furthermore, COVID‐19 can cause changes in plasma proteins, with upregulation of alpha 1‐acid glycoprotein (AAG) and a reduction of human serum albumin (HSA) concentrations. 33 , 34 Pyronaridine was assumed to mainly be bound to AAG and amodiaquine to HSA. Thus, an analysis was conducted using both the decreased pH of 6 and plasma levels of 1.695 g/dL and 40 g/dL for AAG and HSA, respectively, consistent with the values reported from COVID‐19 patients.…”