Figure 3. Effect of hepatic (A) and renal (B) impairments on
plasma concentration–time profiles of COVID-19 drugs
The black continuous line represents the median prediction using the
PBPK model for healthy population. The shaded area represents the 95%
prediction intervals of healthy population. Blue line represents mild
hepatic impairment. Green line represents moderate renal or hepatic
impairment; red line represents severe renal or hepatic impairment.
Doses used for hepatic impairment: Acalabrutinib 50 mg single dose,
azithromycin 500mg single dose, atazanavir 400mg single dose,
chloroquine 300mg single dose, dapagliflozin 10mg single dose,
hydroxychloroquine base(HCQ) 155 mg single dose, baricitinib 4mg single
dose, ritonavir 600mg single dose, ruxolitinib 25mg single dose,
lopinavir 400 mg single dosing interval (with 100mg ritonavir
concomitant interaction), darunavir 600 mg single dosing interval (with
100 mg ritonavir concomitant interaction), ibrutinib 140mg single dose,
dexamethasone8 mg single dose. Only parent acalabrutinib was measured in
organ dysfunction or DDI studies of acalabrutinib.
Doses used for renal impairment: Azithromycin 500mg single dose,
atazanavir 400mg single dose, hydroxychloroquine base 155 mg,
baricitinib 4mg single dose, chloroquine 300mg single dose,
dapagliflozin 50 mg single dose, acalabrutinib 50 mg single dose,
ruxolitinib 25 mg single dose, ritonavir 600mg single dose, lopinavir
400 mg single dose (with 100mg ritonavir concomitant interaction),
darunavir 800 mg single dose, dexamethasone 8 mg single dose.
Figure 4. PBPK model-based simulations of conc-profiles in
plasma and lung tissue using multiple-compartmental lung model in
geriatric patients after verification of models using adult data for
drugs that are being tested in COVID-Trial . Dashed lines represents a
relevant potency value either IC50 or
IC90.
Doses used for simulating lung exposure: multiple doses 14 days of
dosing to steady state azithromycin 500 mg single dose, atazanavir 400
mg, hydroxychloroquine base 155 mg, baricitinib 4 mg, chloroquine 300
mg, dapagliflozin 10 mg, acalabrutinib 100 mg, ruxolitinib 25 mg,
ritonavir 600 mg, lopinavir 400 mg, darunavir 800 mg , dexamethasone 8
mg.
Figure 5. Sensitivity analysis on the possible effect of
cytokines, and consequent CYP3A4 abundance suppression in both liver and
the gut on acalabrutinib (A) and ibrutinib (B) exposures