3.3 Simulations of the plasma concentration-time profile of
chloroquine when co-administered with lopinavir (LPV/r)
Simulation based on standard DDIs study approach: The recommended dosage
of chloroquine for rheumatoid arthritis treatment (250 mg once daily) in
combination with LPV/r (400/100 mg twice-daily dose) resulted in a
1.45-fold increase in the AUC for chloroquine indicating a significant
but weak DDI. The average unbound Ctrough at 24 hours,
and the average unbound Cmax were 0.10±0.01, and
0.30±0.05 mg l-1, respectively.
Simulation based on actual clinical use approach: The recommended
once-daily dose of 250 mg chloroquine co-administered with LPV/r
(400/100 mg twice-daily dose) provided a 1.50-fold increase in the AUC
of chloroquine (AUCR=1.50). The average unbound Ctroughat 24 hours, and the average unbound Cmax were 0.11±0.03
mg l-1, and 1.82±0.15 mg l-1,
respectively. The time to reach EC50 was 5 days. The
weak DDI (AUCR > 1.25 to <2 fold) resulted in the
lower average unbound Ctrough at 24 hours than the
EC50, and the lower unbound Cmax than
the toxicity level, and thus significant dose reduction is probably not
requiring. Subsequent simulation of the once-daily regimen of 250 mg
chloroquine co-administered with LPV/r (800/100 mg once-daily dose)
resulted in the average unbound Ctrough at 24 hours, and
unbound Cmax of 0.11±0.02 mg l-1, and
0.80±0.15 mg l-1, respectively. A 500 mg once-daily
dose of chloroquine co-administered with LPV/r (400/100 mg once-daily
dose was simulated. The average unbound Ctrough at 24
hours, and unbound Cmax were 0.22±0.04 mg
l-1, 1.62±0.27 mg l-1, respectively.
Besides, the average unbound Ctrough at 24 hours, and
unbound Cmax following the once-daily regimen of 500 mg
chloroquine co-administered with LPV/r (800/100 mg once-daily dose) were
0.22±0.05 mg l-1, and 1.62±0.30 mg
l-1, respectively. None of the current clinically used
dosage regimens of chloroquine provided unbound Ctroughabove the EC50 level.
Subsequent simulations were performed to identify the potential dose
regimen(s) of chloroquine that could result in chloroquine plasma
concentrations above the EC50 level. Chloroquine at the
twice-daily regimen of 500 mg co-administered with 400/100 mg
twice-daily dose, or 800/200 mg once-daily dose LPV/r provided adequate
unbound Cmax, but insufficient unbound
Ctrough at 24 hours (figure 2 (regimen A), and 3
(regimen A)). Time to reach EC50 for the 400/100 mg
twice-daily dose, and 800/100 mg once-daily dose LPV/r dose regimen was
48 hours. Chloroquine at the dose of 400 mg given three times a day in
combination with 400/100 mg twice-daily dose (figure 2 (regimen B)) or
800/200 mg once-daily dose LPV/r (figure 3 (regimen B)) provided toxic
level of unbound Cmax, and inadequate unbound
Ctrough at 8 hours. This regimen, however, reduced the
time to reach EC50 to 24 hours. The pharmacokinetic
parameters of chloroquine following other dose regimens (i.e. , a
once-daily dose of 1000 mg, a loading dose of 1,000 mg, followed by
twice-daily dose of 500 mg, and a loading dose of 1,000 mg, followed by
twice-daily dose of 500 mg for 8 doses, and twice-daily dose of 400 mg
for 18 doses) are shown in figure 2 (co-administered with 400/100 mg
LPV/r regimen C,D, E, respectively), and figure 3 (co-administered with
800/200 mg LPV/r regimen C, D, E, respectively). All three doses of
chloroquine regimens provided unbound Ctrough above the
EC50 level within 24 hours.