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.