4.3 Chloroquine and LPV/r combination for the treatment of COVID-19 infection
Based on the results of the simulation, co-administration of LPV/r (400/100 mg twice-daily dose, or 800/200 mg once-daily dose), and once-daily regimen of 250 mg, and 500 mg are not optimal due to inadequate concentration-time profiles of chloroquine above the EC50 level (Ctrough). Increasing chloroquine dose to reach EC50 should offer better clinical benefits in term of treatment efficacy. Based on the simulations, only one chloroquine dosage regimen provided adequate plasma drug concentrations for preventing viral entry, and below the toxic levels i.e., a 1,000 mg loading dose, followed by the twice-daily dose of 500 mg for 8 doses on the second day, and the twice-daily dose of 400 mg for 18 doses, co-administered with once-daily dose of 400/100 mg, and 800/200 mg LPV/r (figure 2 (regimen E), and figure 3 (regimen E)). The regimen offered chloroquine unbound Ctrough of higher than EC50. Although plasma chloroquine concentrations following both regimens of LPV/r were similar, the desirable dose of LPV/r should be 800/200 mg once-daily dose to ensure sufficient cytopathic effect at 24 hours (Chu et al., 2004). The results of this study provide a focus for further clinical studies to confirm this proposed regimen.
Although other two regimens also provided adequate plasma concentration-time profiles for COVID-19 infection, the unbound Cmax was over toxic level (figure 2 (regimen C&D), and figure 3 (regimen C&D)), therefore, is an inappropriate dosage.
The simulated once-daily dose regimen of chloroquine (i.e., 1000 mg once-daily dose) may be desirable when considering the reduction of frequency of drug administration; this regimen however, provided unbound Cmax of chloroquine over the toxic level (figure 3 (regimen C)).
Apart from efficacy, chloroquine-induced irreversible retinopathy is also of great concern when used in combination with LPV/r. The reported threshold dose of chloroquine-induced retinopathy was 5ยท1 mg/kg/day (300 mg for the average body weight of 60 kg) (Mackenzie, 1983). However, the retinopathy from chloroquine is due to the accumulation of chloroquine after long-term use for at least 5 years (Mackenzie, 1983). Based on the previous clinical study, the high dose of chloroquine (20 mg kg-1 body weight day-1, or total dose of 1,200 day-1 for the average body weight of 60 kg) was safe for short-term treatment (6 weeks) (Furst et al., 1999). The chloroquine dose regimen used in our study is therefore, likely to be safe as the total duration of chloroquine administration for COVID-19 treatment is only 14 days.
One of the limitations of this study was that the contributions of P-glycoprotein transporter in the disposition of ritonavir, lopinavir, and chloroquine were not included in the model construction. Nevertheless, the inhibitory effect of ritonavir on P-glycoprotein may have a less significant impact on chloroquine disposition as chloroquine is a weak substrate of this transporter (Crowe, Ilett, Karunajeewa, Batty, & Davis, 2006).
In summary, the developed PBPK models successfully predicted a potentially suitable regimen of chloroquine and LPV/r for COVID-19 infected patients. The proposed dosage regimen is the combination of the once-daily dose of 800/200 mg LPV/r, in combination with chloroquine at a loading dose of 1,000 mg (16.67 mg kg-1 body weight day-1), followed by twice-daily 500 mg for 8 doses on the second day, and twice-daily 400 mg for 18 doses. The total duration of treatment is 14 days. The simulated results in this study represent an advanced framework to rationalize the selection of dose regimens to fight against this COVID-19 infection outbreak. The study provides a focus for further clinical studies to confirm the efficacy of the proposed dosage regimen as a novel treatment for COVID-19 infection.