ABSTRACT
Chloroquine (CQ) efficacy was shown in some coronavirus disease 2019 (COVID-19) adult clinical studies. However, its data in children is still limited. Therefore, this study aims to assess the suitability of the dosage regimens from the literature and regimens proposed by the authors for pediatric COVID-19 patients aged 2-12 years old. The efficacy pharmacodynamic (PD) target was calculated for CQ blood concentration based on the literature's successfully treated COVID-19 adult regimen. The safety PD targets were derived from the literature regarding any adverse effects (AEs) and QTc prolongation. The adult pharmacokinetic (PK) parameters were transformed into pediatrics by allometric scaling (AS) method. A 10,000-time Monte Carlo simulation (MCS) was performed to calculate the percentage of probability to target attainment (%PTA). The literature's regimens were not capable of achieving 90%PTA efficacy PD target. The proposed regimens without loading dose (LD) achieved the efficacy target at day 8-10 which was later than the proposed regimens with LD (day 4-7). The 90%PTA below any AEs target was achieved in the first few days of the literature and proposed regimens but was unavoidable thereafter. Nevertheless, the 90%PTA below QTc prolongation target was favorably achieved by all regimens. This study revealed that the proposed regimen with LD seems to be the optimal dosage regimen. Additional studies are needed to validate our proposed regimens, especially among early-stage COVID-19 patients and recent major variants.
ABSTRACT
Hydroxychloroquine may be used to treat COVID-19 infections when remdesivir is unavailable. There is currently no hydroxychloroquine dosage regimen for pediatrics with COVID-19 infections. We aimed to determine the optimal dosage regimen needed to rapidly achieve pharmacokinetic and pharmacodynamic (PKPD) targets for virological clearance in pediatrics. A 10,000-subject Monte Carlo simulation was performed to calculate probabilities of efficacy and safety attainment, using allometrically scaled PKPD targets based on published adult pharmacokinetic studies. Allometric scaling of hydroxychloroquine clearance was also performed. The simulation predicted the probability of target attainment (PTA) of each dosage regimen to achieve an 80% PTA and 80% cumulative fraction of response, with <10% PTA for toxicity. The loading dosage of 6 mg/kg/dose, four times daily for 2 days, was found to provide rapid virological clearance with a high PTA (92.2%) within 2 days of treatment. Maintenance dosage of 3.25 mg/kg/dose, three times daily for the next 8 days, achieved the appropriate plasma hydroxychloroquine level until treatment cessation, with a PTA >80%. As to safety, this dosage regimen achieved a PTA <10% of the safety target, giving a probability of cardiotoxicity of <0.01%. The optimal hydroxychloroquine regimen is the loading dosage of 6 mg/kg/dose, four times daily for 2 days, followed by maintenance dosage of 3.25 mg/kg/dose, three times daily, on days 3–10. This regimen achieves virological clearance of COVID-19 and low cardiotoxicity in pediatrics. However, clinical studies are needed to confirm its efficacy and safety. © 2021. by Faculty of Pharmacy, Mahidol University, Thailand is licensed under CC BY-NC-ND 4.0. To view a copy of this license, visit https://www.creativecommons.org/licenses/by-nc-nd/4.0/.
ABSTRACT
Optimized dosage regimens of hydroxychloroquine (HCQ) in coronavirus disease 2019 (COVID-19) are currently unknown. We aimed to determine regimens that rapidly achieved the pharmacokinetic-pharmacodynamic (PKPD) target for virological clearance in COVID-19 patients. Plasma HCQ concentration was simulated using a non-steady state, 2-compartment linear model. The plasma trough concentration (Ctrough) > 0.7 mg/L was used as the PKPD target. The loading dose of 800 mg three times daily and 1,200 mg twice daily achieved the target on the first day with the probability of target attainment (PTA) 97.53% and 82.63%, respectively. Maintenance dose of 200 mg three times daily and 400 mg twice daily provided PTA > 80% from day 3 through day 10 after the initiation of HCQ therapy. All proposed regimens had the PTA < 1% to achieve toxic level of 4 mg/L. The optimal dose regimens for early viral clearance in COVID-19 patients were HCQ 800 mg three times daily on the first day followed by 200 mg three times daily for 9 days, and HCQ 1,200 mg twice daily on the first day followed by 400 mg twice daily for 9 days. Further clinical study is needed to ensure clinical efficacy and safety of these regimens. © 2021 Pharmaceutical Sciences Asia by Faculty of Pharmacy, Mahidol University, Thailand is licensed under CC BY-NC-ND 4.0. To view a copy of this license, visit https:// www.creativecommons.org/licenses/by-nc-nd/4.0/. All Rights Reserved.