Development of a Physiologically Based Pharmacokinetic Model for Hydroxychloroquine and Its Application in Dose Optimization in Specific COVID-19 Patients.

In Feb 2020, we developed a physiologically-based pharmacokinetic (PBPK) model of hydroxychloroquine (HCQ) and integrated in vitro anti-viral effect to support dosing design of HCQ in the treatment of COVID-19 patients in China. This, along with emerging research and clinical findings, supported broader uptake of HCQ as a potential treatment for COVID-19 globally at the beginning of the pandemics. Therefore, many COVID-19 patients have been or will be exposed to HCQ, including specific populations with underlying intrinsic and/or extrinsic characteristics that may affect the disposition and drug actions of HCQ. It is critical to update our PBPK model of HCQ with adequate drug absorption and disposition mechanisms to support optimal dosing of HCQ in these specific populations. We conducted relevant in vitro and in vivo experiments to support HCQ PBPK model update. Different aspects of this model are validated using PK study from 11 published references. With parameterization informed by results from monkeys, a permeability-limited lung model is employed to describe HCQ distribution in the lung tissues. The updated model is applied to optimize HCQ dosing regimens for specific populations, including those taking concomitant medications. In order to meet predefined HCQ exposure target, HCQ dose may need to be reduced in young children, elderly subjects with organ impairment and/or coadministration with a strong CYP2C8/CYP2D6/CYP3A4 inhibitor, and be increased in pregnant women. The updated HCQ PBPK model informed by new metabolism and distribution data can be used to effectively support dosing recommendations for clinical trials in specific COVID-19 patients and treatment of patients with malaria or autoimmune diseases.

Review on the Clinical Pharmacology of Hydroxychloroquine Sulfate for the Treatment of COVID-19.

BACKGROUND: As the number of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infected people is greatly increasing worldwide, the international medical situation becomes very serious. Potential therapeutic drugs, vaccine and stem cell replacement methods are emerging, so it is urgent to find specific therapeutic drugs and the best treatment regimens. After the publications on hydroxychloroquine (HCQ) with anti- SARS-COV-2 activity in vitro, a small, non-randomized, open-label clinical trial showed that HCQ treatment was significantly associated with reduced viral load in patients with coronavirus disease-19 (COVID-19). Meanwhile, a large prophylaxis study of HCQ sulfate for COVID-19 has been initiated in the United States. HCQ offered a promising efficacy in the treatment of COVID-19, but the optimal administration is still being explored. METHODS: We used the keyword "hydroxychloroquine" to conduct a literature search in PubMed to collect relevant literature on the mechanism of action of HCQ, its clinical efficacy and safety, pharmacokinetic characteristics, precautions for clinical use and drug interactions to extract and organize information. RESULTS: This paper reviews the mechanism, clinical efficacy and safety, pharmacokinetic characteristics, exposureresponse relationship and precautions and drug interactions of HCQ, and summarizes dosage recommendations for HCQ sulfate. CONCLUSION: It has been proved that HCQ, which has an established safety profile, is effective against SARS-CoV-2 with sufficient pre-clinical rationale and evidence. Data from high-quality clinical trials are urgently needed worldwide.

Updates on the Pharmacology of Chloroquine against Coronavirus Disease 2019 (COVID-19): A Perspective on its Use in the General and Geriatric Population.

BACKGROUND: Chloroquine has been used to treat malaria for more than 70 years. Its safety profile and cost-effectiveness are well-documented. Scientists have found that chloroquine has in vitro activity against novel coronavirus (SARS-CoV-2). Currently, chloroquine has been adopted in the Protocol for Managing Coronavirus Disease 2019 (COVID-19) (Version 7) issued by the China National Health Commission for clinically managing COVID-19. OBJECTIVE: This review will focus on the antiviral mechanism, effectiveness and safety, dosage and DDIs of chloroquine, for the purpose of providing evidence-based support for rational use of chloroquine in the treatment of COVID-19. METHODS: Use the search terms "chloroquine" linked with "effectiveness", "safety", "mechanism", "drug-drug interaction (DDIs)" or other terms respectively to search relevant literature through PubMed. RESULTS: After searching, we found literature about antivirus mechanism, dosage, DDIs of chloroquine. However, studies on the effectiveness and safety of chloroquine treatment for COVID-19 for the general and geriatric patients are not enough. CONCLUSION: According to literature reports, chloroquine has been proven to have anti-SARS-CoV-2 effect in vitro and the potential mechanism of chloroquine in vivo. Pharmacokinetic characteristics and DDIs study are helpful in guiding rational drug use in general and geriatric patients. Although there have been reports of successful clinical application of chloroquine in the treatment COVID-19, more clinical test data are still needed to prove its effectiveness and safety.

Dose selection of chloroquine phosphate for treatment of COVID-19 based on a physiologically based pharmacokinetic model.

Chloroquine (CQ) phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019 (COVID-19). To develop a physiologically-based pharmacokinetic (PBPK) model for predicting tissue distribution of CQ and apply it to optimize dosage regimens, a PBPK model, with parameterization of drug distribution extrapolated from animal data, was developed to predict human tissue distribution of CQ. The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism. Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships. The model was also validated by clinical data from Chinese patients with COVID-19. The novel PBPK model allows in-depth description of the pharmacokinetics of CQ in several key organs (lung, heart, liver, and kidney), and was applied to design dosing strategies in patients with acute COVID-19 (Day 1: 750 mg BID, Days 2-5: 500 mg BID, CQ phosphate), patients with moderate COVID-19 (Day 1: 750 mg and 500 mg, Days 2-3: 500 mg BID, Days 4-5: 250 mg BID, CQ phosphate), and other vulnerable populations (e.g., renal and hepatic impairment and elderly patients, Days 1-5: 250 mg BID, CQ phosphate). A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.