Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways.

Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants. Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models. Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated). Results: The predicted maximum concentration (Cmax), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range. Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children.

Physiologically based pharmacokinetic model of renally cleared antibacterial drugs in Chinese renal impairment patients.

To preliminarily develop physiologically based population models for Chinese renal impairment patients and to evaluate the prediction performance of new population models by renally cleared antibacterial drugs. First, demographic data and physiological parameters of Chinese renal impairment patients were collected, and then the coefficients of the relative demographic and physiological equation were recalibrated to construct the new population models. Second, drug-independent parameters of ceftazidime, cefodizime, vancomycin, and cefuroxime were collected and verified by Chinese healthy volunteers, Caucasian healthy volunteers, and Caucasian renal impairment population models built in Simcyp. Finally, the newly developed population models were applied to predict the plasma concentration of four antibacterial drugs in Chinese renal impairment patients. The new physiologically based pharmacokinetic (PBPK) population models can predict the main pharmacokinetic parameters, including area under the plasma concentration-time curve extrapolated to infinity (AUCinf ), renal clearance (CLr ), and peak concentration (Cmax ), of ceftazidime, cefodizime, vancomycin, and cefuroxime following intravenous administrations with less than twofold error in mild, moderate, and severe Chinese renal impairment patients. The accuracy and precision of the predictions were improved compared with the Chinese healthy volunteers and Caucasian renal impairment population models. The PBPK population models were preliminarily developed and the first-step validation results of four antibacterial drugs following intravenous administration showed acceptable accuracy and precision. The population models still need more systematic validation by using more drugs and scenarios in future studies to support their applications on dosage recommendation for Chinese renal impairment patients.

Development of a physiologically based pharmacokinetic (PBPK) population model for Chinese elderly subjects.

AIMS: This study aims to develop and verify a physiologically based pharmacokinetic (PBPK) population model for the Chinese geriatric population in Simcyp. METHODS: Firstly, physiological information for the Chinese geriatric population was collected and later employed to develop the Chinese geriatric population model by recalibration of corresponding physiological parameters in the Chinese adult population model available in Simcyp (i.e., Chinese healthy volunteer model). Secondly, drug-dependent parameters were collected for six drugs with different elimination pathways (i.e., metabolized by CYP1A2, CYP3A4 or renal excretion). The drug models were then developed and verified by clinical data from Chinese adults, Caucasian adults and Caucasian elderly subjects to ensure that drug-dependent parameters are correctly inputted. Finally, the tested drug models in combination with the newly developed Chinese geriatric population model were applied to simulate drug concentration in Chinese elderly subjects. The predicted results were then compared with the observations to evaluate model prediction performance. RESULTS: Ninety-eight per cent of predicted AUC, 95% of predicted Cmax , and 100% of predicted CL values were within two-fold of the observed values, indicating all drug models were properly developed. The drug models, combined with the newly developed population model, were then used to predict pharmacokinetics in Chinese elderly subjects aged 60-93. The predicted AUC, Cmax , and CL values were all within two-fold of the observed values. CONCLUSION: The population model for the Chinese elderly subjects appears to adequately predict the concentration of the drug that was metabolized by CYP1A2, CYP3A4 or eliminated by renal clearance.

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.

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.

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.

Time-Dependent Distribution of Hydroxychloroquine in Cynomolgus Macaques Using Population Pharmacokinetic Modeling Method.

To evaluate the biodistribution of hydroxychloroquine (HCQ) in cynomolgus macaques and receive dynamic quantitative relationship between plasma, blood, and lung tissue concentration using the population pharmacokinetic modeling method, seventeen cynomolgus macaques were divided into six groups according to different HCQ dosing regimens over 5 days. The monkeys were euthanized, and blood, plasma, urine, feces and ten tissues were collected. All the samples were prepared by protein precipitation and analyzed by HPLC-MS/MS detection. The population pharmacokinetics of HCQ in the plasma, red blood cells, and lung tissue was conducted and simulated via ADAPT program. Results demonstrated that the maximum concentration (C max) of HCQ was 292.33 ng/mL in blood and 36.90 ng/mL in plasma after single dose of 3 mg/kg. The value of area under curve (AUC0-∞) was determined as 5,978.94 and 363.31 h* ng/mL for the blood and plasma, respectively. The descending order of the tissue-to-plasma concentration ratio was liver > spleen > kidney > lung > heart > subcutaneous fat > brain. The tissue-to-plasma concentration ratio and the tissue-to-blood concentration ratio for lung were found to be time-dependent with 267.38 and 5.55 at 120 h postdose, respectively. A five-compartment model with first-order oral absorption and elimination best described the plasma, blood, and lung tissue pharmacokinetics. The estimated elimination rate constant (ke) for a typical monkey was 0.236 h-1. The volume of distribution in central (Vc/F) and other two peripheral compartments (Vb/F and Vl/F) were 114, 2.68, and 5.55 L, respectively. Model-based simulation with PK parameters from cynomolgus macaques showed that the ratio of the blood or plasma to lung tissue was a dynamic change course, which suggested that the rate of HCQ concentration decrease in the blood or plasma was faster than that in the lung tissue. HCQ was found to be accumulated in tissues, especially in the liver, kidney, lung, and spleen. Also, the tissue-to-plasma concentration ratio increased over time. The population pharmacokinetic model developed could allow for the assessment of pharmacokinetics-pharmacodynamics relationships, especially relevant tissue concentration-response for HCQ. Determining appropriate treatment regimens in animals allows translation of these to clinical studies.

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.