ABSTRACT
Background: and Purpose: Ritonavir-boosted lopinavir and chloroquine were withdrawn for COVID-19 treatment according to WHO recommendation. However, lopinavir is still being used for COVID-19 treatment in a clinical practice guideline without supportive evidence. We demonstrated the utility of physiologically-based pharmacokinetic (PBPK)/pharmacodynamic (PD) models to support clinical use of lopinavir and the withdrawal of chloroquine for COVID-19 treatment. Experimental approach: The developed whole-body PBPK models were validated against clinical data. Model validation was performed using acceptable methods. The inhibitory effect (%E) was calculated to demonstrate drug efficacy. The recommended drug regimen for COVID-19 was the combination of 400/100 mg lopinavir/ritonavir given twice daily and 300 mg base chloroquine given twice daily for 14 days. Key Results: This study successfully developed whole-body PBPK models (AAFEs of 1.2-fold). For patients with a 70 kg body weight, %E for chloroquine in epithelial lining fluid (ELF) and bronchial epithelial cells (BEC) were about 2% and 12%, respectively. The corresponding values for lopinavir were 66% and 87.4%, respectively. With the increased body weight to 90 kg, %E for lopinavir in BEC dramatically dropped to lower than 60%, while that in ELF was slightly decreased (86.87%). Conclusion and Implications: The results support the decision of withdrawing chloroquine and using lopinavir in asymptomatic (with positive antigen kit test) or mild COVID-19 cases. In addition, results support the administration of antiviral drugs within the ten days of infection to prevent treatment failure.
Subject(s)
COVID-19 , Parkinson DiseaseABSTRACT
Ineffective selection of therapeutic drugs during an urgent situation leads to failure for COVID-19 treatment in large clinical trials, resulting in wasting time and cost. We aimed to demonstrate the utility of physiologically-based pharmacokinetic (PBPK)/pharmacodynamic (PD) modeling to support the withdrawal of chloroquine and ritonavir-boosted lopinavir (LPV/r) for COVID-19 treatment. The developed whole-body PBPK models were validated against clinical data. Model validation was performed using acceptable methods. The inhibitory effect was calculated to demonstrate drug efficacy. Various regimens of chloroquine and LPV/r for COVID-19 treatment in different clinical trials were used for a simulation. The risk of cardiotoxicity following high dose chloroquine administration was assessed. The effect of lung pH on drug concentrations in epithelial lining fluid (ELF) following a high dose of chloroquine and LPV/r was evaluated. The whole-body PBPK models were successfully developed (AAFEs of 1.2-fold). The inhibitory effect (%E) of chloroquine following high dose regimens in both ELF and bronchial epithelial cells (BEC) were lower than 2 and 1%, respectively. The corresponding values for the high dose of LPV/r were 40 and 2%, respectively. The risk of prolonged QTc in the population was higher than 20%. In addition, the %E of chloroquine was increased to 76% at pH 5.6 and decreased to 0.13% at pH 7.5. The change in pH in ELF had no influence on LPV/r concentrations. PBPK/PD modelling supports the withdrawal of chloroquine and LPV/r for COVID-19 treatment as an effective tool for the selection of therapeutic drug regimens in urgent situation.
Subject(s)
COVID-19 , CardiotoxicityABSTRACT
Background and objective : Globally, COVID-19 has caused a number of challenges including the functioning of research ethics committees (RECs) with the impact being expected to be more pronounced in resource-limited countries. The objective of this study was to describe RECs' functions and challenges experienced during the pandemic in Africa.Method A cross-sectional study covering Anglophone and Francophone countries in Africa was done. Data was collected using an online Google form questionnaire. The link to the form was sent to REC chairs and secretaries to fill in online. Descriptive data analysis was done using Microsoft Excel and SPSS version 25.Result A total of 98 study participants (50 members and 48 chairs) responded from 16 African countries. The mean (standard deviation) age of REC members was 47 (12) and over half of them, 27 (54%) were female. Most REC members and chairs were physicians, while 48% of RECs were affiliated with academic institutes. Ninety percent of REC chairs reported that their REC was accredited; however, only three had recognition by Strategic Initiative for Developing Capacity in Ethics Review (SIDCER). RECs reported reviewing COVID-19 related protocols. In 2019, chairs reported RECs reviewing 5,860 protocols with a 13% increment in 2020. During the COVID-19 pandemic, there was an increment in protocol amendment (79%), deviation (29%), and early protocol termination (25%). Most (96%) RECs followed COVID-19 prevention institutional policies including limiting face-to-face meetings and shifting to virtual platforms. RECs challenges in reviewing COVID-19 related proposals were issues related to risk/benefit, scientific design, and informed consent.Conclusion The COVID-19 pandemic has impacted the functions of RECs in Africa, both in the increase in the volume of proposals for review and presenting new ethical challenges including in risk-benefit analysis. There is a need to strengthen RECs in the region through different mechanisms, by building their capacity through initiatives like the SIDCER recognition program. To strengthen African RECs in a sustainable manner, some of the interventions could be establishing National and regional REC databases, and putting in place continuous training opportunities preferably through an online platform.