Cytotoxicity evaluation of chloroquine and hydroxychloroquine in multiple cell lines and tissues by dynamic imaging system and PBPK model

Authors: Yang et al.

Link to paper: https://www.biorxiv.org/content/10.1101/2020.04.22.056762v1

Journal/ Pre-Print: BioRxiv

Tags: In vitro, Drug, treatment, Biochemistry, Bioinformatics.

Research Highlights 

1. CQ and HCQ have certain cytotoxicity on 8 different cell line in a dose-and time-dependent manner.

2. selectivity index (SI) of HCQ, which is used to evaluate the drug safety range, is higher than that of CQ in most cell types.

3. By using the physiologically-based pharmacokinetic models (PBPK), they predict that the toxicity risk of HCQ in the lung, heart, kidney and liver tissues is much lower than that of CQ.

Summary

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been in the public eye since several anecdotal reports treating patients with these drugs were recently published. The paper tried to address its safety from cell-based approaches by using 8 cell lines originating from different tissues including the retina, myocardium, lung, liver, kidney, vascular endothelium and intestinal epithelium. They measured the proliferation of these cell lines under treatment with different doses of HCQ and CQ at several time points. They found that HCQ is less toxic than CQ in 7 out of 8 cell lines. In addition, they applied PBPK model to assess the drug safety. They revealed that HCQ has ansafer profile than CQ in different tissues. Interestingly, they found that HCQ is toxic for the heart and the retina, indicating that paying special attention to patients have eye or cardiac disease when using HCQ is warranted.

Impact for SARS-CoV2/COVID19 research efforts

Treat of SARS-CoV2/COVID19 positive individuals

The authors provide a warning of using HCQ and CQ in COVID patients. Despite the fact that HCQ has shown a safer profile than CQ, both drugs showed accumulated cytotoxicity with time in the different types of cell lines. These data suggest the necessity to review the period of administration of these two drugs. In the other hand, the data predict serious toxicity of HCQ in heart and eye tissue. Attention should be paid to monitoring these two tissues in the treated patients.

Study Type

· In vitro study

Strengths and limitations of the paper

Novelty: The study provides no novelty as safety, cytotoxicity and side effects of CQ and HCQ had been widely studied before this study.

Standing in the field: There are some studies support the data about cytotoxicity of HCQ and CQ, like the study by Liu et al, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.

Appropriate statistics: No statistical tests were used in the paper. Methodology, number of experiments and replication are all missing.

Viral model used: No SARS-CoV was used in this study.

Translatability: The findings are translatable, greater consideration should be given when prescribing HCQ to Covid-19 patients or other patients, especially those who have cardiovascular disease.

Main limitations:

- Immortalised cell lines may not be a good representation of their corresponding tissue

- The cell lines were not infected with SARS-CoV so the study does not reflect the disease state