Use of therapeutic drug monitoring (TDM) to optimise oral/enteral hydroxychloroquine dosing in critically ill patients with COVID-19

Based on preclinical and non-randomised studies, the Royal Brisbane and Women’s Hospital Intensive Care Unit clinical Consultant Medical Staff, in agreement with the Infectious Diseases Department and the Pharmacy Department, have decided that all patients admitted to the ICU with COVID-19 infection should receive hydroxychloroquine as standard care. Therefore, hydroxychloroquine is NOT considered a trial intervention for the purpose of this study. The dose of hydroxychloroquine used for COVID-19 infection is extrapolated from that in common use for malaria and other approved indications. However, the organ dysfuction that accompanies critical illness suggests dosing is likely to require adjustment. This study will adjust the dose of hydroxychloroquine using therapeutic drug monitoring (TDM) to a goal concentration known to be safe. The observation period for TDM will be a total of up to 10 days or until the time of ICU discharge, which ever is sooner. As is routine practice at the RBWH ICU, TDM will be led by the senior ICU pharmacist after initiation of therapy. Trough venous blood samples (3 ml) will be taken via an indwelling arterial cannula. The first TDM should ideally occur before the administration of the FIRST MAINTENANCE DOSE, provided the appropriate loading dose schedule has been completed. Sampling thereafter can occur every 24-48 hours to confirm the appropriateness of ongoing dosing as guided by the Pharmacy and Medical Team. Blood samples will be transported to Queensland Pathology on the Herston Campus for drug analysis. Prescribing of initial and ongoing/revised dosing will remain the responsibility of medical officers, whilst fidelity of the intervention will be maintained through pharmacy dosing adjustment notes which are subjected to auditing. Blood samples will continue to be collected daily until the participant is discharged from ICU. Samples for assay will be spiked with stable isotope labelled internal standards and drugs extracted by liquid-liquid extraction with tertbutyl methyl ether. Extracts will be analysed by a validated UHPLC-MS/MS chromatographic method to measure total drug concentrations. Test samples will be assayed alongside calibrators and quality controls and be subjected to industry standard batch acceptance criteria. A pharmacogenetic evaluation of CYP3A4 and CYP2D6 expression will be performed on existing blood samples to ascertain information regarding HCQ metabolism and drug exposure. In order to further interrogate the collected data and scientifically evaluate the appropriateness of hydroxychloroquine, as a secondary analysis, we will analyse the dosing and concentration data of 100 patients and subject this to population pharmacokinetic modelling using non-parametric pharmacokinetic modelling approach in Pmetrics®. The final pharmacokinetic population parameters estimated from all possible covariates will be chosen based on the value of mean weighted error (describing the precision), mean weighted squared error (describing the bias), and coefficient of determination (r2). Monte Carlo simulations will be performed to identify the most optimal dosing regimens that will target drug concentrations.