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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a global pandemic of coronavirus disease 2019 (COVID-19). Early in the pandemic, efforts were made to test the SARS-CoV-2 antiviral efficacy of repurposed medications that were already approved and available for other indications, including hydroxychloroquine (HCQ) and azithromycin (AZI). To reduce the risk of SARS-CoV-2 exposure for clinical-trial study participants and to conform with lockdowns and social distancing guidelines, biospecimen collection for HCQ and AZI included at-home dried blood spot (DBS) collection rather than standard venipuncture by trained clinicians. In this study, we developed and validated the first sensitive and selective simultaneous LC-MS/MS method to accurately quantitate the concentration of HCQ, HCQ metabolites (Desethylchloroquine [DCQ], Bisdesethylchloroquine [BDCQ], Monodesethylhydroxychloroquine [DHCQ]) and AZI extracted from DBS. The validated method was successfully applied for the quantification of over 2000 DBS specimens to evaluate the pharmacokinetic profile of AZI, HQC, and its metabolites. This new method has a small sample volume requirement (~ 10 µL), results in high sensitivity (1 ng/mL), and would facilitate remotely conducted therapeutic drug monitoring., (© 2023. Springer Nature Limited.)

Hydroxychloroquine (HCQ) is Food and Drug Administration (FDA)-approved for malaria, systemic and chronic discoid lupus erythematosus, and rheumatoid arthritis. Because HCQ has a proposed multimodal mechanism of action and a well-established safety profile, it is often investigated as a repurposed therapeutic for a range of indications. There is a large degree of uncertainty in HCQ pharmacokinetic (PK) parameters which complicates dose selection when investigating its use in new disease states. Complications with HCQ dose selection emerged as multiple clinical trials investigated HCQ as a potential therapeutic in the early stages of the COVID-19 pandemic. In addition to uncertainty in baseline HCQ PK parameters, it was not clear if disease-related consequences of SARS-CoV-2 infection/COVID-19 would be expected to impact the PK of HCQ and its primary metabolite desethylhydroxychloroquine (DHCQ). To address the question whether SARS-CoV-2 infection/COVID-19 impacted HCQ and DHCQ PK, dried blood spot samples were collected from SARS-CoV-2(-)/(+) participants administered HCQ. When a previously published physiologically based pharmacokinetic (PBPK) model was used to fit the data, the variability in exposure of HCQ and DHCQ was not adequately captured and DHCQ concentrations were overestimated. Improvements to the previous PBPK model were made by incorporating the known range of blood to plasma concentration ratios (B/P) for each compound, adjusting HCQ and DHCQ distribution settings, and optimizing DHCQ clearance. The final PBPK model adequately captured the HCQ and DHCQ concentrations observed in SARS-CoV-2(-)/(+)participants, and incorporating COVID-19-associated changes in cytochrome P450 activity did not further improve model performance for the SARS-CoV-2(+) population., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Hydroxychloroquine (HCQ) has been shown to disrupt autophagy and sensitize cancer cells to radiation and chemotherapeutic agents. However, the optimal delivery method, dose, and tumor concentrations required for these effects are not known. This is in part due to a lack of sensitive and reproducible analytical methods for HCQ quantitation in small animals. As such, we developed and validated a selective and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for simultaneous quantitation of hydroxychloroquine and its metabolites in mouse blood and tissues. The chromatographic separation and detection of analytes were achieved on a reversed phase Thermo Aquasil C 18 (50×4.6mm, 3μ) column, with gradient elution using 0.2% formic acid and 0.1% formic acid in methanol as mobile phase at a flow rate of 0.5mL/min. Simple protein precipitation was utilized for extraction of analytes from the desired matrix. Analytes were separated and quantitated using MS/MS with an electrospray ionization source in positive multiple reaction monitoring (MRM) mode. The MS/MS response was linear over the concentration range from 1 to 2000ng/mL for all analytes with a correlation coefficient (R 2 ) of 0.998 or better. The within- and between-day precision (relative standard deviation, % RSD) and accuracy were within the acceptable limits per FDA guidelines. The validated method was successfully applied to a preclinical pharmacokinetic mouse study involving low volume blood and tissue samples for hydroxychloroquine and metabolites., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Hydroxychloroquine (HCQ) is Food and Drug Administration (FDA)‐approved for malaria, systemic and chronic discoid lupus erythematosus, and rheumatoid arthritis. Because HCQ has a proposed multimodal mechanism of action and a well‐established safety profile, it is often investigated as a repurposed therapeutic for a range of indications. There is a large degree of uncertainty in HCQ pharmacokinetic (PK) parameters which complicates dose selection when investigating its use in new disease states. Complications with HCQ dose selection emerged as multiple clinical trials investigated HCQ as a potential therapeutic in the early stages of the COVID‐19 pandemic. In addition to uncertainty in baseline HCQ PK parameters, it was not clear if disease‐related consequences of SARS‐CoV‐2 infection/COVID‐19 would be expected to impact the PK of HCQ and its primary metabolite desethylhydroxychloroquine (DHCQ). To address the question whether SARS‐CoV‐2 infection/COVID‐19 impacted HCQ and DHCQ PK, dried blood spot samples were collected from SARS‐CoV‐2(−)/(+) participants administered HCQ. When a previously published physiologically based pharmacokinetic (PBPK) model was used to fit the data, the variability in exposure of HCQ and DHCQ was not adequately captured and DHCQ concentrations were overestimated. Improvements to the previous PBPK model were made by incorporating the known range of blood to plasma concentration ratios (B/P) for each compound, adjusting HCQ and DHCQ distribution settings, and optimizing DHCQ clearance. The final PBPK model adequately captured the HCQ and DHCQ concentrations observed in SARS‐CoV‐2(−)/(+)participants, and incorporating COVID‐19‐associated changes in cytochrome P450 activity did not further improve model performance for the SARS‐CoV‐2(+) population. [ABSTRACT FROM AUTHOR]