Abstract
We use a mechanistic lung model to demonstrate that accumulation of chloroquine (CQ), hydroxychloroquine (HCQ), and azithromycin (AZ) in the lungs is sensitive to changes in lung pH, a parameter that can be affected in patients with coronavirus disease 2019 (COVID-19). A reduction in pH from 6.7 to 6 in the lungs, as observed in respiratory disease, led to 20-fold, 4.0-fold, and 2.7-fold increases in lung exposure of CQ, HCQ, and AZ, respectively. Simulations indicated that the relatively high concentrations of CQ and HCQ in lung tissue were sustained long after administration of the drugs had stopped. Patients with COVID-19 often present with kidney failure. Our simulations indicate that renal impairment (plus lung pH reduction) caused 30-fold, 8.0-fold, and 3.4-fold increases in lung exposures for CQ, HCQ, and AZ, respectively, with relatively small accompanying increases (20 to 30%) in systemic exposure. Although a number of different dosage regimens were assessed, the purpose of our study was not to provide recommendations for a dosing strategy, but to demonstrate the utility of a physiologically-based pharmacokinetic modeling approach to estimate lung concentrations. This, used in conjunction with robust in vitro and clini...Continue Reading
References
Jan 1, 1991·Biochemical Pharmacology·V Ferrari, D J Cutler
Nov 1, 1969·The Journal of Clinical Investigation·R M Effros, F P Chinard
Nov 1, 1982·The Journal of Pharmacy and Pharmacology·S A Adelusi, L A Salako
Jan 1, 1982·General Pharmacology·S A Adelusi, L A Salako
Dec 1, 1995·Antimicrobial Agents and Chemotherapy·R BohteP J van den Broek
Jul 13, 2002·Arthritis and Rheumatism·Tino MunsterDaniel E Furst
Nov 26, 2003·Respiratory Medicine·Christian GessnerHubert Wirtz
Apr 29, 2005·Journal of Pharmaceutical Sciences·Trudy RodgersMalcolm Rowland
May 2, 2006·Proteomics·Jia WanFuchu He
Nov 9, 2006·The Journal of Membrane Biology·Horst Fischer, Jonathan H Widdicombe
May 2, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·David Hallifax, J Brian Houston
Sep 12, 2007·Antimicrobial Agents and Chemotherapy·Sungmin Kiem, Jerome J Schentag
Feb 7, 2008·The Journal of Antimicrobial Chemotherapy·M LucchiM Del Tacca
Feb 23, 2010·Clinical Pharmacokinetics·Trevor N JohnsonAmin Rostami-Hodjegan
Nov 26, 2011·Expert Review of Clinical Pharmacology·Karen Rowland YeoAmin Rostami-Hodjegan
Jan 5, 2013·The Journal of Infection·Diego ViasusJordi Carratalà
Jul 25, 2013·Clinical Pharmacokinetics·M JameiK Rowland-Yeo
Aug 16, 2013·CPT: Pharmacometrics & Systems Pharmacology·Hm Jones, K Rowland-Yeo
Jan 1, 2014·International Journal of Clinical Practice·Y M WiK R Peck
Nov 5, 2015·CPT: Pharmacometrics & Systems Pharmacology·L GaohuaI Gardner
Feb 11, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Trevor N JohnsonKaren Rowland-Yeo
Feb 14, 2018·The Journal of Pharmacology and Experimental Therapeutics·Keagan P CollinsDaniel L Gustafson
Mar 10, 2018·Journal of Pharmacokinetics and Pharmacodynamics·Sebastian PolakDebra Hanna
Sep 19, 2018·Pharmaceutical Research·Kasiram KatneniSusan A Charman
Jan 15, 2020·Cell Discovery·Kuo LiuBin Zhou
Feb 6, 2020·Cell Research·Manli WangGengfu Xiao
Feb 20, 2020·Bioscience Trends·Jianjun GaoXu Yang
Apr 3, 2020·Intensive Care Medicine·Xiu-Wu PanXin-Gang Cui
Apr 6, 2020·Kidney International·Yichun ChengGang Xu
Apr 9, 2020·Clinical and Translational Science·Samuel L M Arnold, Frederick Buckner
May 4, 2020·Mayo Clinic Proceedings·John R GiudicessiMichael J Ackerman
Jan 7, 2021·Cell Discovery·Kuo LiuBin Zhou
Citations
Jul 3, 2020·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Miao ZhangDongyang Liu
Aug 7, 2020·American Journal of Physiology. Endocrinology and Metabolism·Emile LevySchohraya Spahis
Sep 7, 2020·Naunyn-Schmiedeberg's Archives of Pharmacology·Yanxiang ZangYue Li
Dec 31, 2020·Drug Research·Nasir IdkaidekNour Obeidat
Nov 24, 2020·British Journal of Clinical Pharmacology·Venkatesh Pilla ReddyAmin Rastomi-Hodjegan
Feb 2, 2021·Frontiers in Pharmacology·Qi LiuChunli Song
Feb 9, 2021·Clinical Pharmacology and Therapeutics·Craig R RaynerKaren Rowland-Yeo
Mar 2, 2021·Frontiers in Pharmacology·Miao ZhangDongyang Liu
Jan 7, 2021·Clinical and Translational Science·James M Gallo
Feb 20, 2021·Clinical and Translational Science·Hualou LiangHongbin Wang
Jan 5, 2022·Clinical Pharmacokinetics·Emily N Drwiega, Keith A Rodvold