Impact of Disease on Plasma and Lung Exposure of Chloroquine, Hydroxychloroquine and Azithromycin: Application of PBPK Modeling

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 clinical data, can help in the assessment of COVID-19 therapeutics going forward.

Effect of Combination Therapy of Hydroxychloroquine and Azithromycin on Mortality in Patients With COVID‐19

“…21 Anyway, despite its limitations, PBPK modeling is one of the most valuable approaches to estimate tissue-specific drug concentrations. 22 Because of the risk of arrhythmias, the dosage used in many patients was the one approved in malaria and autoimmune diseases. Similarly, in our study, HCQ has been administered with the schedule dose 200 mg t.i.d.…”

Time-Dependent Distribution of Hydroxychloroquine in Cynomolgus Macaques Using Population Pharmacokinetic Modeling Method

“…Considering that it is impossible to carry out biodistribution research in clinical studies, the additional pharmacokinetics experiments in animals are necessary to understand its exposure in tissues. It is especially helpful when the PBPK modeling strategy was recognized to be supportive but need more validated data, such as lung tissue or lung lining fluid concentrations ( Rowland Yeo et al, 2020b ; Maharaj et al, 2020 ). It has been reported the elimination rate of the drug was rapid in mice and its tissue distribution kinetics data are very different from those of human tissue distribution ( Chhonker et al, 2018 ).…”

“…Since the HCQ concentration in the lung tissue is higher than that in the plasma or blood, we could confirm that it might be effective in the lung. In addition, there has been simulated that lung pH reduction from 6.7 to 6 in COVID-19 patients could cause 4.0-fold increases in lung exposure of HCQ, indicating that higher concentrations of HCQ in patients’ lung tissue with COVID-19 were sustained for a longer period after administration ( Rowland Yeo et al, 2020a ). Many other weakly basic drugs have also been demonstrated to accumulate in lysosomes ( Ohkuma and Poole, 1981 ; Duvvuri and Krise, 2005 ).…”

Pharmacokinetics under the COVID‐19 storm

“…The permeability-limited lung model is particularly suitable for modeling and simulating drug disposition within the lung mass compartment and epithelial lining fluid compartment, which are the target sites for anti-viral effects. The methodology of simulating these concentrations has been applied previously to tuberculosis [22], and recently for three COVID-19 repurposed drugs [25]. In this work, lung epithelial lining fluid concentrations were simulated using geriatric population within PBPK simulator with age range from 65 to 95 years old, with 50% female subjects.…”