Track: Clinical Pharmacology - Chemical - Modeling and Simulation - Physiologically Based Pharmacokinetics (PBPK) Model
Category: Late Breaking Poster Abstract
Physiologically-Based Pharmacokinetic Modeling of Chloroquine in Rat and Man
Purpose: A PBPK model for rat was developed for chloroquine (CQ) describing the involvement of diverse tissues in its pharmacokinetics, particularly the role of lysosomal sequestration of this highly ionized weak base. With scaling, the model was extended to disposition of CQ in man. The established models may be applicable to other highly ionized lysosomotropic cations. Methods: Published CQ concentration versus time data for plasma and tissues of rats , and plasma CQ concentration versus time for man  were digitized. Figure 1 shows the proposed PBPK model structure for CQ. The PBPK model consisted of red blood cells (RBC), plasma, liver, kidney, lung, spleen, heart, brain, muscle, skin, eye and a lumped remainder space. Nonlinear partition coefficients (Kp) and permeability coefficients (PS) were needed capture the variable tissue to plasma concentration ratios and slow distribution to tissues. Intrinsic hepatic and renal clearances and parameters for Kp were estimated. A lysosome-based sub-model based on mass balance was used to calculate lysosome, cytosol, and phospholipid-bound concentrations of CQ in tissues over time based on fitted plasma and interstitial concentrations, literature-based pH and pKa values, and the Henderson-Hasselbalch equation . The RBC to plasma ratio was assumed to reflect phospholipid partitioning of CQ. The 5.0 to 7.0 pH differential between lysosomes and cytosol was applied as the initial condition to assess sequestration of CQ in lysosomes. Human data were fitted by estimating clearances and skin Kp parameters and sharing other parameters with rat. All fittings and simulations were implemented using ADAPT 5 using maximum likelihood estimation. Results: Figure 2 shows the measured CQ concentrations in plasma and tissues for rat  and plasma concentrations for man  along with the PBPK model-fitted time-course profiles. Tissue to plasma CQ ratios in rat at 50-hr after dosing were highest in lung, kidney, liver, and spleen (183-304) and lower in heart, muscle, brain, eye, and skin (10-67), reflecting extensive tissue distribution of CQ. The RBC to plasma ratio of 11.6 was assumed to indicate cell membrane phospholipid partitioning. The CQ tissue concentrations ranked: lysosome > > phospholipid > interstitial = cytosol with extensive lysosome sequestration occurring and changing over time (Figure 3). The man to rat Vss ratio of 7 was used to scale tissue partitioning and application of known 30% hepatic and 70% renal clearance allowed excellent fitting of a range of oral doses (150-600 mg) of CQ with a 50-day half-life in man. Conclusion:
The preliminary PBPK model captures the plasma, RBC, and tissue PK of CQ well for rat.
The rat PBPK model is easily applied to man by adjusting the physiologic parameters and clearances with most PK parameters shared between man and rat.
The lysosome sub-model uses mass balance and basic physiologic and physicochemical principles to predict CQ concentrations in cytosol, phospholipids and lysosomes with extremely high concentrations of CQ expected in lysosomes.
The observed tissue compositional concentration profiles of CQ have relevance to treatment of viral and malaria infections.
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