Physiologically-Based Pharmacokinetics Modeling for Hydroxychloroquine as a Treatment for Malaria and Optimized Dosing Regimens for Different Populations

Abstract

Malaria is a severe parasite infectious disease with high fatality. As one of the approved treatments of this disease, hydroxychloroquine (HCQ) lacks clinical administration guidelines for patients with special health conditions and co-morbidities. This may result in improper dosing for different populations and lead them to suffer from severe side effects. One of the most important toxicities of HCQ overdose is cardiotoxicity. In this study, we built and validated a physiologically based pharmacokinetic modeling (PBPK) model for HCQ. With the full-PBPK model, we predicted the pharmacokinetic (PK) profile for malaria patients without other co-morbidities under the HCQ dosing regimen suggested by Food and Drug Administration (FDA) guidance. The PK profiles for different special populations were also predicted and compared to the normal population. Moreover, we proposed a series of adjusted dosing regimens for different populations with special health conditions and predicted the concentration-time (C-T) curve of the drug plasma concentration in these populations which include the pregnant population, elderly population, RA patients, and renal impairment populations. The recommended special population-dependent dosage regimens can maintain the similar drug levels observed in the virtual healthy population under the original dosing regimen provided by FDA. Last, we developed mathematic formulas for predicting dosage based on a patient’s body measurements and two indexes of renal function (glomerular filtration rate and serum creatine level) for the pediatric and morbidly obese populations. Those formulas can facilitate personalized treatment of this disease. We hope to provide some advice to clinical practice when taking HCQ as a treatment for malaria patients with special health conditions or co-morbidities so that they will not suffer from severe side effects due to higher drug plasma concentration, especially cardiotoxicity.

In-Depth Analysis of Physiologically Based Pharmacokinetic (PBPK) Modeling Utilization in Different Application Fields Using Text Mining Tools

“…The application of PBPK modeling is even wider during the clinical development phase, where it can be applied in numerous areas such as the simulation/prediction of drugs’ PK in different populations, e.g., pediatric [ 13 , 14 , 15 , 16 , 17 ], elderly [ 18 , 19 , 20 , 21 ], pregnant women [ 22 , 23 , 24 ] etc. It can also be used for the prediction of changes in the intrinsic physiological factors, such as organ impairment on a drug’s PK [ 25 , 26 , 27 , 28 ], drug-drug interactions (DDIs) [ 29 , 30 , 31 ], oral drugs absorption and formulation effects on drug absorption and disposition [ 32 , 33 , 34 , 35 ]. This constant increase in the number of publications related to PBPK modeling can be attributed to a variety of factors, including the increased availability of user-friendly PBPK dedicated platforms, which have largely facilitated the use of PBPK modeling tools, even by users with limited modeling experience [ 36 ].…”