Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development

Abstract

emerging drug resistance and high-attrition rates in early and late stage drug development necessitate accelerated development of antimalarial compounds. However, systematic and meaningful translation of drug efficacy and host-parasite dynamics between preclinical testing stages is missing. We developed an ensemble of mathematical within-host parasite growth and antimalarial action models, fitted to extensive data from four antimalarials with different modes of action, to assess host-parasite interactions in two preclinical drug testing systems of murine parasite P. berghei in mice, and human parasite P. falciparum in immune-deficient mice. We find properties of the host-parasite system, namely resource availability, parasite maturation and virulence, drive P. berghei dynamics and drug efficacy, whereas experimental constraints primarily influence P. falciparum infection and drug efficacy. Furthermore, uninvestigated parasite behavior such as dormancy influences parasite recrudescence following non-curative treatment and requires further investigation. Taken together, host-parasite interactions should be considered for meaningful translation of pharmacodynamic properties between murine systems and for predicting human efficacious treatment.

Parasite-Host Dynamics throughout Antimalarial Drug Development Stages Complicate the Translation of Parasite Clearance

“…For MMV048, we captured the parasite clearance data after treatment by including a delayed parasite clearance of parasites damaged or killed by the drug, modelled by the clearance rate of dead parasites Cl Y , in both murine hosts (Table S5-clearance PD model selection: Cl Y range of 0.036 to 0.041 (1/h) in P. berghei-NMRI and Cl Y range of 0.068 to 0.071 (1/h) in P. falciparum-SCID infection over all mechanistic parasite growth models). In contrast, for OZ439, we observed a delayed drug effect through a turnover (Table S5-turnover PD model selection: k R range of 0.013-0.06 (1/h) in P. berghei-NMRI and k R range of 0.013-0.016 (1/h) in P. falciparum-SCID infection over all mechanistic parasite growth models) (15). In both murine experimental systems, we found that assumptions on parasite-host dynamics result in differing estimates of parasite clearance times therefore influencing the evaluation of new compounds (see Fig.…”

“…Through extensive simulation of these models and comparison with data for several drugs, we found that the experimental systems and differences between the two murine malaria infections had appreciable effects on measured drug efficacy and treatment outcomes. More specifically, we found drug efficacy is influenced by host-parasite dynamics in P. berghei-NMRI mouse infection where resource limitation is caused by aggressive parasite growth, namely limitations of red blood cells (RBC) (15). In P. falciparum-SCID mouse infection, we found continued injections of human RBCs has a noticeable impact on subsequent clearance patterns of uninfected and infected RBCs.…”

“…In the two murine systems, several experimental and parasite-host traits were examined by including them in a suite of models (further details in Methods and Table S5) (15). From an experimental perspective, data availability and experimental design differ between the two murine infection systems.…”

“…We additionally identified mechanisms of observed recrudescence patterns after non-curative treatment that are not discernable from the experimental data nor captured by current modelling approaches of antimalarial drugs. These unknown mechanisms may include altered parasite maturation or dormancy and affect experimental measures of cure, thus limiting interpretations of curative dose for a particular drug (15).…”

Leveraging Computational Modeling to Understand Infectious Diseases

“…Within-host models of host-parasite interactions paired with pharmacokinetic and pharmacodynamic (PK/PD) models have also been used to predict the mechanisms of action and efficacy of various antimalarial therapies [ 43 , 46 – 48 ]. In a recent clinical trial, modeling the effects of the novel antimalarial drug SJ733 predicted that this compound induces rapid parasite clearance and two-staged efficacy, with maximal results following recirculation of the drug [ 43 ].…”