Improving Pharmacokinetic-Pharmacodynamic Modeling to Investigate Anti-Infective Chemotherapy with Application to the Current Generation of Antimalarial Drugs

Abstract

Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a single drug is used, it acts only in its unconverted form, and that oral drugs are instantaneously absorbed across the gut wall to their site of action. For drugs with short half-lives, this absorption period accounts for a significant period of their time in the body. Treatment of infectious diseases often uses combination therapies, so we refined and substantially extended the PK/PD methodologies to incorporate (i) time lags and drug concentration profiles resulting from absorption across the gut wall and, if required, conversion to another active form; (ii) multiple drugs within a treatment combination; (iii) differing modes of action of drugs in the combination: additive, synergistic, antagonistic; (iv) drugs converted to an active metabolite with a similar mode of action. This methodology was applied to a case study of two first-line malaria treatments based on artemisinin combination therapies (ACTs, artemether-lumefantrine and artesunate-mefloquine) where the likelihood of increased artemisinin tolerance/resistance has led to speculation on their continued long-term effectiveness. We note previous estimates of artemisinin kill rate were underestimated by a factor of seven, both the unconverted and converted form of the artemisinins kill parasites and the extended PK/PD methodology produced results consistent with field observations. The simulations predict that a potentially rapid decline in ACT effectiveness is likely to occur as artemisinin resistance spreads, emphasising the importance of containing the spread of artemisinin resistance before it results in widespread drug failure. We found that PK/PD data is generally very poorly reported in the malaria literature, severely reducing its value for subsequent re-application, and we make specific recommendations to improve this situation.

Author Summary

Pharmacokinetic-pharmacodynamic (PK/PD) models of infectious diseases provide vital insights into the effectiveness of drug treatments (including the optimal dosage level, frequency and duration) by explicitly relating drug concentration after treatment to a pathogen kill rate, and ultimately the models describe whether an infection is likely to be cleared. Furthermore, they can address issues such as poor patient compliance and the spread of drug resistance that are too expensive and/or unethical to determine in the field. Despite their potential, the methodologies used in previous PK/PD models have been based upon the assumptions that only one drug is used in treatment, that the drug is immediately available in its active form at the site of action, and that the parent drug is not further converted to active metabolites. These assumptions severely limit the application of such models. We therefore extend the methodology to remove these assumptions and use this model to investigate two first-line treatments of malaria. The model accurately replicated field data and was then used to predict the impact of increasing drug tolerance and resistance on treatment outcome. We identified key PK/PD data that can, and should, be measured and reported in future field studies to maximise the predictive ability of mathematical models.