Abstract
BackgroundStandard treatment for severe malaria is with artesunate; patient survival in the 24 hours immediately posttreatment is the key objective. Clinical trials use clearance rates of circulating parasites as their clinical outcome, but the pathology of severe malaria is attributed primarily to noncirculating, sequestered, parasites, so there is a disconnect between existing clinical metrics and objectives.MethodsWe extend existing pharmacokinetic/pharmacodynamic modeling methods to simulate the treatment of 10000 patients with severe malaria and track the pathology caused by sequestered parasites.ResultsOur model recovered the clinical outcomes of existing studies (based on circulating parasites) and showed a “simplified” artesunate regimen was noninferior to the existing World Health Organization regimen across the patient population but resulted in worse outcomes in a subgroup of patients with infections clustered in early stages of the parasite life cycle. This same group of patients were extremely vulnerable to resistance emerging in parasite early ring stages.ConclusionsWe quantify patient outcomes in a manner appropriate for severe malaria with a flexible framework that allows future researchers to implement their beliefs about underlying pathology. We highlight with some urgency the threat posed to treatment of severe malaria by artemisinin resistance in parasite early ring stages.
Highlights
Standard treatment for severe malaria is with artesunate; patient survival in the 24 hours immediately post-treatment is the key objective
As will be discussed later, there are no clinical estimates of this ‘recovery rate’ so our strategy was to quantify the impact of dosing regimen and artemisinin resistance across a range of values of recovery rate to test whether our results were dependent on assumed values for recovery rate
Ratios of outcome metrics are calculated as simplified regimens scaled by standard regimen and as resistant parasites scaled by sensitive parasites
Summary
We utilized a computer-based PK/PD model to track changes in the number of sequestered iRBCs following drug administration. The model was implemented in the statistical programming software. R [23] version 3.4.1. P. falciparum parasites undergo a 48-hour developmental cycle in human erythrocytes with two main implications for pathology and treatment. Parasites initially circulate freely in blood vessels but sequester (i.e. bind to capillaries) at mature stages of their intraerythrocytic cycle. Parasites differ in their sensitivity to drugs over the course of this 48- hour cycle. As previously described [22], we separated the parasite population within a patient into 48 ‘age-bins’
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
