Evaluating the pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative PCR

Marquart, Louise, Baker, Mark, O'Rourke, Peter and McCarthy, James S. (2015) Evaluating the pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative PCR. Antimicrobial Agents and Chemotherapy, 59 7: 4249-4259. doi:10.1128/AAC.04942-14

Author Marquart, Louise
Baker, Mark
O'Rourke, Peter
McCarthy, James S.
Title Evaluating the pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative PCR
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 1098-6596
Publication date 2015-07-01
Year available 2015
Sub-type Article (original research)
DOI 10.1128/AAC.04942-14
Open Access Status DOI
Volume 59
Issue 7
Start page 4249
End page 4259
Total pages 11
Place of publication Washington, DC United States
Publisher American Society for Microbiology
Collection year 2016
Language eng
Abstract The ongoing development of new antimalarial drugs and the increasing use of controlled human malaria infection (CHMI) studies to investigate their activity in early-stage clinical trials require the development of methods to analyze their pharmacodynamic effect. This is especially so for studies where quantitative PCR (qPCR) is becoming the preferred method for assessing parasite clearance as the study endpoint. We report the development and validation of an analytic approach for qPCR-determined parasite clearance data. First, in a clinical trial with the licensed antimalarial combination sulfadoxine-pyrimethamine (S/P), qPCR data were collected from 12 subjects and used to determine qPCR replicate variability and to identify outliers. Then, an iterative analytic approach based on modeling the log-linear decay of parasitemia following drug treatment was developed to determine the parasite reduction ratio (PRR) and parasite clearance half-life, both measures of parasite clearance. This analytic approach was then validated with data from 8 subjects enrolled in a second study with the licensed antimalarial drug mefloquine. By this method, the PRR and parasite clearance half-lives for S/P and Mefloquine were determined to be 38,878 (95% confidence interval [95% CI], 17,396 to 86,889) at 3.15 (95% CI, 2.93 to 3.41) days and 157 (95% CI, 130 to 189) at 6.58 (95% CI, 6.35 to 6.83) days for the respective studies. No serious adverse events occurred in the two trials, and pharmacokinetic values were within expected ranges for sulfadoxine and pyrimethamine. The robust statistical method that we have developed to analyze qPCR-derived pharmacodynamic data from CHMI studies will facilitate the assessment of the activity of a range of experimental antimalarial drugs now entering clinical trials. (This trial was registered with the Australian New Zealand Clinical Trials Registry under registration numbers ACTRN12611001203943 and ACTRN12612000323820.)
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
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