Authors: Qigui Li, Mark R. Hickman

Pharmacokinetics and Pharmacodynamics of Antimalarial Drugs Used in Combination Therapy

eBook: US $129 Special Offer (PDF + Printed Copy): US $239
Printed Copy: US $175
Library License: US $516
ISBN: 978-1-68108-055-0 (Print)
ISBN: 978-1-68108-054-3 (Online)
Year of Publication: 2015
DOI: 10.2174/97816810805431150101


Malaria takes a great toll on human health and well-being, particularly in tropical regions including Sub-Saharan Africa, Southeast Asia, Oceania and parts of the Americas. In recent years, some Plasmodium strains have become increasingly resistant to all classes of conventional antimalarial drugs currently in use. Researchers have, therefore, stepped up efforts to revise atimalarial drug policies, develop new drugs, and implement new strategies to combat this disease. In order to prevent widespread resistance, antimalarial combination therapies (ACTs) have been deployed and a World Antimalarial Resistance Network has been established as a means of anitimalarial drug resistance surveillance. Artemisinin-based combination therapies have proven to be useful as a replacement for standard regimens. Currently, these ACTs successfully cure patients suffering from uncomplicated malaria with superior efficacy and lower toxicity, but there remains a huge challenge (high mortality rate) associated with treatment of severe malaria. Studies of drug disposition and drug efficacy (PK/PD evaluations) are essential to understanding why drugs work as antimalarials as they illustrate issues with drug resistance, drug safety and drug toxicity that are critical to finding the appropriate drug dose for patients. This eBook illustrates how currently available combination antimalarial drugs can be optimized for effective malaria treatment. Chapters in this book explain methods to select combination drugs based on PK/PD evaluations followed by methods o reduce drug toxicity based on these evaluations. The book also summarizes efforts that are being made by the research community to improve ACT. It is, therefore, a handy reference for medical professionals and pharmacologists working on antimalarial drugs.


Prior to World War II, Department of Defense efforts to control malaria relied primarily on vector control measures, largely unchanged from those of COL William C. Gorgas in early 20th century Cuba and Panama. With the outbreak of the war, the US government greatly accelerated antimalarial drug research with limited access to quinine and the poor tolerability of atabrine. After the establishment of the Army’s Malaria Drug Development Program, novel antimalarial drugs such as chloroquine, amodiaquine, proguanil, and pyrimethamine were developed. In 1944, the 8-aminoquinolines underwent testing by research teams under contract to the U.S. Army, ultimately resulting in the approval of primaquine as a radical cure for P. vivax malaria in U.S. troops returning from the Korean conflict. Subsequently, with the advent of chloroquine resistance during the Vietnam War, the U.S. Army established a long-term malaria drug research program under the direction of the Division of Experimental Therapeutics at the Walter Reed Army Institute of Research (WRAIR), leading to the FDA approval of mefloquine and halofantrine. With the subsequent evolution of mefloquine resistance and the recognition of its adverse effects, the WRAIR obtained FDA approval of doxycycline for prophylaxis against both P. falciparum and P. vivax malaria. The continued development of drug resistance, most recently against artemisinins as well as piperaquine in Southeast Asia, has renewed urgency for the development of both new ways to use existing drugs in addition to the development of new drug candidates.

The WRAIR’s Dr. Qigui Li and Dr. Mark Hickman continue this tradition and have provided numerous insights in the pharmacology of antimalarial drugs for more than two decades, to include seminal work on the pharmacology of artemisinins. With the emergence of multi-drug resistant malaria, and in particular resistance to artemisinins, the cornerstone of current malaria treatment with artemisinin combination therapy (ACT) is now at risk. It is now time for the malaria field to apply the lessons of HIV and TB, where multiple drug therapy to avoid the development of drug resistance is standard practice. To this end, understanding the complex pharmacokinetic-pharmacodynamic relationships of current and future antimalarials used in combination therapy will be critical to curbing further resistance and continued progress towards malaria control and elimination. This monograph provides a detailed overview of these challenges and the experimental methods and tools needed to accelerate the clinical development of new antimalarial combination therapies.

Robert M. Paris
Colonel, Medical Corps
Director, Military Malaria Research Program
Walter Reed Army Institute of Research
Silver Spring, MD