Foreword

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 20^th 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.