Pharmacokinetics and Pharmacodynamics of Antimalarial Drugs Used in Combination Therapy


by

Qigui Li, Mark R. Hickman

DOI: 10.2174/97816810805431150101
eISBN: 978-1-68108-054-3, 2015
ISBN: 978-1-68108-055-0



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Malaria takes a great toll on human health and well-being, particularly in tropical regions including Sub-Saharan Africa, Southeast As...[view complete introduction]

Table of Contents

Foreword

- Pp. i

Robert M. Paris

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Preface

- Pp. iii

Qigui Li and Mark R. Hickman

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Acknowledgements

- Pp. v

Qigui Li and Mark R. Hickman

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Introduction

- Pp. vii-xi (5)

Qigui Li and Mark R. Hickman

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Current Issues in Antimalarial Drug Resistance

- Pp. 3-30 (28)

Qigui Li and Mark R. Hickman

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Currently Used Antimalarial Drug Combination Therapies

- Pp. 31-62 (32)

Qigui Li and Mark R. Hickman

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Clinical Significance of Antimalarial Combinations

- Pp. 63-94 (32)

Qigui Li and Mark R. Hickman

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Pharmacokinetics (PK) and Pharmacodynamics (PD) of Antimalarial Drugs

- Pp. 95-148 (54)

Qigui Li and Mark R. Hickman

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PK/PD Evaluations of Antimalarial Drugs and Their Combinations

- Pp. 149-218 (70)

Qigui Li and Mark R. Hickman

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Use of PK/PD Assessments for Selecting the Best ACTs

- Pp. 219-265 (47)

Qigui Li and Mark R. Hickman

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PK/PD Modeling of Antimalarial Drug Combinations

- Pp. 267-339 (73)

Qigui Li and Mark R. Hickman

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Population PK/PD of Antimalarial Combinations

- Pp. 341-394 (54)

Qigui Li and Mark R. Hickman

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Combination Therapy to Avoid Antimalarial Drug Toxicity

- Pp. 395-440 (46)

Qigui Li and Mark R. Hickman

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Efforts to Improve Antimalarial Combination Therapy

- Pp. 441-482 (42)

Qigui Li and Mark R. Hickman

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Conclusion

- Pp. 483-485 (3)

Qigui Li and Mark R. Hickman

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References

- Pp. 487-515 (29)

Qigui Li and Mark R. Hickman

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Subject Index

- Pp. 517-529 (13)

Qigui Li and Mark R. Hickman

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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 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
USA


Preface

Antimalarial drug discovery and development is a lengthy process, and given the lack of resources available for development of antimalarial drugs, discovery and development of antimalarials as single entities or combinations can take much longer than development of drugs for treatment of diseases that affect patients from first world countries. Given the limited resources for development of drugs to treat a disease not found in first world countries, drug development processes must be as efficient as possible, and expensive clinical studies must be well-planned and geared toward yielding the maximum amount of information to get the best “bang for the buck”.

Safety, comparative efficacy, and dose determination studies are all best conducted by thorough consideration of pharmacokinetic and pharmacodynamic variables that impact on how quickly all of the relevant questions can be answered to develop a drug for clinical use in man. Development of drugs to the standards to regulatory standards set by first world regulatory agencies like the FDA or EMA, in particular, imposes a high threshold that must be met with limited funds.

Well-planned clinical trials of comparative efficacy that have a sound foundation of safety and PK studies are more likely to be successful than clinical trials developed with minimal PK and safety data. The use of physiologic based pharmacokinetic/pharmacodynamic (PB PK/PD) studies, innovative population PK/PD studies, factorial study designs, and drug resistance models are all modern tools that can provide a faster path forward than simple empirical trial designs that do not utilize these techniques. The issue of malaria drug resistance in the modern era imposes yet another burden on drug developers as development of an antimalarial drug for treatment of a disease, which is difficult to begin with due to limited funds, is not a “one and done” activity. Every antimalarial drug developed to date eventually has come up against problems with drug resistance, and all of these drugs come with a limitation on their use in terms of the length of time on market until clinical resistance is encountered.

Drug combinations offer the potential to extend the life of existing antimalarial drugs, and drug combinations also have the potential to limit the development of drug resistance through disease treatment with two or more drugs whose different or synergistic mechanisms of action are mutually protective. The development and deployment of artemisinin combination therapies (ACTs), in particular, over the last decade has revolutionized malaria treatment in endemic areas. While ACTs have become the wonder drug antimalarial combination treatment of the new millennia, all ACTs on market will eventually run into drug resistance problems that preclude their use in various endemic areas. Accordingly, new and novel antimalarial drug combinations must be innovated to try and stay ahead of the growing tide of malaria drug resistance. Fundamentally, this is a contest between a parasite’s ability to mutate and man’s ability to innovate.

We believe that proper application of new, modern PK/PD tools can radically improve clinical trial design and execution which maximizes the “bang for the buck” and speeds the development of new antimalarial drug combinations.

Qigui Li & Mark R. Hickman
Walter Reed Army Institute of Research
USA
E-mail: qigui.li.civ@mail.mil

List of Contributors

Author(s):
Qigui Li
Walter Reed Army Institute of Research
USA


Mark R. Hickman
Walter Reed Army Institute of Research
USA




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