Pharmacological considerations in the design of anti-malarial drug combination therapies - is matching half-lives enough?

Hastings, Ian ORCID: https://orcid.org/0000-0002-1332-742X and Hodel, Eva Maria ORCID: https://orcid.org/0000-0001-5821-1685 (2014) 'Pharmacological considerations in the design of anti-malarial drug combination therapies - is matching half-lives enough?'. Malaria Journal, Vol 13, Issue 1, e62.

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Abstract

Anti-malarial drugs are now mainly deployed as combination therapy (CT), primarily as a mechanism to prevent or slow the spread of resistance. This strategy is justified by mathematical arguments that generally assume that drug 'resistance' is a binary all-or-nothing genetic trait. Herein, a pharmacological, rather than a purely genetic, approach is used to investigate resistance and it is argued that this provides additional insight into the design principles of anti-malarial CTs. It is usually suggested that half-lives of constituent drugs in a CT be matched: it appears more important that their post-treatment anti-malarial activity profiles be matched and strategies identified that may achieve this. In particular, the considerable variation in pharmacological parameters noted in both human and parasites populations may compromise this matching and it is, therefore, essential to accurately quantify the population pharmacokinetics of the drugs in the CTs. Increasing drug dosages will likely follow a law of diminishing returns in efficacy, i.e. a certain increase in dose will not necessarily lead to the same percent increase in efficacy. This may allow individual drug dosages to be lowered without proportional decrease in efficacy, reducing any potential toxicity, and allowing the other drug(s) in the CT to compensate for this reduced dosage; this is a dangerous strategy which is discussed further. Finally, pharmacokinetic and pharmacodynamic drug interactions and the role of resistance mechanisms are discussed. This approach generated an idealized target product profile (TPP) for anti-malarial CTs. There is a restricted pipeline of anti-malarial drugs but awareness of pharmacological design principles during the development stages could optimize CT design pre-deployment. This may help prevent changes in drug dosages and/or regimen that have previously occurred post-deployment in most current anti-malarial drugs.

Item Type:	Article
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials WA Public Health > Preventive Medicine > WA 110 Prevention and control of communicable diseases. Transmission of infectious diseases WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1186/1475-2875-13-62
Depositing User:	Mary Creegan
Date Deposited:	08 Aug 2014 09:06
Last Modified:	19 Sep 2019 11:29
URI:	https://archive.lstmed.ac.uk/id/eprint/3835

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