PK/PD indices carry over, with caveats. Dose-fractionation studies in murine and humanized mouse models identify the governing index [1,2], but these analyses usually work with total rather than unbound concentrations, since the compounds are often bound above 99% [3]. Which index wins is compound-specific, not a class property.
Sustained exposure beats peak. For slowly eliminated antimalarials the driver is exposure maintained across a full asexual cycle [3,4].
Mechanistic extrapolation. PBPK is the established modality, used to extrapolate antimalarial exposure into groups trials rarely reach, young children, pregnancy and breastmilk, and to select doses there [5,6].
Combination therapy. Combination therapy pairs a short-acting drug with a long-acting partner [7], and the partner’s terminal tail is itself a resistance selection pressure [8].
References
[1]
Lakshminarayana SB et al. Pharmacokinetic-pharmacodynamic analysis of spiroindolone analogs and
KAE609 in a murine malaria model. Antimicrobial Agents and Chemotherapy 2015;59:1200–10.
https://doi.org/10.1128/AAC.03274-14.
[2]
Gibhard L et al. Dose-fractionation studies of a
Plasmodium phosphatidylinositol 4-kinase inhibitor in a humanized mouse model of malaria. Antimicrobial Agents and Chemotherapy 2024;68:e00842–24.
https://doi.org/10.1128/aac.00842-24.
[3]
White NJ. Pharmacokinetic and pharmacodynamic considerations in antimalarial dose optimization. Antimicrobial Agents and Chemotherapy 2013;57:5792–807.
https://doi.org/10.1128/AAC.00287-13.
[4]
Pica K et al. Pharmacokinetics and pharmacodynamics of antimalarial agents: Optimizing combination therapies to overcome resistance mechanisms. The Journal of Clinical Pharmacology 2026;66:e70291.
https://doi.org/10.1002/jcph.70291.
[5]
Johnson TN, Cleary Y, Parrott N, Reigner B, Smith JR, Toovey S. Development of a physiologically based pharmacokinetic model for mefloquine and its application alongside a clinical effectiveness model to select an optimal dose for prevention of malaria in young
Caucasian children. British Journal of Clinical Pharmacology 2019;85:100–13.
https://doi.org/10.1111/bcp.13764.
[6]
Almond LM, Abduljalil K, Pansari A, Kusmider B, Jones HM, Rowland Yeo K, et al.
PBPK-led assessment of antimalarial drug concentrations in breastmilk: A strategy for optimal use of prediction methods to guide decision making in an understudied population. CPT: Pharmacometrics & Systems Pharmacology 2025;14:738–50.
https://doi.org/10.1002/psp4.13311.
[7]
Hastings IM, Hodel EM. Pharmacological considerations in the design of anti-malarial drug combination therapies — is matching half-lives enough? Malaria Journal 2014;13:62.
https://doi.org/10.1186/1475-2875-13-62.
[8]
Stepniewska K, White NJ. Pharmacokinetic determinants of the window of selection for antimalarial drug resistance. Antimicrobial Agents and Chemotherapy 2008;52:1589–96.
https://doi.org/10.1128/aac.00903-07.