Modulation of Triple Artemisinin-Based Combination Therapy Pharmacodynamics by Plasmodium falciparum Genotype

Megan R. Ansbro; Zina Itkin; Lu Chen; Gergely Zahoranszky-Kohalmi; Chanaki Amaratunga; Olivo Miotto; Tyler Peryea; Charlotte V. Hobbs; Seila Suon; Juliana M. Sá; Arjen M. Dondorp; Rob W. van der Pluijm; Thomas E. Wellems; Anton Simeonov; Richard T. Eastman

doi:https://doi.org/10.1021/acsptsci.0c00110

Modulation of Triple Artemisinin-Based Combination Therapy Pharmacodynamics by Plasmodium falciparum Genotype

Megan R. Ansbro, Zina Itkin, Lu Chen, Gergely Zahoranszky-Kohalmi, Chanaki Amaratunga, Olivo Miotto, Tyler Peryea, Charlotte V. Hobbs, Seila Suon, Juliana M. Sá, Arjen M. Dondorp, Rob W. van der Pluijm, Thomas E. Wellems, Anton Simeonov, Richard T. Eastman

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Abstract

The first-line treatments for uncomplicated Plasmodium falciparum malaria are artemisinin-based combination therapies (ACTs), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread of P. falciparum with decreased susceptibility to artemisinin and partner drugs presents a significant challenge to malaria control efforts. To stem the spread of drug resistant parasites, novel chemotherapeutic strategies are being evaluated, including the implementation of triple artemisinin-based combination therapies (TACTs). Currently, there is limited knowledge on the pharmacodynamic and pharmacogenetic interactions of proposed TACT drug combinations. To evaluate these interactions, we established an in vitro high-throughput process for measuring the drug concentration-response to three distinct antimalarial drugs present in a TACT. Sixteen different TACT combinations were screened against 15 parasite lines from Cambodia, with a focus on parasites with differential susceptibilities to piperaquine and artemisinins. Analysis revealed drug-drug interactions unique to specific genetic backgrounds, including antagonism between piperaquine and pyronaridine associated with gene amplification of plasmepsin II/III, two aspartic proteases that localize to the parasite digestive vacuole. From this initial study, we identified parasite genotypes with decreased susceptibility to specific TACTs, as well as potential TACTs that display antagonism in a genotype-dependent manner. Our assay and analysis platform can be further leveraged to inform drug implementation decisions and evaluate next-generation TACTs.

Original language	English
Pages (from-to)	1144-1157
Number of pages	14
Journal	ACS Pharmacology and Translational Science
Volume	3
Issue number	6
Early online date	2020
DOIs	https://doi.org/10.1021/acsptsci.0c00110
Publication status	Published - 11 Dec 2020

Keywords

Plasmodium
antimalarial
malaria
pharmacodynamics
pharmacogenetics
triple-drug combination

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https://doi.org/10.1021/acsptsci.0c00110

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Ansbro, M. R., Itkin, Z., Chen, L., Zahoranszky-Kohalmi, G., Amaratunga, C., Miotto, O., Peryea, T., Hobbs, C. V., Suon, S., Sá, J. M., Dondorp, A. M., van der Pluijm, R. W., Wellems, T. E., Simeonov, A., & Eastman, R. T. (2020). Modulation of Triple Artemisinin-Based Combination Therapy Pharmacodynamics by Plasmodium falciparum Genotype. ACS Pharmacology and Translational Science, 3(6), 1144-1157. https://doi.org/10.1021/acsptsci.0c00110

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title = "Modulation of Triple Artemisinin-Based Combination Therapy Pharmacodynamics by Plasmodium falciparum Genotype",

abstract = "The first-line treatments for uncomplicated Plasmodium falciparum malaria are artemisinin-based combination therapies (ACTs), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread of P. falciparum with decreased susceptibility to artemisinin and partner drugs presents a significant challenge to malaria control efforts. To stem the spread of drug resistant parasites, novel chemotherapeutic strategies are being evaluated, including the implementation of triple artemisinin-based combination therapies (TACTs). Currently, there is limited knowledge on the pharmacodynamic and pharmacogenetic interactions of proposed TACT drug combinations. To evaluate these interactions, we established an in vitro high-throughput process for measuring the drug concentration-response to three distinct antimalarial drugs present in a TACT. Sixteen different TACT combinations were screened against 15 parasite lines from Cambodia, with a focus on parasites with differential susceptibilities to piperaquine and artemisinins. Analysis revealed drug-drug interactions unique to specific genetic backgrounds, including antagonism between piperaquine and pyronaridine associated with gene amplification of plasmepsin II/III, two aspartic proteases that localize to the parasite digestive vacuole. From this initial study, we identified parasite genotypes with decreased susceptibility to specific TACTs, as well as potential TACTs that display antagonism in a genotype-dependent manner. Our assay and analysis platform can be further leveraged to inform drug implementation decisions and evaluate next-generation TACTs.",

keywords = "Plasmodium, antimalarial, malaria, pharmacodynamics, pharmacogenetics, triple-drug combination",

author = "Ansbro, {Megan R.} and Zina Itkin and Lu Chen and Gergely Zahoranszky-Kohalmi and Chanaki Amaratunga and Olivo Miotto and Tyler Peryea and Hobbs, {Charlotte V.} and Seila Suon and S{\'a}, {Juliana M.} and Dondorp, {Arjen M.} and {van der Pluijm}, {Rob W.} and Wellems, {Thomas E.} and Anton Simeonov and Eastman, {Richard T.}",

year = "2020",

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doi = "https://doi.org/10.1021/acsptsci.0c00110",

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Ansbro, MR, Itkin, Z, Chen, L, Zahoranszky-Kohalmi, G, Amaratunga, C, Miotto, O, Peryea, T, Hobbs, CV, Suon, S, Sá, JM, Dondorp, AM, van der Pluijm, RW, Wellems, TE, Simeonov, A & Eastman, RT 2020, 'Modulation of Triple Artemisinin-Based Combination Therapy Pharmacodynamics by Plasmodium falciparum Genotype', ACS Pharmacology and Translational Science, vol. 3, no. 6, pp. 1144-1157. https://doi.org/10.1021/acsptsci.0c00110

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T1 - Modulation of Triple Artemisinin-Based Combination Therapy Pharmacodynamics by Plasmodium falciparum Genotype

AU - Ansbro, Megan R.

AU - Itkin, Zina

AU - Chen, Lu

AU - Zahoranszky-Kohalmi, Gergely

AU - Amaratunga, Chanaki

AU - Miotto, Olivo

AU - Peryea, Tyler

AU - Hobbs, Charlotte V.

AU - Suon, Seila

AU - Sá, Juliana M.

AU - Dondorp, Arjen M.

AU - van der Pluijm, Rob W.

AU - Wellems, Thomas E.

AU - Simeonov, Anton

AU - Eastman, Richard T.

PY - 2020/12/11

Y1 - 2020/12/11

N2 - The first-line treatments for uncomplicated Plasmodium falciparum malaria are artemisinin-based combination therapies (ACTs), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread of P. falciparum with decreased susceptibility to artemisinin and partner drugs presents a significant challenge to malaria control efforts. To stem the spread of drug resistant parasites, novel chemotherapeutic strategies are being evaluated, including the implementation of triple artemisinin-based combination therapies (TACTs). Currently, there is limited knowledge on the pharmacodynamic and pharmacogenetic interactions of proposed TACT drug combinations. To evaluate these interactions, we established an in vitro high-throughput process for measuring the drug concentration-response to three distinct antimalarial drugs present in a TACT. Sixteen different TACT combinations were screened against 15 parasite lines from Cambodia, with a focus on parasites with differential susceptibilities to piperaquine and artemisinins. Analysis revealed drug-drug interactions unique to specific genetic backgrounds, including antagonism between piperaquine and pyronaridine associated with gene amplification of plasmepsin II/III, two aspartic proteases that localize to the parasite digestive vacuole. From this initial study, we identified parasite genotypes with decreased susceptibility to specific TACTs, as well as potential TACTs that display antagonism in a genotype-dependent manner. Our assay and analysis platform can be further leveraged to inform drug implementation decisions and evaluate next-generation TACTs.

AB - The first-line treatments for uncomplicated Plasmodium falciparum malaria are artemisinin-based combination therapies (ACTs), consisting of an artemisinin derivative combined with a longer acting partner drug. However, the spread of P. falciparum with decreased susceptibility to artemisinin and partner drugs presents a significant challenge to malaria control efforts. To stem the spread of drug resistant parasites, novel chemotherapeutic strategies are being evaluated, including the implementation of triple artemisinin-based combination therapies (TACTs). Currently, there is limited knowledge on the pharmacodynamic and pharmacogenetic interactions of proposed TACT drug combinations. To evaluate these interactions, we established an in vitro high-throughput process for measuring the drug concentration-response to three distinct antimalarial drugs present in a TACT. Sixteen different TACT combinations were screened against 15 parasite lines from Cambodia, with a focus on parasites with differential susceptibilities to piperaquine and artemisinins. Analysis revealed drug-drug interactions unique to specific genetic backgrounds, including antagonism between piperaquine and pyronaridine associated with gene amplification of plasmepsin II/III, two aspartic proteases that localize to the parasite digestive vacuole. From this initial study, we identified parasite genotypes with decreased susceptibility to specific TACTs, as well as potential TACTs that display antagonism in a genotype-dependent manner. Our assay and analysis platform can be further leveraged to inform drug implementation decisions and evaluate next-generation TACTs.

KW - Plasmodium

KW - antimalarial

KW - malaria

KW - pharmacodynamics

KW - pharmacogenetics

KW - triple-drug combination

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C2 - 33344893

SN - 2575-9108

VL - 3

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EP - 1157

JO - ACS Pharmacology and Translational Science

JF - ACS Pharmacology and Translational Science

IS - 6

ER -

Modulation of Triple Artemisinin-Based Combination Therapy Pharmacodynamics by Plasmodium falciparum Genotype

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Keywords

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