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Pharmacokinetics-Pharmacodynamics of High-Dose Ivermectin with Dihydroartemisinin-Piperaquine on Mosquitocidal Activity and QT-prolongation (IVERMAL)

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Smit, Menno ORCID: https://orcid.org/0000-0003-3405-6638, Ochomo, Eric O, Waterhouse, David, Kwambai, Titus K, Abong'o, Bernard O, Bousema, Teun, Bayoh, Nabie M, Gimnig, John E, Samuels, Aaron M, Desai, Meghna R, Phillips-Howard, Penelope ORCID: https://orcid.org/0000-0003-1018-116X, Kariuki, Simon K, Wang, Duolao ORCID: https://orcid.org/0000-0003-2788-2464, terKuile, Feiko ORCID: https://orcid.org/0000-0003-3663-5617, Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 and Aljayyoussi, Ghaith (2019) 'Pharmacokinetics-Pharmacodynamics of High-Dose Ivermectin with Dihydroartemisinin-Piperaquine on Mosquitocidal Activity and QT-prolongation (IVERMAL)'. Clinical Pharmacology and Therapeutics, Vol 105, Issue 2, pp. 388-401.

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Smit MR (2018) IVERMAL PK-PD-accepted.pdf - Accepted Version
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Smit MR (2018) IVERMAL PK-PD-accepted-supplement.pdf - Accepted Version

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Smit MR (2018) IVERMAL PK-PD-dose-response calculator.xlsx - Accepted Version

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Smit_et_al-2018-Clinical_Pharmacology_%26_Therapeutics.pdf

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Abstract

High-dose ivermectin, co-administered for 3-days with dihydroartemisinin-piperaquine (DP), killed mosquitoes feeding on individuals for at least 28-days post-treatment in a recent trial (IVERMAL), while 7-days was predicted pre-trial. The current study assessed the relationship between ivermectin blood concentrations and the observed mosquitocidal effects against Anopheles gambiae. 3-days ivermectin 0, 300, or 600 mcg/kg/day plus DP was randomly assigned to 141 adults with uncomplicated malaria in Kenya. During 28-days follow-up, 1,393 venous and 335 paired capillary plasma samples, 850 mosquito-cluster mortality rates, and 524 QTcF-intervals were collected. Using pharmacokinetic-pharmacodynamic (PK-PD) modeling, we show a consistent correlation between predicted ivermectin concentrations and observed mosquitocidal-effects throughout the 28-day study duration, without invoking an unidentified mosquitocidal metabolite or drug-drug-interaction. Ivermectin had no effect on piperaquine’s pharmacokinetics or QTcF-prolongation. The PK-PD model can be used to design new treatment regimens with predicted mosquitocidal effect. This methodology could be used to evaluate effectiveness of other endectocides.

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QV Pharmacology > QV 38 Drug action.
QX Parasitology > Protozoa > QX 135 Plasmodia
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI): https://doi.org/10.1002/cpt.1219
Depositing User: Helen Wong
Date Deposited: 24 Aug 2018 08:21
Last Modified: 21 Jun 2019 14:53
URI: https://archive.lstmed.ac.uk/id/eprint/9190

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