Skip to main content
Key Specialties
Anesthesiology Cardiology Dermatology Diabetology Endocrinology Gastroenterology General Medicine Geriatrics Hematology Infectious Diseases Internal Medicine Nephrology Neurology Obstetrics and Gynecology Oncology Pediatrics Psychiatry Radiology Respiratory Medicine Rheumatology Surgery Urology
Congress Coverage
2024 ESMO Congress 2024 ERS Congress 2024 EASD Congress 2024 ESC Congress 2024 EAN Congress 2024 ASCO Annual Meeting 2024 ACC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote series | Spotlight on menopause

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the systemic effects of menopause, so you can help patients in your clinics through the transition.

Published: Thursday 12th December 2024
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in:

Open Access 01-12-2024 | Antimalaria | Research article

Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria

Authors: Azrin N. Abd-Rahman, Daniel Kaschek, Anne Kümmel, Rebecca Webster, Adam J. Potter, Anand Odedra, Stephen D. Woolley, Stacey Llewellyn, Lachlan Webb, Louise Marquart, Stephan Chalon, Myriam El Gaaloul, James S. McCarthy, Jörg J. Möhrle, Bridget E. Barber

Published in: BMC Medicine | Issue 1/2024

Login to get access

Abstract

Background

The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results.

Methods

Twenty-four healthy adults enrolled over three consecutive cohorts were inoculated with Plasmodium falciparum-infected erythrocytes on day 0. Participants were randomized within each cohort to one of seven dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42 ± 2. The general pharmacodynamic interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study.

Results

For a dose of 800 mg artefenomel administered with 640 mg, 960 mg, or 1440 mg piperaquine, the simulated adequate parasitological response at day 28 (APR28), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR28 in the phase 2b trial of 67.0%, 65.5%, and 75.4%, respectively.

Conclusions

These results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development.

Trial registration

This study was registered on ClinicalTrials.gov on 11 May 2018 with registration number NCT03542149.
Appendix
Available only for authorised users
Literature
1.
2.
3.
Conrad MD, Asua V, Garg S, Giesbrecht D, Niare K, Smith S, et al. Evolution of partial resistance to artemisinins in malaria parasites in Uganda. N Engl J Med. 2023;389(8):722–32.CrossRefPubMedPubMedCentral
4.
Mihreteab S, Platon L, Berhane A, Stokes BH, Warsame M, Campagne P, et al. Increasing prevalence of artemisinin-resistant HRP2-negative malaria in Eritrea. N Engl J Med. 2023;389(13):1191–202.CrossRefPubMedPubMedCentral
5.
White NJ. Emergence of artemisinin-resistant Plasmodium falciparum in East Africa. N Engl J Med. 2021;385(13):1231–2.CrossRefPubMed
6.
7.
Charman SA, Arbe-Barnes S, Bathurst IC, Brun R, Campbell M, Charman WN, et al. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria. Proc Natl Acad Sci U S A. 2011;108(11):4400–5.CrossRefPubMedPubMedCentral
8.
McCarthy JS, Baker M, O’Rourke P, Marquart L, Griffin P, Hooft van Huijsduijnen R, et al. Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers. J Antimicrob Chemother. 2016;71(9):2620–7.CrossRefPubMedPubMedCentral
9.
Moehrle JJ, Duparc S, Siethoff C, van Giersbergen PL, Craft JC, Arbe-Barnes S, et al. First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials. Br J Clin Pharmacol. 2013;75(2):524–37.CrossRefPubMed
10.
Phyo AP, Jittamala P, Nosten FH, Pukrittayakamee S, Imwong M, White NJ, et al. Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet Infect Dis. 2016;16(1):61–9.CrossRefPubMedPubMedCentral
11.
Meshnick SR, Taylor TE, Kamchonwongpaisan S. Artemisinin and the antimalarial endoperoxides: from herbal remedy to targeted chemotherapy. Microbiol Rev. 1996;60(2):301–15.CrossRefPubMedPubMedCentral
12.
de Vries PJ, Dien TK. Clinical pharmacology and therapeutic potential of artemisinin and its derivatives in the treatment of malaria. Drugs. 1996;52(6):818–36.CrossRefPubMed
13.
Macintyre F, Adoke Y, Tiono AB, Duong TT, Mombo-Ngoma G, Bouyou-Akotet M, et al. A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria. BMC Med. 2017;15(1):181.CrossRefPubMedPubMedCentral
14.
Pasay CJ, Rockett R, Sekuloski S, Griffin P, Marquart L, Peatey C, et al. Piperaquine monotherapy of drug-susceptible Plasmodium falciparum infection results in rapid clearance of parasitemia but is followed by the appearance of gametocytemia. J Infect Dis. 2016;214(1):105–13.CrossRefPubMedPubMedCentral
15.
McCarthy JS, Ruckle T, Elliott SL, Ballard E, Collins KA, Marquart L, et al. A single-dose combination study with the experimental antimalarials artefenomel and DSM265 to determine safety and antimalarial activity against blood-stage Plasmodium falciparum in healthy volunteers. Antimicrob Agents Chemother. 2019;64(1):e01371–419.CrossRefPubMedPubMedCentral
16.
Dini S, Zaloumis SG, Price DJ, Gobeau N, Kummel A, Cherkaoui M, et al. Seeking an optimal dosing regimen for OZ439/DSM265 combination therapy for treating uncomplicated falciparum malaria. J Antimicrob Chemother. 2021;76(9):2325–34.CrossRefPubMedPubMedCentral
17.
Rockett RJ, Tozer SJ, Peatey C, Bialasiewicz S, Whiley DM, Nissen MD, et al. A real-time, quantitative PCR method using hydrolysis probes for the monitoring of Plasmodium falciparum load in experimentally infected human volunteers. Malar J. 2011;10: 48.CrossRefPubMedPubMedCentral
18.
Wang CYT, Ballard EL, Pava Z, Marquart L, Gaydon J, Murphy SC, et al. Analytical validation of a real-time hydrolysis probe PCR assay for quantifying Plasmodium falciparum parasites in experimentally infected human adults. Malar J. 2021;20(1):181.CrossRefPubMedPubMedCentral
19.
Wang CYT, Ballard E, Llewellyn S, Marquart L, Bousema T, McCarthy JS, et al. Assays for quantification of male and female gametocytes in human blood by qRT-PCR in the absence of pure sex-specific gametocyte standards. Malar J. 2020;19(1):218.CrossRefPubMedPubMedCentral
20.
Tarning J, Lindegardh N. Quantification of the antimalarial piperaquine in plasma. Trans R Soc Trop Med Hyg. 2008;102(5):409–11.CrossRefPubMed
21.
Nyberg J, Ueckert S, Stromberg EA, Hennig S, Karlsson MO, Hooker AC. PopED: an extended, parallelized, nonlinear mixed effects models optimal design tool. Comput Methods Programs Biomed. 2012;108(2):789–805.CrossRefPubMed
22.
Wicha SG, Chen C, Clewe O, Simonsson USH. A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions. Nat Commun. 2017;8(1):2129.CrossRefPubMedPubMedCentral
23.
World Health Organization. Methods for surveillance of antimalarial drug efficacy. Geneva: World Health Organization; 2009.
24.
Dietz K, Raddatz G, Molineaux L. Mathematical model of the first wave of Plasmodium falciparum asexual parasitemia in non-immune and vaccinated individuals. Am J Trop Med Hyg. 2006;75(2 Suppl):46–55.CrossRefPubMed
25.
Simpson JA, Aarons L, Collins WE, Jeffery GM, White NJ. Population dynamics of untreated Plasmodium falciparum malaria within the adult human host during the expansion phase of the infection. Parasitology. 2002;124(Pt 3):247–63.CrossRefPubMed
26.
Marquart L, Baker M, O’Rourke P, McCarthy JS. Evaluating the pharmacodynamic effect of antimalarial drugs in clinical trials by quantitative PCR. Antimicrob Agents Chemother. 2015;59(7):4249–59.CrossRefPubMedPubMedCentral
27.
28.
Darpo B, Ferber G, Siegl P, Laurijssens B, Macintyre F, Toovey S, et al. Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria. Br J Clin Pharmacol. 2015;80(4):706–15.CrossRefPubMedPubMedCentral
29.
Wicha SG, Walz A, Cherkaoui-Rbati MH, Bundgaard N, Kuritz K, Gumpp C, et al. New in vitro interaction-parasite reduction ratio assay for early derisk in clinical development of antimalarial combinations. Antimicrob Agents Chemother. 2022;66(11):e0055622.CrossRefPubMed
30.
Demarta-Gatsi C, Andenmatten N, Jimenez-Diaz MB, Gobeau N, Cherkaoui-Rabti MH, Fuchs A, et al. Predicting optimal antimalarial drug combinations from a standardized Plasmodium falciparum humanized mouse model. Antimicrob Agents Chemother. 2023;67(6): e0157422.CrossRefPubMed
Metadata
Title
Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood-stage Plasmodium falciparum to predict efficacy in patients with malaria
Authors
Azrin N. Abd-Rahman
Daniel Kaschek
Anne Kümmel
Rebecca Webster
Adam J. Potter
Anand Odedra
Stephen D. Woolley
Stacey Llewellyn
Lachlan Webb
Louise Marquart
Stephan Chalon
Myriam El Gaaloul
James S. McCarthy
Jörg J. Möhrle
Bridget E. Barber
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2024
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-024-03787-0

Other articles of this Issue 1/2024

ABO and Rhesus blood groups and multiple health outcomes: an umbrella review of systematic reviews with meta-analyses of observational studies

From conceptualising to modelling structural determinants and interventions in HIV transmission dynamics models: a scoping review and methodological framework for evidence-based analyses

The associations of post-stroke delirium with outcomes: a systematic review and meta-analysis

  • Open Access
  • Delirium
  • Original Research

Associations between long-term night shift work and incidence of chronic obstructive pulmonary disease: a prospective cohort study of 277,059 UK Biobank participants

Integration of non-randomized studies with randomized controlled trials in meta-analyses of clinical studies: a meta-epidemiological study on effect estimation of interventions

  • Open Access
  • Original Research

EEG signatures of cognitive decline after mild SARS-CoV-2 infection: an age-dependent study

Keynote webinar | Spotlight on adolescent vaping

  • Live
  • Webinar | 29-01-2025 | 18:00 (CET)

Growing numbers of young people are using e-cigarettes, despite warnings of respiratory effects and addiction. How can doctors tackle the epidemic, and what health effects should you prepare to manage in your clinics?

Watch it live: Wednesday 29th January, 18:00-19:30 CET
 

Prof. Ann McNeill
Dr. Debbie Robson
Benji Horwell
Developed by: Springer Medicine
Join the webinar

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Read more
Image Credits