title: Estimation of the In Vivo MIC of Cipargamin in Uncomplicated Plasmodium falciparum Malaria.
abstract: The MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation of low-density malaria parasitemia enables the prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects and now allows identification of the in vivo MIC. An adaptive design and a PK-PD modeling approach were used to determine prospectively the MIC of the new antimalarial cipargamin (KAE609) in adults with uncomplicated Plasmodium falciparum malaria in an open-label, dose-ranging phase 2a study. Vietnamese adults with acute P. falciparum malaria were allocated sequentially to treatment with a single 30-mg (n = 6), 20-mg (n = 5), 10-mg (n = 7), or 15-mg (n = 7) dose of cipargamin. Artemisinin-based combination therapy was given after parasite densities had fallen and then risen as cipargamin levels declined below the MIC but before a return of signs or symptoms. The rates of parasite clearance were dose dependent, with near saturation of the effect being seen at an adult dose of 30 mg. The developed PK-PD model accurately predicted the therapeutic responses in 23/25 patients. The predicted median in vivo MIC was 0.126 ng/ml (range, 0.038 to 0.803 ng/ml). Pharmacometric characterization of the relationship between antimalarial drug concentrations and parasite clearance rates following graded subtherapeutic antimalarial drug dosing is safe and provides a rational framework for dose finding in antimalarial drug development. (This study has been registered at ClinicalTrials.gov under identifier NCT01836458.).
authors.affiliation: Oxford University Clinical Research Unit-Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Oxford University Clinical Research Unit-Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Thanh
authors.initials: NT
authors.lastname: Thuy-Nhien
authors.affiliation: Oxford University Clinical Research Unit-Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Nhu Thi
authors.initials: NT
authors.lastname: Hoa
authors.affiliation: Oxford University Clinical Research Unit-Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Phung Duc
authors.initials: PD
authors.lastname: Thuan
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Joel
authors.identifier: 0000-0003-4566-4030
authors.initials: J
authors.lastname: Tarning
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Shoklo Malaria Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: François
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Baldur
authors.initials: B
authors.lastname: Magnusson
authors.affiliation: Novartis Healthcare Pvt. Ltd., Hyderabad, India.
authors.forename: Jay Prakash
authors.initials: JP
authors.lastname: Jain
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA kamal.hamed@novartis.com.
authors.forename: Kamal
authors.identifier: 0000-0003-1896-9736
authors.initials: K
authors.lastname: Hamed
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044466:Asian People; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D013141:Spiro Compounds / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000962:Antimalarials; D007211:Indoles; C552304:NITD 609; D013141:Spiro Compounds
keywords: cipargamin; clinical trial; malaria; pharmacokinetic-pharmacodynamic model; resistance