Estimation of the In Vivo MIC of Cipargamin in Uncomplicated Plasmodium falciparum Malaria

• Published in: Antimicrobial agents and chemotherapy Vol. 61; no. 2
• Main Authors: Hien, Tran Tinh, White, Nicholas J, Thuy-Nhien, Nguyen Thanh, Hoa, Nhu Thi, Thuan, Phung Duc, Tarning, Joel, Nosten, François, Magnusson, Baldur, Jain, Jay Prakash, Hamed, Kamal
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.02.2017
• Subjects: Adult; Antimalarials; Antimalarials - adverse effects; Antimalarials - pharmacokinetics; Antimalarials - therapeutic use; Asian Continental Ancestry Group; Clinical Therapeutics; Humans; Indoles; Indoles - adverse effects; Indoles - pharmacokinetics; Indoles - therapeutic use; Malaria, Falciparum; Malaria, Falciparum - drug therapy; Malaria, Falciparum - metabolism; Male; Microbial Sensitivity Tests; Middle Aged; Plasmodium falciparum; Spiro Compounds; Spiro Compounds - adverse effects; Spiro Compounds - pharmacokinetics; Spiro Compounds - therapeutic use; Young Adult; clinical trial; malaria; pharmacokinetic-pharmacodynamic model; resistance; cipargamin
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.01940-16

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.).