title: Pharmacokinetics and pharmacodynamics of arterolane maleate following multiple oral doses in adult patients with P. falciparum malaria.
abstract: Arterolane (RBx 11160) maleate is a novel, rapidly acting synthetic trioxolane antimalarial compound being developed by Ranbaxy Research Laboratories (Haryana, India). It is presently under phase III in combination with piperaquine phosphate. The present work reports the relationship between pharmacokinetic (PK) parameter (AUC(0-8h) on day 0/day 6) and indices of pharmacodynamic (PD) response (50% parasite clearance [PC(50)], 90% parasite clearance [PC(90)], parasite clearance time [PCT], recrudescence) from a phase II, double-blind, multicenter, randomized, parallel-group, dose-ranging trial. Patients with acute uncomplicated P. falciparum malaria were randomized to 1 of 3 arterolane maleate (50, 100, and 200 mg) doses for 7 consecutive days. Plasma concentration data were available from 78, 76, and 75 patients receiving a 50-, 100-, and 200-mg dose, respectively. Based on PD modeling, its limitations and assumptions, minimum 150-mg dose arterolane maleate was recommended to optimize the probability of maximum therapeutic benefits for an adult. Doses higher than 100 mg are unlikely to reduce the probability of recrudescence. This study re-stresses the need of combining short and long-acting drugs to prevent resistance development and minimize recrudescence.
authors.affiliation: Metabolism and Pharmacokinetics Department, Ranbaxy Research Laboratories, Plot # 20, Sector-18, Udhyog Vihar Industrial Area, Gurgaon-122015, Haryana, India. jyoti.paliwal@ranbaxy.com
authors.forename: Anirudh
authors.initials: A
authors.lastname: Gautam
authors.forename: Tausif
authors.initials: T
authors.lastname: Ahmed
authors.forename: Pradeep
authors.initials: P
authors.lastname: Sharma
authors.forename: Brijesh
authors.initials: B
authors.lastname: Varshney
authors.forename: Monika
authors.initials: M
authors.lastname: Kothari
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Saha
authors.forename: Arjun
authors.initials: A
authors.lastname: Roy
authors.forename: Joerg J
authors.initials: JJ
authors.lastname: Moehrle
authors.forename: Jyoti
authors.initials: J
authors.lastname: Paliwal
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000962:Antimalarials / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000469:parasitology; D008297:Male; D008298:Maleates; D008875:Middle Aged; D010545:Peroxides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010963:Plasmodium falciparum; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000962:Antimalarials; D006573:Heterocyclic Compounds, 1-Ring; D008298:Maleates; D010545:Peroxides; D013141:Spiro Compounds; C489136:arterolane