Safety, tolerability, and single- and multiple-dose pharmacokinetics of piperaquine phosphate in healthy subjects.
Piperaquine phosphate is an orally active bisquinolone antimalarial drug that has been used for the past 3 decades. The authors report the safety, tolerability, and pharmacokinetics of piperaquine from a classical controlled phase I study. It was a double-blind, randomized, parallel-group, placebo-controlled, and single- and multiple-dose study. During the rising single-dose study, single ascending oral doses of 500, 750, 1000, 1250, and 1500 mg of piperaquine phosphate were administered, whereas in rising multiple-dose study, once-daily ascending oral doses of 500, 750, 1000, and 1500 mg were administered for 3 consecutive days. Pharmacokinetic analysis for both the rising single- and multiple-dose studies was done using the noncompartmental approach. The mean apparent terminal half-life ranged from 11 to 23 days. Increase in exposure was less than dose proportional and linear. Piperaquine concentrations were measurable up to 60 days postdose. Multiple peaks were observed in the plasma piperaquine concentration-time profiles and exhibited 3- to 7-fold accumulation following multiple dosing. Piperaquine was well tolerated following single and multiple doses.
Ahmed
Tausif
T
Metabolism and Pharmacokinetics Department, Ranbaxy Research Laboratories, Gurgaon-122015, Haryana, India.
Sharma
Pradeep
P
Gautam
Anirudh
A
Varshney
Brijesh
B
Kothari
Monica
M
Ganguly
Sanjeev
S
Moehrle
Joerg J
JJ
Paliwal
Jyoti
J
Saha
Nilanjan
N
Batra
Vijay
V
D000284:Administration, Oral; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011804:Quinolines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013607:Tablets; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced; D010879:Piperazines
D000962:Antimalarials; D011804:Quinolines; D013607:Tablets; C034759:piperaquine; D010879:Piperazines