Pharmacokinetic properties and bioequivalence of two sulfadoxine/pyrimethamine fixed-dose combination tablets: a parallel-design study in healthy Chinese male volunteers.
BACKGROUND
Sulfadoxine/pyrimethamine fixed-dose combination (FDC) tablet is the long-acting portion of the antimalaria product Artecospe(®), coblister containing artesunate tablets plus sulfadoxine/pyrimethamine FDC tablets. This study was conducted to support the efficacy and tolerability of the sulfadoxine/pyrimethamine FDC tablet in the World Health Organization's (WHO) Prequalification of Medicines Programme, as well as to obtain marketing authorization in China.


OBJECTIVE
The aim of the present study was to compare the pharmacokinetic profiles between a new generic and the branded reference formulation of sulfadoxine/pyrimethamine FDC tablets, and to assess the bioequivalence of the 2 products in healthy Chinese volunteers.


METHODS
This single-dose, open-label, randomized, parallel-group study was conducted in healthy Chinese male volunteers who were randomly assigned (1:1) to receive a single 1500/75-mg dose (3 × 500/25-mg tablets) of either the test or reference formulation after a 12-hour overnight fast. Seventeen blood samples were obtained over a 168-hour interval, and plasma concentrations of sulfadoxine and pyrimethamine were determined by 2 separate validated liquid chromatography-isotopic dilution mass spectrometry methods. Pharmacokinetic properties (C(max), AUC(0-72), AUC(0-168), and T(max)) were calculated and analyzed statistically. The 2 formulations were to be considered bioequivalent if 90% CIs for the log-transformed ratios of C(max) and AUC(0-72) were within the predetermined bioequivalence range of 80% to 125%, in accordance with the guidelines of WHO and China's Food and Drug Administration (FDA). Tolerability was evaluated throughout the study by vital signs, physical examinations, clinical laboratory tests, 12-lead ECGs, and subject interviews on adverse events (AEs).


RESULTS
Forty-six healthy subjects completed the study. The mean values of sulfadoxine C(max) (183.07 and 165.15 mg/L), AUC(0-72) (11,036.52 and 10,536.78 mg/L/h), and AUC(0-168) (22,247.05 and 21,761.02 mg/L/h) were not significantly different between the test and reference formulations, respectively. The same was true for pyrimethamine (0.55 and 0.58 mg/L, 29.85 and 31.44 mg/L/h, and 56.18 and 59.27 mg/L/h, respectively). The 90% CIs for the log-transformed ratios of C(max), AUC(0-72), and AUC(0-168) of both sulfadoxine (105.4%-116.6%, 99.3%-110.6%, and 96.4%-108.1%) and pyrimethamine (88.8%-100.9%, 89.5%-101.0%, and 88.3%-101.6%) were within the acceptance limits for bioequivalence. A total of 7 mild AEs were reported in 7 subjects (15.2%).


CONCLUSIONS
The findings from this single-dose (1500/75-mg) study suggest that the test and reference formulations of sulfadoxine/pyrimethamine FDC 500/25-mg tablet have similar pharmacokinetic profiles both in terms of rate and extent of absorption. The formulations met WHO's and China's FDA regulatory criteria for bioequivalence in these healthy Chinese volunteers under fasting conditions. Both formulations were generally well-tolerated.
Phase I Clinical Research Unit, Shanghai Xuhui Central Hospital, Shanghai, China.
Yan-Mei
YM
Liu
Kanyin E
KE
Zhang
Yun
Y
Liu
Hai-Chen
HC
Zhang
Yun-Xiao
YX
Song
Hua-Hua
HH
Pu
Chuan
C
Lu
Gang-Yi
GY
Liu
Jing-Ying
JY
Jia
Qing-Si
QS
Zheng
Jian-Min
JM
Zhu
Chen
C
Yu
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000962:Antimalarials / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D044466:Asian People; D002626:Chemistry, Pharmaceutical; D016009:Chi-Square Distribution; D002681:China; D002853:Chromatography, Liquid; D004338:Drug Combinations; D016568:Drugs, Generic / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007201:Indicator Dilution Techniques; D016014:Linear Models; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D008954:Models, Biological; D011739:Pyrimethamine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D013413:Sulfadoxine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D013607:Tablets; D013810:Therapeutic Equivalency; D055815:Young Adult
D000962:Antimalarials; D004338:Drug Combinations; D016568:Drugs, Generic; D013607:Tablets; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D011739:Pyrimethamine