Abstract
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 (Cmax, AUC0–72, AUC0–168, and Tmax) were calculated and analyzed statistically. The 2 formulations were to be considered
bioequivalent if 90% CIs for the log-transformed ratios of Cmax and AUC0–72 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 Cmax (183.07 and 165.15 mg/L), AUC0–72 (11,036.52 and 10,536.78 mg/L/h), and AUC0–168 (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 Cmax, AUC0–72, and AUC0–168 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.
Key words
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Article info
Publication history
Published online: October 19, 2012
Accepted:
October 1,
2012
Identification
Copyright
© 2012 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
