Bioequivalence study of two formulations of candesartan cilexetil tablet in healthy subjects under fasting conditions

Figures & data

Figure 1 Chemical structure of candesartan cilexetil (CAS 139481-59-7).

Table 1 The validation data of the analytical method used to determine candesartan in human plasma by UPLC-MS/MS using irbesartan as the internal standard

Parameters	At concentration of
	Low (30.03 ng/mL)	Medium (150.13 ng/mL)	High (400.53 ng/mL)
Precision*
Intraassay CV	5.54%	2.94%	2.51%
Interassay CV	5.57%	4.72%	3.08%
Accuracy*
Intraassay CV	−3.10% to +11.62%	+4.64% to +12.65%	+ 1.66% to +8.36%
Interassay CV	−13.91% to +11.62%	−3.08% to +14.83%	−4.83% to +8.36%
Recovery	103.97% to 115.77%	101.00% to 106.88%	97.00% to 105.63%
Stability with accuracy*
At equal to or less than −20°C
Stable until 60 days	−13.98% to 14.66%	–	−14.95% to 13.51%
At room temperature
Stable until 6 hours	−7.40% to 5.73%	–	−7.24% to 3.88%
Freeze–thaw process
Stable until 3 cycles	−14.70% to 8.21%	–	−13.93% to 3.24%

Notes: The standard calibration curve of candesartan ranged from 10.01 ng/mL: to 500.43 ng/mL. Linear relationships between concentration and signal intensity were obtained (r = 0.9999). The limit of quantitation was 10.01 ng/mL. Selectivity: the chromatograms showed there were no interfering substances in six blank plasma. The lowest concentration CV was 4.07% with recovery ranging between 97.60% to 111.01%.

* Expressed in the percent difference from the actual value.

Abbreviations: UPLC-MS/MS, ultra-pressure high-performance liquid chromatography with a tandem mass spectrometer detector; CV, coefficient of variations; r, coefficient correlation.

Table 2 Pharmacokinetic parameters and statistical comparison of candesartan after single-dose oral administration of a 16 mg candesartan cilexetil tablet of the test and the reference drug

Parameter	Test product mean (SD)	Reference mean (SD)	Geometric mean ratio of test/reference drug (90% CI)	% CV
AUCt (ng/hour/mL^−1)	1515.12 (392.99)	1508.09 (425.21)	100.92% (92.15%–110.52%)	18.33%
AUCinf (ng/hour/mL^−1)	1619.73 (425.16)	1645.1 (449.3)	100.24% (92.24%–108.95%)	16.79%
Cmax (ng/mL^−1)	155.47 (52.63)	146.33 (50.96)	106.71% (93.20%–122.18%)	27.31%
t1/2 (hours)	10.21 (2.48)	11.46 (3.42)	NSb	–
tmax (hours)a	4.00 (2.00–7.00)	4.00 (2.00–7.00)	NSc	–

Notes:

a The values are expressed in terms of median (range);

b analysis was performed by Wilcoxon matched-pair test;

c analysis was performed by Student’s paired t-test. Statistical calculations for AUC and C_max were based on logarithmic-transformed data. Bioequivalence criteria are defined as 90% CI of the geometric mean ratios of the test/reference drug of between 80.0% and 125.0% for AUC_t, AUC_inf, and C_max.

Abbreviations: SD, standard deviation; CI, confidence interval; CV, coefficient of variations; AUC_t, area under the plasma concentration time curve from time zero to the last measurable concentration time; AUC_inf, area under the plasma concentration time curve from time zero extrapolated to infinite time; C_max, maximum plasma concentration of the drug; t_1/2, terminal elimination half-life; NS, not significant; t_max, time to achieve the peak plasma concentration; AUC, area under the plasma concentration time curve.

Figure 2 Mean plasma concentrations versus time profiles of candesartan in human subjects (n = 24) after single-dose oral administration of 16 mg of candesartan cilexetil tablets of the test drug and the reference drug.

Abbreviation: n, number.