Bioequivalence of generic alendronate sodium tablets (70 mg) to Fosamax^® tablets (70 mg) in fasting, healthy volunteers: a randomized, open-label, three-way, reference-replicated crossover study

Figures & data

Table 1 Pharmacokinetic parameters of alendronic acid for each treatment/period in 36 healthy Chinese volunteers after a single oral dose of 70 mg of alendronate sodium

Parameters	Test (alendronate sodium)	Reference (Fosamax^®) (first administration)	Reference (Fosamax^®) (second administration)
N	36	36	36
AUC0–t, h·ng/mL	150.36 (82.90)	148.15 (85.97)	167.11 (110.87)
AUC0–∞, h·ng/mL	158.29 (87.09)	155.53 (90.22)	175.99 (115.93)
Residual area, %	4.51 (2.34)	4.31 (1.83)	5.28 (3.83)
Cmax, ng/mL	64.78 (43.76)	56.62 (31.95)	60.15 (37.12)
tmax, h	1.00 (0.33–3.00)a	1.00 (0.33–2.00)a	1.33 (0.33–4.00)a
t1/2, h	1.76 (0.43)	1.73 (0.30)	1.84 (0.64)

Note: Data are presented as mean (SD) or

a median (range).

Abbreviations: AUC_0–∞, area under the plasma concentration–time curve from time 0 to infinity; AUC_0–t, area under the plasma concentration time curve from time 0 to the last timepoint; C_max, maximum concentration; t_1/2, terminal elimination half-life; t_max, time to reach C_max; SD, standard deviation.

Figure 1 Plasma concentration–time curves of alendronic acid after a single oral dose of 70 mg of the test product (alendronate sodium) or the reference product (Fosamax^®) (first and second doses) administered to 36 healthy Chinese male volunteers.

Note: Data are presented as arithmetic mean ± SD.
Abbreviation: SD, standard deviation.

Table 2 Statistical analysis of the results obtained using the FDA’s RSABE method

Parameters	GMR	sWR	CVWR (%)	Criteria bound	Bioequivalent limits
AUC0–t	1.00	0.546	58.91	−0.17	Criteria bound ≤0, and
AUC0–∞	1.00	0.527	56.58	−0.15	GMR in 0.8–1.25
Cmax	1.08	0.571	62.05	−0.16

Abbreviations: AUC_0–∞, area under the plasma concentration–time curve from time 0 to infinity; AUC_0–t, area under the plasma concentration time curve from time 0 to the last time point; C_max, maximum concentration; CV_WR, within-subject coefficient of variation of reference product; FDA, US Food and Drug Administration; GMR, geometric mean ratio; RSABE, reference-scaled average bioequivalence; SD, standard deviation; s_WR, within-subject SD of the reference product.

Table 3 Statistical analysis of results obtained using the EMA’s RSABE method

Parameters	GMR	90% CI	sWR	CVWR (%)	Bioequivalent limits
AUC0–t	1.00	85.31%–117.15%	0.569	61.83	80.00%–125.00%
AUC0–∞	1.00	85.29%–116.15%	0.548	59.14	80.00%–125.00%
Cmax	1.08	90.35%–129.04%	0.607	66.71	69.84%–143.19%

Abbreviations: AUC_0–∞, area under the plasma concentration–time curve from time 0 to infinity; AUC_0–t, area under the plasma concentration–time curve from time 0 to the last time point; CI, confidence interval; C_max, maximum concentration; CV_WR, within-subject coefficient of variation of reference product; EMA, European Medicines Agency; GMR, geometric mean ratio; RSABE, reference-scaled average bioequivalence; s_WR, within-subject SD of the reference product.

Figure S1 Typical chromatograms of alendronic acid derivative (I) and d6-alendronic acid derivative (IS, II) in plasma.

Notes: (A) Blank plasma sample, (B) blank plasma sample spiked with alendronic acid at 0.200 ng/mL and d6-alendronic acid at 10.0 ng/mL, and (C) a plasma sample collected at 20 min after a single oral administration of 70 mg of alendronate sodium.
Abbreviations: IS, internal standard; Rel int, relative intensity; MRM, multiple-reaction monitoring; LLOQ, low limit of quantification; XIC, extracted ion chromatogram.

Table S1 Precision and accuracy of the LC–MS/MS method to determine alendronic acid in human plasma (in pre-study validation, n=3 days, six replicates per day)

Concentration (ng/mL)		RSD (%)		RE (%)
Added	Found	Intra-day	Inter-day
0.600	0.640	7.3	8.9	6.7
5.00	5.17	2.0	2.4	3.4
24.0	23.5	1.5	5.2	−2.2

Abbreviations: LC–MS/MS, liquid chromatography–tandem mass spectrometry; RE, relative error; RSD, relative standard deviation.