Journal List > J Korean Soc Clin Pharmacol Ther > v.21(2) > 1055125

Kim, Jin, Choi, Min, Lee, Chung, Nam, Jung, Kim, Lee, and Hong: Bioequivalence of Two Erlotinib Formulations in Healthy Volunteers

Abstract

Background:

Erlotinib is a tyrosine kinase inhibitor prescribed for the treatment of non-small cell lung cancer and pancreatic cancer. The aim of this study was to compare the safety and pharmacokinetics (PK) of a generic (test) formulation of erlotinib with those of a reference formulation in healthy volunteers.

Methods:

A randomized, open-label, single-dose two-treatment, two-period, two-sequence, crossover study was conducted in Clinical Trials Center, Chungnam National University Hospital with 40 healthy men. Subjects orally received either one 150 mg tablet of the test or the corresponding dose of the reference, and crossover phases were separated by 14-day washout. Plasma samples were collected up to 72 hr post-dose. Plasma erlotinib concentrations were determined by liquid chromatography-tandem mass spectrometry. PK parameters were calculated by non-compartmental analysis. The safety was monitored throughout the study.

Results:

A total of 21 cases of adverse events were reported. They are mild and relieved without an intervention. There was no serious adverse event. Median times to peak concentration of two formulations were 3.0. Means [SD] for peak concentration (Cmax) and area under the plasma concentration-time curve (AUC) of the test were 1,298 [346] µg/L and 25,318 [7,668] hr×µg/L. Those of the reference were 1,193 [378] µg/L and 24,853 [8,419] hr×µg/L. Geometric mean ratios (90 % confidence intervals) for the test to the reference were 1.10 (1.02 - 1.18) for Cmax and 1.02 (0.97 - 1.09) for AUC.

Conclusion:

Two formulations were safe and well-tolerated. PK findings suggest that the test formulation is equivalent to the reference in terms of pharmacokinetics.

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Figure 1.
Mean plasma erlotinib concentration versus time profiles after single oral administration of test products (open circles) and reference products (closed triangles) made of erlotinib 150 mg to 37 healthy volunteers (lower left: linear scale, upper right: log-linear scale).
jkscpt-21-159f1.tif
Table 1.
Subject demography
Demographics Sequence A (n=20) Sequence B (n=20) Total P - value*
Age (year) 24.0 ± 1.5 23.3 ± 1.8 23.6 ± 1.8 0.158
Height (cm) 176.6 ± 5.8 174.4 ± 4.8 175.5 ± 5.4 0.239
Weight (kg) 69.5 ± 7.4 66.8 ± 6.8 68.1 ± 7.1 0.285

Values are presented as mean ± standard deviation. * Mann-Whitney U test.

Table 2.
Comparison of pharmacokinetic parameters by formulation
Parameters Summary Statistics Test product (n=37) Reference product (n=37)
tmax Median 3.0 3.0
(hr) Minimum 0.5 1.0
Maximum 4.0 6.0
AUC Geometric mean 24179 23652
(hr·µg/L) Arithmetic mean 25318 24853
Standard deviation 7668 8419
CV (%) 30.3 33.9
Cmax Geometric mean 1241 1129
(µg/L) Arithmetic mean 1298 1193
Standard deviation 346 378
CV (%) 26.6 31.7
t1/2β Arithmetic mean 14.8 15.4
(hr) Standard deviation 5.6 5.7
CV (%) 37.7 36.7
CL/F Arithmetic mean 6.3 6.3
(L/hr) Standard deviation 2.4 2.0
CV (%) 38.4 32.2

*N: number of subjects. CV: coefficient of variation. tmax: time to peak concentration. AUC: area under the time-concentration curve. Cmax: peak concentration. t1/2ß: terminal half-life. CL/F: apparent clearance.

Table 3.
The ratio of least-squares means and 90 % confidence intervals for pharmacokinetic parameters
Parameters Geometric mean ratio 90 % confidence intervals
AUC 1.02 0.97-1.09
Cmax 1.10 1.02-1.18

*AUC: area under the time-concentration curve. Cmax: peak concentration.

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