Discussion
This randomized, open-label, and two-period crossover studies were firstly investigated under both fasted and fed conditions in healthy male volunteers. In this bioequivalent study, a total of 250 volunteers were screeded, and the baseline characteristics of all subjects were similar regarding age and BMIs. As demonstrated in Figure 2 and Figure 3 , the concentration-time profiles of fasting and fed states were constant in both absorptive rates and degrees. It was observed that gefitinib absorbs slowly and undergoes rapid plasma clearance, with the Tmax of 4-5 hour after single administration. Moreover, the results of the main pharmacokinetic parameters were generally similar to those of the published literatures[10, 11].
Generally speaking, the variations of the primary pharmacokinetic parameters (e.g., Cmax, AUC, t1/2) are due to food-facilitated variation in physiological processes (e.g., gastric emptying rate, fluctuations in gastrointestinal pH, increase luminal fluids, release of bile salts, inhibition of transporters)[12]. Besides, several literatures have reported that CYP2D6 was associated with gefitinib exposure and may contribute to the high inter-subject variability, but it did not influence the bioequivalence result [13].
Undoubtedly, the property of Biopharmaceutics Classification System (BCS) class II for gefitinib-high permeability and low solubility-may influence the oral absorption [14]. Gefitinib dissolves rapidly in acidic agents, but the solubilityreduces with increasing pH until neutral pH in the intestinal tract. In the present study, our results conclusively show higher exposure under feeding conditions compared with studies conducted in the fasted state. In addition, feeding conditions can alter the pH of the stomach, which can increase dissolution and absorption by approximately 10%. Although some literature has reported studies on the bioequivalence of gefitinib in healthy subjects, these have shortcomings such as limited sample size (25 cases[15], 50 cases[16]).
Besides, the range of Intra-CV was less than 22% (ranged from 10.68% to 21.61%, Table 3) and was constant with previous literature[7, 17], which suggests that the various aspects of quality control of this protocol are well established. The statistical requirements were fully satisfied in the forty healthy volunteers. Furthermore, for both formulations, rosacea, oral ulcers, and urticaria were the most commonly reported treatment emergent adverse event (TEAEs). The incidence of TEAEs was in agreement with what is known for commercial formulations. [10].
It has to be admitted that there are several limitations in this study. Firstly, according to our previous study, we partially determined the genotypes of metabolic enzymes or transporters (e.g., CYP3A4, CYP3A5, CYP2D6, ABCG2) that metabolize gefitinib, so we could not analyze the variation of pharmacokinetic parameters completely[18]. Secondly, we conducted bioequivalence studies only in healthy subjects and did not evaluate the equivalence of T to R formulation in cancer patients. Besides, other dosage regimens should be integrated to fully assess the comparative pharmacokinetics.