4 DISCUSSION
The canagliflozin/metformin FDC tablet was recommended to be taken with meals to reduce the symptoms of gastrointestinal intolerability associated with metformin[23]. The variations in the rate of clarithromycin-extended release absorption were higher in the feeding condition-in which the tablets resided longer in the stomach-than in the fasting condition among healthy Jordanian men[24]. Diclofenac potassium oral solution and tablet formulations produced statistically and significantly different C max andt max yet similar AUC under both feeding and fasting conditions. The feeding condition produced a significantly lower C max for both formulations and profoundly delayed the t max for the tablet but did not influence the t max for the solution formulation[25]. No spikes were observed in the plasma concentration versus time profiles up to median t max or beyond. Therefore, we found no evidence to support the dose dumping of the test formulation in either the fasting or feeding conditions. No bioequivalence limits were set for percentage of AUCE (AUCINF_pred due to extrapolation from Tlast to infinity), but the application of standard BE (Bioequivalence) limits of 80% to 125% suggested that the feeding study was clearly underpowered given the high WSV (withjn—subjectvariability) at the early time points[15]. Pantoprazole might not be a highly variable drug product when co-administered with high-fat diet at a single oral dose[26]. The administration of canagliflozin with a high-fat meal also had no effect on the pharmacokinetic parameters, thereby suggesting that canagliflozin tablets may be taken with or without high-fat diet[27]. BUP was allowed to be used as a probe substrate across different sexes and ethnicities as a measure of CYP2B6 activity[28]. TheC max and AUC (0→96) of BUP and HBUP were higher in the feeding condition than in the fasting condition, while the t max of BUP was delayed in feeding condition than in the fasting condition. The maximum plasma concentration and absorptive extent of BUP were enhanced by the intake of high-fat breakfast. The maximum absorption time of BUP was delayed and the speed of absorption was lower in the feeding condition than in the fasting condition. The effects of BUP on treatment were increased by the high plasma concentration.
Tables 1 and 2 showed that the C max andt max of BUP as well as theAUC (0→96) and C max of HBUP increased by 1.18-, 1.41-, 1.38-, and 1.33-fold in the feeding group relative to the fasting group, respectively (P<0.05). Both high-fat diet and CYP2B6 mutants influenced the pharmacokinetic parameters of BUP and HBUP among the Chinese subjects.
The CYP2B6 mutants also influenced the pharmacokinetic parameters. Specifically, the C max andt 1/2 of BUP increased by 1.33- and 1.39-fold among those subjects carrying aCYP2B6*1/*1 genotype in the feeding group relative to the fasting group, respectively (P<0.05). Similarly, the V d andCL of HBUP increased by 1.38- and 1.59-fold, but theC max and AUC (0→96) of HBUP decreased by 1.44- and 1.49-fold among those subjects carrying aCYP2B6*1/*1 genotype in the feeding group relative to the fasting group, respectively (P<0.05). However, no statistical difference among the aforementioned parameters was detected for those subjects carrying aCYP2B6 mutant with the exception of thet max of BUP, which increased by 1.61-fold among the feeding CYP2B6 mutant subjects compared with the fasting subjects (P<0.05). The pharmacokinetic parameters of BUP and HBUP in fasting CYP2B6*1/*1and fasting CYP2B6 mutants are shown in Table 5. TheAUC (0→96), C max,CL , V d, t max, andt 1/2 of BUP and HBUP in fasting wild-type were the same as those in the fasting CYP2B6 mutants. The feeding wild-type and feeding CYP2B6 mutants demonstrated the same trends as shown in Table 6. Table 7 shows that theAUC (0→96) and C max of BUP and HBUP in the feeding wild-type were higher than those in the fasting wild-type. Moreover, the CL and V d of HBUP in the feeding wild-type were less than those in the fasting wild-type (P<0.05). As shown in Table 8, theAUC (0→96) and C max of BUP and HBUP increased in the feeding CYP2B6 mutants than in the fasting CYP2B6 mutants. By contrast, the CL andV d of BUP decreased in the feeding CYP2B6mutants and did not reach statistical significance in the fastingCYP2B6 mutants. Under the same feeding condition, the absorption of BUP and metabolism of HBUP were not influenced in theCYP2B6*1/*1 and CYP2B6mutants. For the same genotypes, the pharmacokinetic parameters ofCYP2B6*1/*1 subjects were obviously affected by high-fat diet, while those of CYP2B6mutants showed the opposite trend. Therefore, BUP should be administered among Chinese subjects carryingCYP2B6*1/*1 after their high-fat food intake in order to improve the effects of the clinical treatments of BUP. Moreover, BUP can be administered among Chinese subjects with CYP2B6 mutants in either fasting or feeding conditions.