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.