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Lack of Dose-Dependent Effects of Itraconazole on the Pharmacokinetic Interaction with Fexofenadine

Department of Clinical Pharmacology, Hirosaki University School of Medicine (T.U., M.S., T.T.); and Department of Pharmacy, Hirosaki University Hospital (K.S.), Hirosaki, Japan

(Received May 11, 2006; accepted August 21, 2006)

	Abstract

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The aim of this study was to determine the inhibitory effect of itraconazole at different coadministered doses on fexofenadine pharmacokinetics. In a randomized four-phase crossover study, 11 healthy volunteers were administered a 60-mg fexofenadine hydrochloride tablet alone on one occasion (control phase) and with three different doses of 50, 100, and 200 mg of itraconazole simultaneously on the other three occasions (itraconazole phase). Although the elimination half-life and the renal clearance of fexofenadine remained relatively constant, a single administration of itraconazole with fexofenadine significantly increased mean area under the plasma concentration-time curve (AUC_0-) of fexofenadine (1701/3554, 4308, and 4107 ng h/ml for control; 50 mg, 100 mg, and 200 mg of itraconazole, respectively). Although mean itraconazole AUC_0-48 from 50 mg to 200 mg increased dose dependently from 214 to 772 ng h/ml (p = 0.003), no significant difference was noted in the three parameters, AUC (p = 0.423), C_max (p = 0.636), and renal clearance (p = 0.495), of fexofenadine among the three doses of itraconazole. Itraconazole exposure at a lower dose (50 mg) compared with the clinical dose (200 mg once or twice daily) had the maximal effect on fexofenadine pharmacokinetics, even though itraconazole plasma concentrations gradually increased after higher doses. These findings suggest that the interaction may occur at the gut wall before reaching the portal vein circulation, and the inhibitory effect must be saturated by substantial local concentrations of itraconazole in the gut lumen after 50-mg dosing.

Itraconazole, an antifungal azole, has been used as a first-line treatment for patients with extensive or recalcitrant cutaneous fungal infections, mixed dermatophytoses, candidiasis and aspergillosis (Haria et al., 1996). Itraconazole is extensively metabolized in the liver, and only one hydroxyitraconazole in over 30 metabolites has an antifungal activity similar to that of the parent drug (Haria et al., 1996). Because itraconazole is a potent inhibitor of CYP3A activity in vitro and in vivo, itraconazole coadministration with a CYP3A substrate can result in clinically significant drug interaction (Dresser et al., 2000). Similar to the inhibition of CYP3A-mediated metabolism, itraconazole significantly inhibits the in vitro activity of P-gp (Venkatakrishnan et al., 2000; Wang et al., 2002a; Keogh and Kunta, 2006), and coadministration of itraconazole has reduced the clearance of poorly metabolized P-gp substrates such as digoxin (Jalava et al., 1997) and celiprolol (Lilja et al., 2003) in volunteer studies. The drug interaction between fexofenadine and itraconazole has been demonstrated in previous volunteer studies (Shon et al., 2005; Shimizu et al., 2006a,b). We demonstrated that concomitant administration of 100 mg of itraconazole with fexofenadine increased fexofenadine AUC by almost 3-fold after a 4-day treatment of 100 mg of itraconazole twice daily (Shimizu et al., 2006a), and the increase of fexofenadine AUC throughout the 6 days of itraconazole treatment at a 200-mg dose once daily was almost constant, even though accumulation of plasma itraconazole concentration depended on duration of the 6-day treatment (Shimizu et al., 2006b). It is interesting that in these two different studies, no significant changes were found in elimination half-life and renal clearance reflecting elimination rates of fexofenadine. These results therefore imply that the increase in fexofenadine AUC by itraconazole is probably due to the reduced first-pass effect by inhibiting P-gp activity. Furthermore, the higher plasma itraconazole concentrations from higher doses of itraconazole might affect OATP-mediated hepatic uptake and/or P-gp-mediated hepatic excretion of fexofenadine to a greater extent and, thus, have an increased effect on fexofenadine pharmacokinetics.

The aim of this study was to determine whether the extent of drug interaction of fexofenadine resulting from P-gp inhibition by itraconazole is dose-dependent. We therefore investigated the effect of single administration of three different itraconazole doses, 50 mg, 100 mg, and 200 mg, on fexofenadine pharmacokinetics, and compared them with the pharmacokinetics of fexofenadine administered alone. We also evaluated the plasma concentration-time profiles of itraconazole and examined their influence on fexofenadine pharmacokinetics.

	Materials and Methods

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Subjects. Eleven healthy Japanese volunteers (six males and five females) were enrolled in this study after giving written informed consent. Each subject was physically normal by clinical examination and routine laboratory testing and had no history of significant medical illness or hypersensitivity to any drugs. The mean (±S.D.) values of age and body weight of volunteers were 22.0 (±1.2) years (range 20–24 years) and 56.9 (±7.2) kg (range 46–66 kg), respectively. This study was approved by the Ethics Committee of Hirosaki University School of Medicine.

Study Design. This randomized open-label study consisted of one control and three itraconazole phases, in which the volunteers received a tablet of 60 mg of fexofenadine hydrochloride (Aventis Pharma Ltd., Tokyo, Japan) at 8:00 AM with 240 ml of tap water after an overnight fast. In the three itraconazole phases, the volunteers were administered a 60-mg fexofenadine hydrochloride tablet with one, two or four 50-mg itraconazole capsules (Janssen Pharmaceutical K.K., Tokyo, Japan) simultaneously at 8:00 AM with 240 ml of tap water after an overnight fast. The order of the control and the itraconazole phases (50 mg, 100 mg, and 200 mg) for each of the 11 volunteers in the study was randomly determined by the Latin-square method. Three volunteers in three groups participated in each respective sequence in the four phases of the study, and two volunteers participated in the sequence of 200 mg of itraconazole, control, 50 mg of itraconazole, and 100 mg of itraconazole phase. Each phase was separated by more than 2 weeks from other phases of the study as a washout period. The volunteers did not take any medication or fruit juices for at least 7 days before the control or the treatment phases, and no meal or beverages were allowed until 4 h after the administration of fexofenadine.

Plasma and Urine Collections and Determination of Fexofenadine, Itraconazole, and Hydroxyitraconazole. Blood samples (10 ml each) were drawn into heparinized tubes before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 h after administration of fexofenadine, and plasma was separated immediately. Just before fexofenadine administration, a spot of urine was collected as a blank sample. After fexofenadine administration, the urine was collected from 0 to 48 h. The plasma and urine samples were stored at –20°C until assayed.

Plasma and urine concentrations of fexofenadine were determined by the high-performance liquid chromatography (HPLC) method developed in our laboratory (Uno et al., 2004). In brief, 10 µl (100 ng) of diphenhydramine as an internal standard and 1 ml of 0.2 M acetate buffer (pH 4.0) were added to 1 ml of plasma or urine samples. Samples were purified with C18 minicolumns (BondElute C18, 500 mg packing in 3 ml cartridge; Varian, Palo Alto, CA), and fexofenadine and the internal standard were eluted in 1 ml of methanol. After the eluates were evaporated with air, the residues were dissolved with a HPLC mobile phase. The flow rate was 1.0 ml/min and the column was maintained at 50°C. The peak was detected with a RF-10AXL fluorescence detector monitored at an excitation wavelength of 220 nm and an emission wavelength of 290 nm, and a CLASS-VP integrator (Shimadzu Co., Kyoto, Japan). The between-day coefficients of variation (CVs) and relative errors were 1.3% and –2.7% at 50 ng/ml (n = 5), respectively. The limit of quantification was 1.0 ng/ml. Plasma and urine samples from the itraconazole treatment did not have any interfering peak for the fexofenadine assay, and the plasma and urine samples before each fexofenadine administration had no fexofenadine peak detected in the assay.

Plasma concentrations of itraconazole and hydroxyitraconazole were determined by the HPLC method developed in our laboratory (Uno et al., 2006). In brief, after 30 µl of an internal standard (R051012, 10 µg/ml) and 0.1 ml of 0.5 M disodium hydrogen phosphate were added to 1 ml of plasma, the mixture was extracted with n-heptane/chloroform (60:40 v/v). The organic phase was evaporated, and the samples were dissolved and injected into column I (TSK precolumn BSA-ODS/S, 5 µm, 10 mm x 4.6 mm i.d.) for clean-up and column II (Develosil C8-5 column, 5 µm, 150 mm x 4.6 mm i.d.) for separation. The mobile phase consisted of phosphate buffer/acetonitrile (68:32 v/v, pH 6.0) and phosphate buffer/acetonitrile (35:65 v/v, pH 6.0) for clean-up and separation, respectively. The peak was detected with an ultraviolet detector set at a wavelength of 263 nm. The validated concentration ranges of this method were 3 to 500 ng/ml and 3 to 1000 ng/ml for itraconazole and hydroxyitraconazole, respectively. The between-day CV was 2.3% at 4 ng/ml (n = 6) and 2.4% at 4 ng/ml (n = 6) for itraconazole and hydroxyitraconazole, respectively. The limit of quantification was 2 ng/ml for both itraconazole and hydroxyitraconazole.

Pharmacokinetic Data Analysis. The maximum plasma concentration (C_max) and the time to reach C_max (t_max) of fexofenadine, itraconazole, and hydroxyitraconazole were determined directly from the observed data. The elimination rate constant (k_e) of fexofenadine was obtained by linear regression analysis by use of at least three sampling points of the terminal log-linear declining phase to the last measurable concentration. The elimination half-life (t_1/2) was calculated as 0.693 divided by k_e. The area under the plasma concentration-time curve from time 0 to the last sampling time (AUC_0-t) was calculated by the trapezoidal rule. AUC from zero to infinity (AUC_0-) was calculated by AUC_0-last + C_last/k_e, where C_last is the last detectable plasma drug concentration. In itraconazole and hydroxyitraconazole, AUC_0-48 was adopted because their plasma concentration-time profiles lacked the terminal log-linear declining phase. The apparent oral clearance (CL/F) was obtained from the equation CL/F = Dose/AUC/kg, and the apparent volume of distribution (V_d/F) was calculated from the equation V_d/F = CL/F/k_e. The renal clearance (CL_renal) was obtained from the following equation: CL_renal = Ae/AUC_0-48/kg, in which Ae is the amount of fexofenadine excreted into the urine within 48 h.

Statistical Analysis. The results are expressed as mean ± S.D. Repeated-measures analysis of variance was used for statistical differences in the mean pharmacokinetic parameters between the phases, and the Bonferroni test was used for post hoc comparison. All data were analyzed with the statistical program SPSS for Windows, version 11.5J (SPSS Inc. Chicago, IL). A p value less than 0.05 was considered statistically significant.

	Results

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None of the enrolled subjects reported any adverse events during the study and they completed all phases according to the study protocol.

Plasma Concentrations and Pharmacokinetics of Fexofenadine. Mean plasma fexofenadine concentration-time profiles following a single oral administration of 60 mg of fexofenadine hydrochloride in the control and the three itraconazole phases are shown in Fig. 1A, and the pharmacokinetic parameters are summarized in Table 1. The mean plasma concentrations of fexofenadine in the itraconazole phases were higher than those in the control phase. Itraconazole coadministration significantly increased fexofenadine AUC (p = 0.009, p < 0.001, and p = 0.002 for 50 mg, 100 mg, and 200 mg of itraconazole, respectively) and C_max (p = 0.028, p = 0.002, and p = 0.011 for 50 mg, 100 mg, and 200 mg of itraconazole, respectively), and reduced its CL/F (p < 0.001 for all itraconazole phases) and V_d/F (p < 0.001 for all itraconazole phases), compared with those in the control phase. However, no significant difference was noted in these parameters of fexofenadine such as AUC (p = 0.423), C_max (p = 0.636), and CL_renal (p = 0.495) between the doses of itraconazole. There was no significant difference in t_max or t_1/2 of fexofenadine between the phases.

View larger version (15K): [in this window] [in a new window]   FIG. 1. A, mean (+S.D.) plasma concentration-time curves of fexofenadine following a single oral administration of 60 mg of fexofenadine hydrochloride in 11 healthy volunteers during the control phase (open circle) and 50-mg (open triangle), 100-mg (open square), and 200-mg (open diamond) treatment phases of itraconazole administered once daily. B, mean (+S.D.) plasma concentration-time curves of itraconazole in 11 healthy volunteers at 50 mg (closed circle), 100 mg (closed triangle), and 200 mg (closed square) of itraconazole treatments.

Urinary Excretion of Fexofenadine. Although the renal clearance of fexofenadine was relatively constant between the control (63.5 ± 15.8 ml/h/kg) and the itraconazole phases (58.9 ± 19.6, 65.9 ± 27.0, and 64.1 ± 24.6 ml/h/kg for 50 mg, 100 mg, and 200 mg of itraconazole, respectively), there was a significant difference in the amount of fexofenadine excreted into the urine within 48 h (Table 1). However, the different doses of itraconazole did not affect the amount of fexofenadine excreted into the urine (Table 1).

Plasma Concentrations and Pharmacokinetics of Itraconazole and Hydoxyitraconazole. Mean plasma concentration-time profiles in the itraconazole phase with the doses of 50, 100, and 200 mg administered once daily are shown in Fig. 1B for itraconazole, and their pharmacokinetic parameters are summarized in Table 2. Mean C_max and AUC_0-48 of itraconazole and hydroxyitraconazole were increased following higher doses of itraconazole in a dose-dependent manner, and mean AUC_0-48 of itraconazole at 100 mg and 200 mg were increased by 1.9- and 3.6-fold, respectively, in comparison with that of 50 mg of itraconazole (p = 0.027 and p = 0.003 for 100 mg and 200 mg of itraconazole, respectively). Similarly, mean AUC_0-48 of hydroxyitraconazole of 100 mg and 200 mg of itraconazole were increased by 2.0- and 3.9-fold, respectively, in comparison with that of 50 mg of itraconazole (p = 0.021 and p = 0.007 for 100 mg and 200 mg of itraconazole, respectively).

	Discussion

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In this study, we investigated the effect of single administration of three different itraconazole doses, 50 mg, 100 mg, and 200 mg on fexofenadine pharmacokinetics. Because our previous findings indicated that the effect of a single dose of 200 mg of itraconazole was almost the same as the effect of multiple dosing of 200 mg of itraconazole once daily up to 6 days in terms of the effect on fexofenadine pharmacokinetics (Shimizu et al., 2006b), itraconazole was coadministered with fexofenadine simultaneously as a single dose, and a significant but similar increase in fexofenadine C_max and AUC_0- was found in any itraconazole phase of the present study. After administration of higher doses of itraconazole, itraconazole C_max and AUC were increased, but the increase in plasma itraconazole concentration did not affect fexofenadine pharmacokinetics. These findings are consistent with the results of our previous studies in which the 2-fold increase in fexofenadine C_max and AUC_0- by the itraconazole coadministration was relatively constant, despite an almost 4-fold increase in itraconazole AUC_0-24 after multiple dosing of itraconazole for 6 days (from 816 ± 415 on day 1 to 3142 ± 1285 ng h/ml on day 6).

Itraconazole coadministration has been reported to increase serum concentrations of digoxin, a substrate of P-gp, most probably by inhibiting P-gp in the small intestine and kidneys (Partanen et al., 1996; Jalava et al., 1997; Greiner et al., 1999). In the present study, although the itraconazole treatment significantly increased the amount of fexofenadine excreted into the urine within 48 h, mean CL_renal of fexofenadine was relatively constant between the control and the itraconazole phases. Therefore, in the interaction between fexofenadine and itraconazole, the effect of itraconazole could be due to a combination of increased bioavailability by inhibiting P-gp, and reduced organic clearance without CL_renal and distribution volume by inhibiting P-gp and/or other transporters, because fexofenadine is a substrate of several OATPs (Cvetkovic et al., 1999; Nozawa et al., 2004; Niemi et al., 2005; Shimizu et al., 2005), as well as P-gp (Cvetkovic et al., 1999; Perloff et al., 2002; Putnam et al., 2002). Itraconazole might inhibit OATP-mediated hepatic uptake and lead to reduced biliary excretion and, thus, increased fexofenadine excretion into urine. Although inhibition of uptake transporters should result in a time shift in t_max, no significant difference was noted in t_max between the control and the itraconazole phases. In addition, there are no in vitro data on itraconazole as an inhibitor of OATPs to date. Although some OATPs are reported to be the major determinant on fexofenadine disposition (Dresser et al., 2002, 2005), the role of OATP in the interaction of the present study may be less than that of P-gp in the small intestine.

Compared with the effective levels of itraconazole in clinical situations (trough itraconazole > 250 ng/ml; Van Cutsem, 1989), a much lower plasma concentration of itraconazole was potent enough to double the fexofenadine concentrations. However, these assumptions seemed to be unlikely because itraconazole concentrations in the systemic circulation would not play a major role in the interaction between fexofenadine and itraconazole, since a 10 times difference in itraconazole AUC (214 ± 113 and 3142 ± 1285 ng h/ml for a single dose of 50 mg and 6-day treatment of 200 mg daily, respectively) showed little effect on fexofenadine pharmacokinetics. In addition to this result, the similar effect that each administration of itraconazole had on fexofenadine AUC_0- and CL/F without significant change in CL_renal or t_1/2 implied that substantial local concentrations of itraconazole in the gut lumen would result in gastrointestinal inhibition of P-gp and an increase in absorption of fexofenadine from the gastrointestinal tract. However, as for this finding, further studies will be required because it is difficult to clarify the first-pass P-gp inhibition between the intestine and the liver since an intravenous fexofenadine preparation is unavailable, as Lemma et al. (2006) suggested.

In conclusion, itraconazole exposure at a much lower dose (50 mg) compared with the clinical dose (200 mg once or twice daily) had the maximal effect on fexofenadine pharmacokinetics, even though itraconazole plasma concentrations have gradually increased following higher doses. These findings suggest that the interaction may occur at the gut wall before reaching the portal vein circulation, and the inhibitory effect must be saturated by substantial local concentrations of itraconazole in the gut lumen after 50 mg of itraconazole was administered. The increase, however, has limited clinical importance because of a relatively wide therapeutic range of fexofenadine.

	Acknowledgments

 
This work was supported by a Grant for Priority Research Designated by the president of Hirosaki University.

	Footnotes

 
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

doi:10.1124/dmd.106.011023.

ABBREVIATIONS: P-gp, P-glycoprotein; OATP, organic anion-transporting polypeptide; HPLC, high-performance liquid chromatography; AUC, area under the plasma concentration-time curve; C_max, maximum plasma concentration; t_max, time to reach C_max; k_e, elimination rate constant; t_1/2, elimination half-life; CL/F, apparent oral clearance; V_d/F, apparent volume of distribution; CL_renal, renal clearance.

Address correspondence to: Dr. Tsukasa Uno, Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan. E-mail: uno-hki{at}umin.ac.jp

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