Abstract
Aims
We determined whether or not the extent of drug interaction of fexofenadine by itraconazole is time-dependent.
Methods
In a randomized two-phase crossover study, itraconazole was administered orally for 6 days, and, on days 1, 3 and 6, fexofenadine was administered simultaneously. On another occasion, fexofenadine was administered alone.
Results
Itraconazole increased fexofenadine AUC(0, ∞), and the % change for difference was 178% (95% CI 1235, 3379), 205% (95% CI 1539, 3319) and 169% (95% CI 1128, 2987) on days 1, 3 and 6 of the 6 day treatment, respectively.
Conclusions
The extent of drug interaction by itraconazole was not time-dependent.
Keywords: drug interaction, fexofenadine, itraconazole, pharmacokinetics, treatment period
Introduction
Itraconazole, an antifungal azole, has been known to interact with many drugs [1]. For example, itraconazole coadministration with a CYP3A substrate can result in a clinically significant drug interaction [2]. In the interaction with midazolam, a CYP3A substrate [3], Olkkola et al. [4] reported that the inhibitory effect of itraconazole was dependent on the duration of the treatment: 6 day treatment with 200 mg itraconazole daily increased midazolam AUC more than a single administration did. From their findings, plasma itraconazole concentrations on the sixth day were approximately four times higher than that on the first day, which presumably led to an increase in the midazolam AUC [4].
Itraconazole also inhibits the in vitro activity of P-glycoprotein [1], and co-administration of itraconazole has reduced the clearance of poorly metabolized P-glycoprotein substrates such as digoxin [5] and celiprolol [6]. P-glycoprotein is known to transport fexofenadine, a selective histamine H1-receptor antagonist, in in vitro models [7–9], and a drug interaction between fexofenadine and itraconazole has been demonstrated in healthy volunteers [10, 11]. Since fexofenadine is a substrate for several organic anion transporting polypeptide (OATP) family transporters such as OATP1A2 (OATP-A) [7], OATP1B1 (OATP-C/OATP2) [12], OATP1B3 (OATP8) [13], and OATP2B1 (OATP-B) [14], as well as P-glycoprotein [7–9], higher plasma itraconazole concentrations from multiple doses of itraconazole might affect OATP-mediated hepatic uptake and/or P-glycoprotein-mediated hepatic excretion of fexofenadine to a greater extent than that resulting from a single dose, and thus have an increased effect on the pharmacokinetics of fexofenadine.
The aim of this study was to determine whether or not the extent of the drug interaction between fexofenadine and itraconazole was time dependent. We also evaluated the plasma concentration-time profiles of itraconazole, and examined their influence on the pharmacokinetics of fexofenadine.
Methods
This study was designed to have 80% power at the 5% significance level to detect a minimum 75% difference in fexofenadine AUC between the four phases, assuming a sample size of eight subjects. Ten healthy Japanese volunteers (nine males and one female) 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. Their mean values of age and body weight were 25.3 years (range 21–34 years) and 61.4 kg (range 46–73 kg), respectively. This study was approved by the Ethics Committee of Hirosaki University School of Medicine.
This randomized open-label study consisted of two (control and 6 day treatment) phases and altogether 4 study days, in which 60 mg fexofenadine hydrochloride was administered. In the control phase, the volunteers received 60 mg fexofenadine hydrochloride (Aventis Pharma Ltd, Tokyo, Japan) at 08.00 h after an overnight fast. In the treatment phase, the volunteers received 200 mg itraconazole (Janssen Pharmaceutical K.K., Tokyo, Japan) at 08.00 h for 6 days. On days 1, 3 and 6, each subject was administered 60 mg fexofenadine hydrochloride with itraconazole simultaneously after overnight fast. The order of the two phases was randomly assigned to each volunteer. Five volunteers started the control phase first and their treatment phase was started more than 24 h after the last blood sampling of the control phase. The others started the treatment phase first, and their control phase was started more than 2 weeks after the last sampling. The volunteers did not take any other medication or fruit juices for at least 7 days before each phase, and no meal or beverages were allowed until 3 h after fexofenadine administration.
Blood samples (10 ml each) were drawn before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 h after fexofenadine administration. A spot of urine was collected as a blank sample before fexofenadine administration and thereafter the urine was collected until 24 h after administration. Plasma concentrations of fexofenadine, itraconazole and hydroxyitraconazole and urine concentrations of fexofenadine were determined by the HPLC method developed in our laboratory [15, 16]. Plasma and urine samples in the treatment phase did not have any interfering peak for the assay, and the plasma and urine samples before fexofenadine administration had no fexofenadine peak detected.
The maximum plasma concentration (Cmax) and the time to reach Cmax (tmax) were determined directly from the observed data. The elimination rate constant (λz) 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 (t½) was calculated as 0.693 divided by λz. The area under the plasma concentration-time curve was calculated by the trapezoidal rule from 0 h to 24 h [ AUC(0,24 h)] and then extrapolated to infinity using λz [AUC(0,∞)]. Although fewer sampling points on the elimination phase might affect the reliability of measurement of the elimination half-life, AUC(0,24 h) of fexofenadine accounted for 96.2% (95% CI 95.3, 97.2) of AUC(0, ∞). For itraconazole and hydroxyitraconazole, AUC(0,24 h) was adopted because their plasma concentration-time profiles lacked the terminal log-linear phase. The apparent oral clearance (CL/F) was obtained from the equation CL/F = Dose/AUC/kg and the apparent volume of distribution (Vd/F) was calculated from the equation Vd/F= CL/F/λz. The renal clearance (CLrenal) was obtained from the equation CLrenal = Ae/AUC(0,24 h), in which Ae is the amount of fexofenadine excreted into the urine within 24 h.
The results are expressed as mean ± SD. Repeated measures anova was used for statistical differences in the mean pharmacokinetic parameters between the 4 study days in the control and treatment phases, and Bonferroni test was used for post hoc comparison. A P value less than 0.05 was considered statistically significant.
Results
None of the enrolled subjects reported any adverse events during the study and completed both phases according to the study protocol.
Itraconazole treatment significantly increased fexofenadine AUC(0, ∞) (P< 0.0001), Cmax (P< 0.005), and Ae (P< 0.0001), and decreased its CL/F (P< 0.0001) and Vd/F (P< 0.0001). However, no significant difference was noted in these parameters between the treatment periods of itraconazole (Table 1). There was no significant difference in tmax, t½, or CLrenal of fexofenadine between the control and the treatment phases (Table 1).
Table 1.
Effects of single and multiple doses of itraconazole treatment on pharmacokinetic parameters of fexofenadine after a single oral 60 mg administration of fexofenadine hydrochloride. Data represent mean ± SD; tmax data are given as median with range. Values in the parenthesis are 95% CI for the difference from control or day 1 except for tmax
| Itraconazole treatment | ||||
|---|---|---|---|---|
| Parameters | Control | Day 1 | Day 3 | Day 6 |
| tmax (h) (range) | 2 (0.5–4) | 2 (1–4) | 2 (1.5–4) | 2.5 (1–4) |
| Cmax (ng ml−1) | 332 ± 252♯ | 709 ± 287 | 679 ± 167 | 595 ± 257 |
| %change for difference from control | 195% (161, 593) | 231% (108, 585) | 180% (17, 508) | |
| %change for difference from day 1 | −22% (−207, 146) | −5% (−339, 110) | ||
| t½(h) | 6.6 ± 3.1 | 4.9 ± 0.8 | 4.6 ± 0.4 | 5.3 ± 0.8 |
| %change for difference from control | −16% (−4.0, 0.6) | −20% (−4.4, 0.4) | −9% (−3.6, 1.0) | |
| %change for difference from day 1 | −4% (−0.8, 0.2) | 9% (−0.1, 0.9) | ||
| AUC(0, ∞) (ng ml−1 h) | 1801 ± 979† | 4108 ± 1429 | 4231 ± 75 | 3859 ± 1057 |
| %change for difference from control | 178% (1235, 3379) | 205% (1539, 3319) | 169% (1128, 2987) | |
| %change for difference from day 1 | 16% (−723, 968) | 4% (−1260, 761) | ||
| CL/F (l h−1 kg−1) | 0.75 ± 0.47† | 0.28 ± 0.14 | 0.24 ± 0.05 | 0.28 ± 0.08 |
| %change for difference from control | −54% (−0.75, −0.20) | −56% (−0.83, −0.19) | −51% (−0.79, −0.16) | |
| %change for difference from day 1 | −3% (−0.13, 0.06) | 11% (−0.09, 0.09) | ||
| Vd/F (l kg−1) | 6.67 ± 4.09† | 2.08 ± 1.47 | 1.62 ± 0.34 | 2.13 ± 0.73 |
| %change for difference from control | −61% (−6.82, −2.36) | −59% (−7.89, −2.21) | −48% (−7.33, −1.74) | |
| %change for difference from day 1 | −1% (−1.43, 0.51) | 27% (−0.82, 0.93) | ||
| Ae (mg) | 5.6 ± 3.3† | 11.5 ± 5.9 | 12.6 ± 6.2 | 13.6 ± 6.1 |
| %change for difference from control | 136% (2.8, 9.0) | 178% (4.6, 10.8) | 184% (3.5, 11.1) | |
| %change for difference from day 1 | 23% (0.5, 3.1) | 28% (−2.1, 4.9) | ||
| CLrenal (ml min−1) | 55.6 ± 21.8 | 50.4 ± 27.3 | 53.4 ± 24.3 | 58.6 ± 23.9 |
| %change for difference from control | −13% (−13.1, 2.7) | −4% (−10.1, 5.8) | 5% (−3.0, 9.1) | |
| %change for difference from day 1 | 18% (−5.8, 12.0) | 31% (−2.2, 18.7) | ||
tmax, observed time to reach the maximum plasma concentration; Cmax, observed maximum plasma concentration; t½ , elimination half-life; AUC(0, ∞), area under plasma drug concentration-time curve from 0 h extrapolated to infinity; CL/F, apparent oral clearance; Vd/F, apparent volume of distribution; Ae, amount of fexofenadine excreted into urine; CLrenal, renal clearance.
P < 0.005 for the control phase vs. the treatment phase.
P < 0.0001 for the control phase vs. the treatment phase.
The pharmacokinetic parameters of itraconazole and its hydroxymetabolite are summarized in Table 2. Mean Cmax of itraconazole and hydroxyitraconazole were increased after repeated administration of itraconazole, and mean AUC(0,24 h) at day 3 or day 6 of the treatment phase was greater than that at day 1 for both itraconazole (P< 0.0001) and hydroxyitraconazole (P< 0.0001).
Table 2.
Pharmacokinetic parameters of itraconazole and hydroxyitraconazole at day 1, day 3 and day 6 of the treatment phases with 200 mg itraconazole once daily for 6 days. Data represent mean ± SD; tmax data are given as median with range. Values in the parenthesis are 95% CI for the difference from day 1 except for tmax
| Parameters | Day 1 | Day 3 | Day 6 |
|---|---|---|---|
| Itraconazole | |||
| tmax (h) (range) | 3 (2–6) | 4 (3–8) | 3 (2–8) |
| Cmax (ng ml−1) | 93 ± 49† | 198 ± 35 | 260 ± 97 |
| % change for difference from day 1 | 179% (69, 142) | 219% (117, 217) | |
| AUC(0,24 h) (ng ml−1 h) | 816 ± 415† | 2393 ± 754 | 3142 ± 1285 |
| % change for difference from day 1 | 299% (964, 2190) | 343% (1545, 3107) | |
| CL/F (l h−1 kg−1) | 4.03 ± 2.30† | 1.00 ± 0.37 | 0.77 ± 0.39 |
| % change for difference from day 1 | −67% (−4.75, −1.31) | −78% (−4.75, −1.77) | |
| Hydroxyitraconazole | |||
| tmax (h) (range) | 3.5 (2–6) | 4 (3–8) | 4 (2–6) |
| Cmax (ng ml−1) | 200 ± 97† | 328 ± 81 | 461 ± 192 |
| % change for difference from day 1 | 103% (54, 203) | 151% (160, 363) | |
| AUC(0,24 h) (ng ml−1 h) | 2244 ± 1260† | 5206 ± 1281 | 6838 ± 2459 |
| % change for difference from day 1 | 225% (1712, 4212) | 264% (3351, 5836) | |
tmax, observed time to reach the maximum plasma concentration; Cmax, observed maximum plasma concentration; AUC(0,24 h), area under plasma drug concentration-time curve from 0 to 24 h after administration; CL/F, apparent oral clearance.
P < 0.0001 for day 1 vs. day 3 and day 6.
Discussion
We investigated the effect of single and multiple doses of 200 mg itraconazole once daily on fexofenadine pharmacokinetics. Itraconazole treatment increased fexofenadine Cmax and AUC(0, ∞) by approximately two-fold, but no significant difference in these parameters was found between the treatment periods of itraconazole. In contrast, the plasma concentration-time profiles of itraconazole and hydroxyitraconazole showed a significant difference between the treatment periods of itraconazole. In spite of an increase in itraconazole concentration after multiple dosing, the increase of fexofenadine Cmax and AUC by the itraconazole co-administration was relatively constant irrespective of the duration of itraconazole treatment. As mean AUC(0,24 h) of itraconazole gradually increased during the 6 day treatment, a time-dependent effect of itraconazole treatment is more realistically regarded as a concentration-dependent effect. A similar effect at each administration of itraconazole on fexofenadine AUC(0, ∞) and CL/F without a significant change in CLrenal or t½ implied that substantial local concentrations of itraconazole in the gut lumen would result in gastrointestinal inhibition of P-glycoprotein and an increase in absorption of fexofenadine from the gastrointestinal tract.
Oral doses of 200 mg itraconazole and 60 mg fexofenadine hydrochloride were selected as a recommended clinical dose, but the relatively short duration or the small dose of itraconazole may affect the results of the present study. For example, a single glass of grapefruit juice increased AUC of many CYP3A substrates without affecting its elimination half-life by presumably inhibiting the intestinal CYP3A but not hepatic CYP3A [17]. However, repeated consumption of grapefruit juice was reported to increase AUC of triazolam, a CYP3A substrate, and prolong its elimination half-life, compared with that after a single drink of the juice. The prolongation of elimination half-life was considered to be a reflection of inhibiting hepatic CYP3A [18]. In the present study, a larger dose of itraconazole and longer treatment might affect the elimination of fexofenadine and lead to results different from our present study. However, the dose of 200 mg itraconazole once daily is used in a clinical situation and a single dose of 200 mg itraconazole is potent enough to double exposure to fexofenadine. If the therapeutic range of fexofenadine were much narrower, a single co-administration of 200 mg itraconazole would lead to serious adverse events with fexofenadine due to high plasma concentrations.
In conclusion, this study indicates that itraconazole co-administration increases fexofenadine exposure and the effect of itraconazole was relatively constant throughout the 6 days of itraconazole treatment. Since accumulation of plasma itraconazole concentration did not alter fexofenadine pharmacokinetics, the increase in fexofenadine exposure by itraconazole is probably due to the reduced first-pass effect by inhibiting P-glycoprotein activity in the gastrointestinal tract. The increase, however, has limited clinical importance because of the relatively wide therapeutic range of fexofenadine.
Acknowledgments
Competing interests: None to declare.
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