Effect of Itraconazole and Its Metabolite Hydroxyitraconazole on the Blood Concentrations of Cyclosporine and Tacrolimus in Lung Transplant Recipients

Abstract

Invasive Aspergillus infection is a major factor for poor prognosis in patients receiving lung transplantation (LT). An antifungal agent, itraconazole (ITCZ), that has antimicrobial activity against Aspergillus species, is used as a prophylactic agent against Aspergillus infection after LT. ITCZ and its metabolite, hydroxyitraconazole (OH-ITCZ), potently inhibit CYP3A and P-glycoprotein that metabolize or excrete calcineurin inhibitors (CNIs), which are the first-line immunosuppressants used after LT; thus, concomitant use of ITCZ and CNIs could induce an increase in the blood concentration of CNIs. However, no criteria for dose reduction of CNIs upon concomitant use with ITCZ in LT recipients have been defined. In this study, the effect of ITCZ and OH-ITCZ on the blood concentrations of two CNIs, tacrolimus and cyclosporine, after LT were retrospectively evaluated. A total of 39 patients who received LT were evaluated. Effects of ITCZ and OH-ITCZ on the concentration/dosage (C/D) ratio of tacrolimus and cyclosporine were analyzed using linear mixed-effects models. The plasma concentrations of OH-ITCZ were about 2.5-fold higher than those of ITCZ. Moreover, there was a significant correlation between the plasma concentrations of ITCZ and OH-ITCZ. Based on parameters obtained in the linear regression analysis, the C/D ratios of cyclosporine and tacrolimus increase by an average of 2.25- and 2.70-fold, respectively, when the total plasma concentration of ITCZ plus OH-ITCZ is 1000 ng/mL. In conclusion, the plasma levels of ITCZ and OH-ITCZ could be key factors in drawing up the criterion for dose reduction of CNIs.

INTRODUCTION

Calcineurin inhibitors (CNIs), such as tacrolimus and cyclosporine, are the first-line immunosuppressants used after lung transplantation (LT). Relatively higher doses of CNIs compared with those used for patients who have undergone transplantation of other organs are routinely administered to LT patients to suppress rejection and improve graft survival.^1,2) However, CNIs have narrow therapeutic concentration windows, and show wide inter- and intraindividual variabilities in their pharmacokinetics. Therefore, a comprehensive understanding of factors that influence the pharmacokinetics of CNIs is necessary to individualize the dosages of CNIs for the prevention of allograft rejection after LT as well as to alleviate adverse effects, such as nephrotoxicity.

Immunosuppressive therapy using CNIs after LT can make the patients susceptible to infectious diseases. Invasive Aspergillus infection is a major factor for the poor prognosis in patients receiving LT.³⁾ Itraconazole (ITCZ) has antimicrobial activity against Aspergillus species and is used as a prophylactic agent against Aspergillus infection after LT.⁴⁾ ITCZ and hydroxyitraconazole (OH-ITCZ), a major metabolite of ITCZ,⁵⁾ potently inhibit the activity of CYP3A and P-glycoprotein, which are key proteins that metabolize or excrete CNIs. Thus, concomitant use of ITCZ and CNIs induces an increase in the blood concentration of CNIs.⁶⁾ It has been shown that coadministration with ITCZ increases the concentration to dose (C/D) ratio of tacrolimus and cyclosporine,^7–10) and that the interaction between tacrolimus and ITCZ is greater than that between cyclosporine and ITCZ.⁸⁾ In view of these findings, there is a need to reduce the dose of CNIs, upon or before initiating ITCZ administration, to prevent the toxicity caused by them. In a previous study, a correlation between the plasma concentrations of ITCZ and the magnitude of interaction between ITCZ and CNIs has been reported.⁸⁾ It has been suggested that the plasma level of ITCZ is a marker to predict the changes in the C/D ratio of CNIs; however, the effect of the plasma concentration of OH-ITCZ on the C/D ratio of CNIs remains unclear. No criteria for dose reduction of CNIs when used concomitantly with ITCZ in lung transplant recipients have been defined.

In this context, we aimed to quantify the effects of ITCZ and its metabolite on the blood concentrations of tacrolimus and cyclosporine after LT.

PATIENTS AND METHODS

Patients

We conducted a single-center retrospective analysis. Patients who received LT at Kyoto University Hospital between June 2008 and September 2013 were eligible if they were administered tacrolimus or cyclosporine orally, along with ITCZ oral solution. Patients were excluded if the data on blood concentrations of ITCZ were not available. A total of 39 patients were analyzed (for cyclosporine: 19 patients, for tacrolimus: 20 patients). This study was performed in accordance with the Declaration of Helsinki and its amendments and was conducted under the authority of the Kyoto University Graduate School and the Kyoto University Hospital Ethics Committee (Approval No. R0012).

Determination of Concentration and Data Collection

We collected all available data on trough blood concentrations of CNIs and ITCZ from the electronic medical database at the Kyoto University Hospital, which were measured simultaneously. The baseline was defined as the CNI concentration just before the ITCZ treatment. To analyze the effect of ITCZ on the concentration of CNIs at steady state, the data in the first 12 d after the initiation of ITCZ administration were excluded. We also collected data on the concomitant use of following drugs that have potentials to induce or inhibit CYP3A4 or P-glycoprotein: rifampicin, antiepileptic drugs (phenytoin, carbamazepine), efavirenz, bosentan, azole antifungals (ketoconazole, voriconazole, fluconazole), macrolide antibiotics (clarithromycin, erythromycin, roxithromycin), calcium channel blockers (diltiazem, verapamil), cimetidine, ranitidine, fluvoxamine, antiviral drugs (ritonavir, glecaprevir, pibrentasvir), proton-pump inhibitors (omeprazole, lansoprazole, esomeprazole, rabeprazole).^11,12) In patients taking potential inhibitors of CYP3A4 or P-glycoprotein, the data during the first 7 d after withdrawal of these inhibitors were excluded. Finally, data on trough blood concentrations of CNIs and ITCZ were collected from a total of 89 and 60 sampling points, respectively. The baseline concentration data of CNIs was 1 point for all patients. The median number of data points on trough levels of CNIs during concomitant use of ITCZ was 1 (range, 1–3) in the cyclosporine group and 2 (range, 1–3) in the tacrolimus group.

Whole blood concentrations of tacrolimus and cyclosporine were determined using the chemiluminescent enzyme Immunoassay (ARCHITECT^® i2000SR, Abbott Laboratories, Chicago, IL, U.S.A.) and the affinity column-mediated immunoassay method (COBAS^® e601, Roche Diagnostics, Basel, Switzerland), respectively. The lower limits of quantitation for tacrolimus and cyclosporine were defined as 0.5 and 25 ng/mL, respectively.

Plasma concentrations of ITCZ and OH-ITCZ, both of which have antifungal activity and inhibitory potential against CYP3A4, were measured using an HPLC method (Shimadzu Prominence HPLC System; Shimadzu, Kyoto, Japan).¹³⁾ Data were collected and analyzed using LabSolutions software (Shimadzu). Separation was carried out on a CHEMCOSORB 5-ODS-H (5.0 µm, 50 × 4.6 mm I.D., ChemcoPlus, Osaka, Japan) kept at 40 °C with a mixture of 20 mM phosphate buffer and acetonitrile (40 : 60, v/v). The flow rate was 1.0 mL/min. The wavelength was set at 254 nm. The lower limits of quantitation for both ITCZ and OH-ITCZ were 50 ng/mL.

Statistical Analysis

Correlation between the plasma concentration of ITCZ and OH-ITCZ, and the dose of ITCZ was assessed by Pearson’s correlation analysis. The effects of ITCZ and OH-ITCZ on the C/D ratios of tacrolimus and cyclosporine were assessed using the linear mixed-effects models:

  

where α is the estimate of intercept, β is the estimate of fixed effect, I_ITCZ is the indicator variable, γ is the estimate of random effect for the intercept (individual-level residual with mean zero and variance σ²_γ), and ε is the estimated residual error (with mean zero and variance σ²_ε). The effect of ITCZ was assessed using five models. In model 1, I_ITCZ = 1, if ITCZ was concomitantly administered; I_ITCZ = 0, if ITCZ was not administered concomitantly. In model 2, I_ITCZ was the dosage of ITCZ (mg/kg). In models 3, 4, and 5, I_ITCZ was the total or individual concentration of ITCZ and OH-ITCZ (ng/mL). Akaike’s information criterion (AIC)¹⁴⁾ was used as the measure to compare goodness-of-fit between competing models. p values less than 0.05 were considered statistically significant. Statistical analyses were carried out using the JMP software version 14 (SAS Institute Inc., Cary, NC, U.S.A.).

RESULTS

Clinical characteristics of patients analyzed in this study are shown in Table 1. Twenty and nineteen patients were administered tacrolimus and cyclosporine, respectively. The median daily doses of ITCZ in the tacrolimus and cyclosporine groups were 4.41 and 4.53 mg/kg, respectively.

Table 1. Clinical Characteristics of Lung Transplant Recipients Taking Tacrolimus or Cyclosporine with Itraconazole (ITCZ)

Clinical characteristics		Tacrolimus	Cyclosporine
Men/Women (n)		11/9	10/9
Age (years)		44.5 (17–61)	44.0 (6–60)
Body weight (kg)		51.0 (34.7–73.3)	46.0 (12.3–82.3)
Deceased-donor LT/Living-donor LT (n)		12/8	7/12
Total sampling points (n)*		54	45
Daily dose of calcineurininhibitors (mg/kg)		0.15 (0.04–0.28)	7.54 (2.61–24.4)
Concentration of calcineurininhibitors (ng/mL)		12.2 (5.1–19.9)	253 (37–417)
Daily dose of ITCZ (mg/kg)		4.41 ± 1.11	4.53 ± 1.02
Concentration of ITCZ (ng/mL)		316 ± 194	289 ± 189
Concentration of OH-ITCZ (ng/mL)		787 ± 550	665 ± 516
Concomitant drug	Proton pump inhibitor	8	6
	Macrolide antibiotic	1	2
	Calcium channel blocker	0	2

Age, body weight, daily dose, and concentrations of calcineurin inhibitors (CNIs) are presented as median values (min-max). Daily doses of CNIs and ITCZ, and concentration of CNIs, ITCZ, and hydroxyitraconazole (OH-ITCZ) are presented as means ± standard deviation (S.D.). *The baseline data was 1 point for all patients. The median number of data points during concomitant use of ITCZ was 2 (range, 1–3) in the tacrolimus group and 1 (range, 1–3) in the cyclosporine group. LT., lung transplantation.

Initially, we examined the correlation between the dose of ITCZ and the plasma concentrations of ITCZ or OH-ITCZ. The data at the latest time point for each patient were included, since we assumed that the concentration at the later time point would reflect the value at steady-state. As shown in Figs. 1A and B, the plasma concentrations of ITCZ and OH-ITCZ were not correlated with the dose of ITCZ (r² = 0.010, r² = 0.015, respectively). On the contrary, the plasma concentrations of OH-ITCZ were significantly correlated with those of ITCZ (Fig. 1C, r² = 0.93). No significant differences in the ratio between ITCZ and OH-ITCZ were observed among patients administered cyclosporine and tacrolimus.

Fig. 1. Relationship between the Plasma Concentration of Itraconazole (ITCZ) or Hydroxyitraconazole (OH-ITCZ) and the Dose of ITCZ

(A, B) The trough plasma concentrations of ITCZ or OH-ITCZ were compared with the dose of ITCZ. The data at the latest time point for each patient were included. Squared correlation coefficients between the dose and plasma concentrations were calculated as 0.010 (p = 0.68) for ITCZ and 0.013 (p = 0.64) for OH-ITCZ. (C) The plasma concentrations of ITCZ and OH-ITCZ at the same sampling points were compared. Squared correlation coefficient between the concentrations of OH-ITCZ and ITCZ was calculated as 0.93 (p < 0.01). Open and closed circles show the data for patients who were concomitantly administered cyclosporine (N = 19) and tacrolimus (N = 20), respectively.

Next, we examined the effects of ITCZ on the C/D ratio of CNIs. We compared the effect of the administration of ITCZ, the dose of ITCZ, and the plasma concentrations of ITCZ and OH-ITCZ on the C/D ratio of CNIs (Figs. 2, 3). The median C/D ratio of cyclosporine increased from 30.9 to 74.0 (ng/mL)/(mg/kg/d) with the concomitant use of ITCZ (Fig. 2A). The median C/D ratio of tacrolimus increased from 70.9 to 338.0 (ng/mL)/(mg/kg/d) with the concomitant use of ITCZ (Fig. 3A).

Fig. 2. Relationship between the Concentration/Dose (C/D) Ratio of Cyclosporine and Coadministration with ITCZ (A), Dose of ITCZ (B), and Concentration of ITCZ or OH-ITCZ (C–E)

The C/D ratio of cyclosporine was expressed as the blood trough concentration normalized by the last dose of cyclosporine. The baseline is the concentration just before the start of the ITCZ treatment. A total of 45 data were included. The baseline data was 1 point for all patients (N = 19). The median number of data points during concomitant use of ITCZ was 1 per patient (range, 1–3). The dose and plasma concentration of ITCZ at the baseline are expressed as zero. (A) Bars and numbers show the median values.

Fig. 3. Relationship between the C/D Ratio of Tacrolimus and Coadministration with ITCZ (A), Dose of ITCZ (B), and Concentration of ITCZ or OH-ITCZ (C–E)

The C/D ratio of tacrolimus is expressed as the blood trough concentration normalized by the last dose of tacrolimus. The baseline is the tacrolimus concentration just before the start of the ITCZ treatment. A total of 54 data were included. The baseline data was 1 point for all patients (N = 19). The median number of data points during concomitant use of ITCZ was 2 per patient (range, 1–3). The dose and plasma concentration of ITCZ at the baseline are expressed as zero. (A) Bars and numbers showed the median values.

Linear regression analyses were performed to quantify the effects of ITCZ on the C/D ratio of CNIs. Although patients who concomitantly used potent inhibitors of CYP3A4 or P-glycoprotein were included in this study (Table 1), the effect of these drugs on the C/D ratio of CNIs was not significant. Therefore, the effect of concomitant drugs was not considered in the models. AIC obtained in the analysis was used to compare the effect of parameters of ITCZ. Table 2 shows the parameters estimated by the linear regression analysis. Based on the estimation of model fitting of statistical models by AIC, models 3, 4, and 5, in which the plasma levels of ITCZ or OH-ITCZ were considered, were more appropriate models to estimate the effect of ITCZ on the C/D ratio of cyclosporine. In contrast, the four models, in which the administration of ITCZ, or the plasma levels of ITCZ or OH-ITCZ were considered, were more appropriate for estimating the effect of ITCZ on the C/D ratio of tacrolimus.

Table 2. Parameters Estimated by the Regression Analysis

Model	Intercept (α)		Fixed effect (β)		Random effect for the intercept (γ)		Residual error (ε)		AIC
	Estimate	S.E.	Estimate	S.E.	Variance (σ2γ)	S.E.	Variance (σ2ε)	S.E.
Cyclosporine
Model 1	41.0	10.7	45.1	10.2	1087.1	556.3	1104.9	316.9	460
Model 2	45.0	11.2	8.4	2.3	1241.3	629.3	1205.5	736.1	467
Model 3	39.7	7.6	0.050	0.004	831.1	338.1	346.8	99.2	437
Model 4	38.2	7.5	0.173	0.015	782.1	323.0	349.1	100.1	434
Model 5	40.5	7.7	0.069	0.006	854.9	348.3	361.7	103.4	438
Tacrolimus
Model 1	89.8	41.3	301.5	40.7	13797.4	7178.0	20265.0	4956.6	698
Model 2	121.0	44.8	57.5	10.0	16178.6	8739.7	25507.0	6253.8	712
Model 3	127.9	33.7	0.217	0.024	11367.5	5614.3	15753.8	3799.9	700
Model 4	122.1	34.4	0.795	0.087	12206.7	5829.6	15368.8	3710.2	698
Model 5	131.5	33.6	0.296	0.033	11125.9	5593.2	16182.8	3901.3	701

Effects of ITCZ and OH-ITCZ on the concentration/dose (C/D) ratio of tacrolimus or cyclosporine were assessed using linear mixed-effects models. Random effects (γ) were considered for assessing the variability among patients. Fixed effects (β) were considered for assessing the effect of the administration of ITCZ (“with ITCZ” = 1, “without ITCZ” = 0; Model 1), the dose of ITCZ (mg/kg; Model 2), the total concentration of ITCZ plus OH-ITCZ (ng/mL; Model 3), the concentration of ITCZ (ng/mL; Model 4), or the concentration of OH-ITCZ (ng/mL; Model 5). Akaike’s information criterion (AIC) was used as a measure to compare the goodness-of-fit between competing models. S.E., standard error.

DISCUSSION

Significant drug–drug interactions between orally administered ITCZ and CNIs, resulting in an increase in the blood concentrations of CNIs, have been previously reported.^{7–10,15,16)} In hematopoietic stem cell transplant recipients, it has been shown that the C/D ratios of tacrolimus and cyclosporine after the cotreatment with ITCZ are 1.8–5.6- and 1.8–2.7-fold higher, respectively, than those before the ITCZ use.^7,8,15) However, the extent of interaction between ITCZ and tacrolimus in patients with LT considering the ITCZ dosage or concentrations has been examined in only a few studies.^9,10) No information is available for the interaction between ITCZ and cyclosporine in LT. Because the target-ranges of CNI concentrations differ with the type of organ transplant, an assessment of the effects of ITCZ on the C/D ratio of CNIs after LT is needed. In this study, we aimed to quantify the effect of ITCZ on the blood concentrations of tacrolimus and cyclosporine in patients with LT. The median C/D ratios of cyclosporine and tacrolimus increased by 2.4- and 4.8-fold, respectively, upon coadministration of ITCZ. We also found that the C/D ratios of cyclosporine and tacrolimus correlated well with the total or individual concentrations of ITCZ and OH-ITCZ, while linear regression analysis showed the effects of the dosage of ITCZ on CNIs were relatively weak. Therefore, the plasma levels of ITCZ and OH-ITCZ were indicated to be useful markers to predict the magnitude of drug–drug interaction between ITCZ and CNIs than the dosage of ITCZ. Based on parameters obtained in the linear regression analysis, the C/D ratios of cyclosporine and tacrolimus increase by an average of 2.13- and 2.63-fold, respectively, when the plasma concentration of ITCZ is 250 ng/mL. When the total plasma concentration of ITCZ plus OH-ITCZ is 1000 ng/mL, the C/D ratios of cyclosporine and tacrolimus increase by an average of 2.25- and 2.70-fold, respectively.

ITCZ is used prophylactically to prevent fungal infection after LT. It has been reported that ITCZ is metabolized to OH-ITCZ by CYP3A4 in the liver,⁶⁾ and that OH-ITCZ circulates in the plasma at similar concentrations compared with ITCZ.¹⁷⁾ In this study, we evaluated the trough plasma concentrations of ITCZ and OH-ITCZ in patients with LT. The results showed that the plasma concentrations of OH-ITCZ were about 2.5-fold higher than those of ITCZ. We found a significant correlation between the plasma levels of ITCZ and OH-ITCZ. However, there was no correlation between the dose of ITCZ and the plasma concentrations of ITCZ or OH-ITCZ in patients with LT. These results suggested a large interindividual variability in the bioavailability of orally administered ITCZ in patients with LT. Itraconazole is a highly lipophilic compound and completely insoluble in water. It has been known that the absorption of ITCZ is dissolution rate limited, and that bioavailability of ITCZ is significantly influenced by gastric pH and food.^18,19) Based on our findings and those of a previous study²⁰⁾ showing that the plasma concentrations of ITCZ plus OH-ITCZ are associated with the anti-fungal activity of the administered ITCZ, we believe that therapeutic drug monitoring of ITCZ and OH-ITCZ should be important for safe and effective treatment or prophylaxis against Aspergillus infection after LT.

The present study has the following limitation: there might be unmeasured factors rather than the plasma concentrations of ITCZ that affect the magnitude of interaction between ITCZ and CNIs. ITCZ and OH-ITCZ inhibit CYP3A4 and 3A5, which are key regulators in the pharmacokinetics of tacrolimus.¹⁶⁾ Although it has been shown that genetic polymorphisms in CYP3A4 are not associated with the pharmacokinetics of tacrolimus in the Asian population,²¹⁾ the CYP3A5 genotype significantly affects the C/D ratio of tacrolimus.²²⁾ Moreover, it has previously been shown that the CYP3A5 genotype significantly affects the rate of change of the C/D ratio of tacrolimus upon coadministration of azole antifungal agents.^23,24) Therefore, the CYP3A5 genotype could contribute to interindividual variability in the effect of ITCZ on the C/D ratio of tacrolimus.

In conclusion, we demonstrate a significant drug–drug interaction between ITCZ and CNIs in patients with LT. Notably, the total or individual plasma concentration of ITCZ and OH-ITCZ could potentially be a key factor for drawing up the criterion for dose reduction of CNIs.

Acknowledgments

This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Nos. JP25928093, JP26928029, and JP15H00526.

Conflict of Interest

The authors declare no conflict of interest.

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