Posaconazole Tablets in Real-Life Lung Transplantation: Impact on Exposure, Drug-Drug Interactions, and Drug Management in Lung Transplant Patients, Including Those with Cystic Fibrosis

ABSTRACT

Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations (C₀) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were <0.7 mg/liter for prophylaxis and 1 to 3 mg/liter for cure. The tacrolimus (TRL) and everolimus (ERL) C₀ measured during PSZ exposure were also collected. The interaction with proton-pump inhibitors (PPI) was evaluated. We recorded the results for 21 CF patients with LT (CFLT patients), 11 non-CF patients with LT (NCFLT patients), and 27 nontransplant (NT) patients in pneumology departments. The weights of the NCFLT, CFLT, and NT patients were 59.2 ± 8.4, 48.8 ± 8.4, and 63.7 ± 16.6 kg, respectively (P = 0.001* [asterisk means that statistical test is significant]), and the PSZ C₀ exposures for these patients were 1.9 ± 1.5, 1.1 ± 0.8, and 2.4 ± 1.8 mg/liter, respectively (P < 0.00001*). More than 60% of the concentrations were in the therapeutic range. In CFLT patients, the administration of one 300-mg PSZ tablet quickly achieved an exposure similar to that achieved with the PSZ oral suspension formulation (OSF) administered 3 or 4 times a day for several months. The TRL C₀/dose ratio (C₀/D) was 7.4 ± 4.4 mg/liter with PSZ tablets, whereas it was 4.6 ± 0.8 mg/liter with the PSZ oral solution (P = 0.034*). The ERL C₀/D was similar with both formulations. PPI had no impact on the PSZ concentration (1.49 ± 1.07 mg/liter without PPI versus 1.33 ± 1.17 mg/liter with PPI; P = 0.4134*). Despite the high levels of exposure, PSZ remained well tolerated (one case of diarrhea and one case of fatigue were reported). PSZ tablet administration allows satisfactory exposure, even in CFLT patients, with a dosage lower than that of the PSZ OSF. This once-a-day formulation was not impacted by PPI, which are extensively used in CF patients.

INTRODUCTION

Posaconazole (PSZ) is a systemic antifungal azole drug available for the treatment of fungal infections. The main indication for this drug is for hematological prophylaxis, but it may also be used for curative purposes and can potentially be of use in the field of lung transplants (LT), including in patients with cystic fibrosis (CF) (1, 2). The rates of fungal colonization ranged from 20% to 50% in LT patients (3), a population particularly at risk for the development of fungal infections because of immunosuppressive therapy (4). This population is also at risk of fungal bronchitis, leading to abnormal healing and stenosis. CF itself (because of frequent colonization before transplantation) and the nature of the transplanted organ greatly increase the rate of fungal colonization in LT patients (5). The incidence of invasive fungal disease after LT is 3 to 14% (6).

PSZ has been used since 2006 as an oral suspension formulation (OSF), which involves a complex dosing regimen (Table 1). Pharmacokinetic limitations have resulted in difficulties with the achievement of significant plasma drug exposure. The OSF indeed has saturable, low, and erratic absorption with nonlinear pharmacokinetics. It requires administration with food and is dramatically impacted by the concomitant administration of proton pump inhibitors (PPI) (1). Therapeutic drug monitoring (TDM) was implemented to control the variability in exposure in CF patients with LT (CFLT patients).

TABLE 1.

Recommended doses according to indication and formulation^a

Indication	Dose by formulation
	PSZ tablets	PSZ OSF
Refractory IFI/intolerance of first-line therapy in patients with IFI	Loading dose of 300 mg (three 100-mg tablets) twice a day on the first day and then 300 mg (three 100-mg tablets) once a day thereafter; each dose may be taken without regard to food intake	200 mg (5 ml) four times a day; alternatively, patients who can tolerate food or a nutritional supplement may take 400 mg (10 ml) twice a day during or immediately following a meal or nutritional supplement
Prophylaxis of IFI	Same as for refractory IFI/intolerance of first-line therapy in patients with IFI	200 mg (5 ml) three times a day; each dose of posaconazole (Noxafil) should be administered during or immediately after a meal or a nutritional supplement in patients who cannot tolerate food to enhance oral absorption and to ensure adequate exposure

^aData are from reference 1. IFI, invasive fungal infections.

Due to the recent introduction of a delayed-release PSZ tablet formulation in June 2015, posaconazole is likely to play an increased role as an alternative to voriconazole (VRZ) in the treatment of fungal infections or colonization, especially aspergillosis (7). PSZ is indeed better tolerated by patients, with only a mild asymptomatic increase in liver function test results being detected (8, 9). The delayed-release, gastrointestinal tract-resistant film-coated tablet consists of a pH-sensitive polymer stabilizer excipient that limits posaconazole release at the low pH found in the stomach and releases posaconazole at the neutral pH found in the small intestine (10). There is a strong and coherent corpus of evidence that use of the tablet results in a drop in the level of exposure with a simplified scheme. The pharmacokinetics of this new solid oral tablet of PSZ supported the clinical evaluation of PSZ at 300 mg once daily as a regimen for the cure of fungal infections, with this regimen demonstrating higher absorption and less variability than the regimen involving the OSF (11). The tablet and OSF are not to be used interchangeably due to differences in the frequency of dosing (Table 1), the need for the administration of the OSF with food, the plasma drug concentrations achieved with the two regimens, as well as the fact that the total daily doses of the two regimens are different (1).

Like other antifungal triazole drugs, PSZ is an inhibitor of the cytochrome P450 3A4 (CYP3A4) isoenzyme (12). Calcineurin inhibitors (CNI), such as cyclosporine (CSA) and tacrolimus (TRL), and the mammalian target of rapamycin inhibitors, such as everolimus (ERL), are substrates of CYP3A4. Administration of azole antifungals to patients under CNI or ERL therapy results in a significant drug-drug interaction characterized by increased levels of exposure to the immunosuppressive therapy (13). As CYP3A4 is expressed by the gastrointestinal tract wall and the liver, inhibition by triazoles can occur at both sites (14). Posaconazole is metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for P-glycoprotein (P-gp) efflux in vitro (1). Strong inhibition of P-gp by PSZ and the BCRP activity of PSZ were observed in vitro (15).

CFLT patients are considered a special population regarding drug disposition (because of their younger age and lower body weight) and the risk for Aspergillus infection (because of airway obstruction, with an important infection rate and frequent Aspergillus colonization) (16). CF patients also have specific pharmacokinetics because of their disease: delayed or decreased absorption, variation in the volume of distribution in proportion to lean body mass index, pancreatic insufficiency, and enhanced clearance in pediatric patients (15). Gastroesophageal reflux disease (GERD) is prevalent in children with CF, the incidence of which is between 35 and 81% (17), and may be an additional problem. Furthermore, transplantation itself is another factor influencing pharmacokinetics because of GERD and gastroparesis due to thoracic surgery and the use of immunosuppressive drugs. Finally, infectious complications in lung transplant recipients are the most common cause of nonimmunological mortality and morbidity because of permanent environmental exposure, airway-related complications, and postoperative graft denervation leading to impaired mucociliary clearance. From this perspective, azoles are widely used for preemptive, prophylactic, or curative treatment. The use of higher doses of azoles may be necessary to achieve therapeutic concentrations in CF patients (6).

We report our experience in LT patients, including CF and non-CF patients, whose therapeutic dose of 300 mg orally once a day was monitored and adapted to the trough levels. Higher levels of exposure to PSZ were sometimes necessary, raising some questions about, first, the safety of the exposure resulting from the drug dose, and second, the management of the inhibition of metabolism resulting from an interaction of PSZ with immunosuppressive drugs.

RESULTS

Study population and baseline demographics.

A total of 59 patients from two centers were included in the study, and 263 PSZ concentrations (average, 4.5 concentrations per patient; range, 1 to 20 concentrations per patient) were available. The patients were divided into 3 groups: CFLT patients (n = 21), non-CF patients with LT (NCFLT patients; n = 11), and nontransplant (NT) patients (n = 27; consisting of patients with asthma [n = 2], graft-versus-host disease after allograft [n = 8], granulomatosis [n = 3], variable sequelae [n = 5], postchemotherapy aplasia [n = 2], and other conditions [n = 7]).

A significant difference in age (P < 0.00001*) and weight (P = 0.002*) was observed between the groups. The sex ratio was similar between the groups (P = 0.1562). CFLT patients were younger and had lower body weights. Baseline demographics are given in Table 2. On average, the first determination of the PSZ concentration was performed during the first week after treatment introduction.

TABLE 2.

Baseline characteristics of NCFLT, CFLT, and NT patients

Characteristic	Value(s) for:			P valuea
	NCFLT patients	CFLT patients	NT patients
No. of patients	11	21	27
No. of males/no. of females	5/6	11/10	20/7	0.1562
Age (yr)	55.6 ± 7.9	30.9 ± 11.3	52.4 ± 17.8	<0.00001*
Wt (kg)	59.2 ± 8.4	48.8 ± 8.4	63.7 ± 16.6	0.002*
Dosage (mg)	252.8 ± 81.0	298.0 ± 101.0	282.0 ± 72.0	0.035*
Concn (mg/liter)	1.9 ± 1.5	1.1 ± 0.8	2.4 ± 1.8	<0.00001*

^aAn asterisk means that the statistical test is significant.

Statistical analysis was then performed two by two, and conclusions are given in Table 3.

TABLE 3.

Comparison of the significance of the difference in the characteristics among NCFLT, CFLT, and NT patients

Patient group and characteristic	Significant difference fora:
	NCFLT patients	CFLT patients
NT patients
Age	≈	1
Wt	≈	1
Concn	≈	1
Dosage	≠	≈
CFLT patients
Age	≠
Wt	≠
Concn	≠
Dosage	≠

^aSignificance was determined using the t test or the Welch test (depending on the difference between variances). ≈, no significant difference; ≠, a significant difference (P ≤ 0.05).

PSZ concentration.

Significant differences in the PSZ dosage (P = 0.035*) and PSZ concentration (P < 0.00001*) were observed between the groups (Table 2). Despite the use of higher doses in CFLT patients, CFLT patients achieved significantly lower PSZ concentrations.

The between-subject variability (calculated as the coefficient of variation [CV]) in the PSZ concentration was 79% in the NCFLT group, 72% in the CFLT group, and 75% in the NT group. The within-subject variability (calculated as the mean CV) in the PSZ concentration was not significantly different between the groups (38% in the NCFLT group, 62% in the CFLT group, and 42% in the NT group; P = 0.2225).

PSZ dosage and concentration/dose ratio.

A PSZ dosage of 300 mg (the recommended daily dose) was observed in 115 out of the 187 samples (61.5%) for which the dosage was available. A PSZ dosage greater than 300 mg was observed in 26 samples (n = 12 patients; 13.9%; n = 187 available dosages), including 85% from the CFLT group (22/26 samples for n = 9 patients). A dosage under 300 mg was observed in 46 samples (24.6%; n = 14 patients). Dosing changes were performed by adding 100 mg to the doses. For CFLT patients, the dose was changed in 14 patients by increasing the dosage in 9 patients and by decreasing the dosage in 5 patients. The dosage remained 300 mg for 7 patients. For NCFLT patients, the dose was changed in 5 patients by decreasing the dosage. The dosage remained 300 mg for 6 patients. For NT patients, the dose was changed in 7 patients by increasing the dosage in 2 patients and by decreasing the dosage for 5 patients. The dosage remained 300 mg for 17 patients. For the patients receiving 300 mg daily, the mean PSZ concentration was 1.0 ± 0.8 mg/liter (n = 7), 1.6 ± 1.0 mg/liter (n = 6), 2.6 ± 1.9 mg/liter (n = 17), in CFLT, NCFLT and NT patients, respectively.

No significant difference in the PSZ concentration was observed if the dosage was less than 300 mg, 300 mg, or greater than 300 mg (1.46 ± 0.96 mg/liter, 1.65 ± 1.50 mg/liter, and 1.87 ± 1.90 mg/liter, respectively; P = 0.506).

Therapeutic range.

As shown in Fig. 1, for all groups, more than 60% of the trough levels were in the therapeutic range of 0.7 to 3 mg/liter. In the CFLT group, 31.6% of the concentrations were detectable but were less than 0.7 mg/liter (n = 43/136 concentrations). In the NT group, 21.7% of the concentrations were above 3 mg/liter (n = 15/69 concentrations). The distribution of the PSZ concentrations was significantly different between the groups (P < 0.00001*) and was significantly different between the CFLT and NCFLT groups (P = 0.0002*). A total of 12 out of the 263 dosages (4.9%) were very high (>3.75 mg/liter).

FIG 1.

Distribution of infratherapeutic and supratherapeutic concentrations in percents, with dark gray for concentrations less than 0.7 mg/liter, black for concentrations between 0.7mg/liter and 3mg/liter, and light gray for concentrations greater than 3 mg/liter.

For NT patients, a therapeutic plasma trough level (0.7 to 3 mg/liter) was obtained directly on the first measurement in 85.2% of the patients (n = 23, with 3 patients having concentrations greater than 3 mg/liter). A therapeutic plasma trough level was achieved during the first month after treatment introduction in 100% of NCFLT patients and 82.4% of CFLT patients. Adaptation of the dosage was performed in 2 CFLT patients to allow achievement of the target concentration, including in one patient with no trough level determination during the first month.

According to the results presented in Fig. 2, the average trough PSZ concentration in the NCFLT group was graphically 1 mg/liter. The PSZ concentration was lower (about 0.7 mg/liter) in the CFLT group than in the other groups. For the NT group, the PSZ concentrations were much more spread out and were found to range from 0.7 to 4 mg/liter.

FIG 2.

Histograms of the density functions of the 263 PSZ concentrations, represented as the cumulative number of samples for each range of PSZ concentrations.

Drug interaction.

The TRL trough concentration-versus-dose ratio (C₀/D) without PSZ was 1.4 ± 0.6 (n = 19) (16). With PSZ tablets, the TRL C₀/D was 7.4 ± 4.4 (n = 20), with the mean dosage being 1.8 ± 1.5 mg daily. The TRL C₀/D was 4.6 ± 0.8 (n = 12) with the PSZ oral solution in a previous study from our group (18). The TRL C₀/D was increased with the tablet formulation (P = 0.034). Eleven of the 32 lung transplant patients (34.4%) experienced a supratherapeutic tacrolimus C₀ (>15 ng/ml) during PSZ coadministration (range, 15.0 to 24.0 ng/ml). The TRL concentration versus the PSZ concentration is given in Fig. 3.

FIG 3.

TRL concentration versus PSZ concentration.

The ERL C₀/D was 8.5 ± 5.3 (n = 10), with the mean dosage being 1.2 ± 0.9 mg daily. The ERL C₀/D was 11.8 ± 6.8 (n = 6) in a comparable cohort of patients dosed with PSZ OSF at the European Hospital Georges Pompidou between 2006 and 2011. The ERL C₀/D was similar with PSZ tablets and the PSZ OSF (P = 0.2955).

The proton pump inhibitor treatment status was found for 25 patients (7 NCFLT patients and 18 CFLT patients). No difference in the distribution of CFLT and NCFLT patients receiving or not receiving a PPI was observed (P = 0.8511). The PSZ concentration was not significantly different according to whether the patient received a PPI: 1.49 ± 1.07 mg/liter in patients not receiving a PPI (n = 6, including 5 CFLT patients) versus 1.33 ± 1.17 mg/liter in patients receiving a PPI (n = 19, including 13 CFLT patients) (P = 0.4134).

Despite the higher level of exposure, PSZ was well tolerated. Only one case of diarrhea and one case of fatigue were reported in our study. These 2 adverse events (fatigue and diarrhea) were the only emergent adverse events which were, in the opinion of the patients and the clinicians, related to PSZ. The patient experiencing fatigue reduced the dosage on his own. The case of diarrhea was associated with lower PSZ concentrations. Of note, a few young patients returned to the use of OSF because they complained that the tablets were hard to swallow.

DISCUSSION

The patients in our prospective cohort were separated into three groups according to their lung transplantation and CF status. As expected, CFLT patients were younger and had lower body weights.

The mean PSZ trough level observed in our cohort compared with what is recommended in the literature was easily achieved (6). With a 300-mg tablet administered orally once a day, the level of exposure was globally correct, including in the CFLT patient group. Almost all the patients had a concentration in the therapeutic range within the first month after treatment introduction. A therapeutic plasma trough level was achieved during the first month after treatment introduction in 82% of the CFLT patients. One of the reasons for the low concentration was diarrhea, which was often observed in CFLT patients treated with mycophenolate, as has already been described (19).

The between-subject variability in the PSZ concentration was high in all groups, and the intrasubject variability in the PSZ concentration was not significantly different in the NT and NCFLT groups.

The French Medicines Agency (ANSM), together with the European Medicines Agency (EMA), warned that the OSF and the tablet formulation may not be used interchangeably (19). Krishna et al. showed that the tablet formulation allowed higher levels of exposure than the OSF in healthy subjects (20). The administration of the PSZ tablet at 300 mg once a day quickly achieved an exposure similar to that achieved with the administration of the PSZ OSF 3 or 4 times a day when it was used for several months in CFLT patients (1.1 ± 0.8 mg/liter in the 21 CFLT patients from this study versus 0.7 ± 0.5 mg/liter in the 17 CFLT patients from a previous study of our group [16]). The dosage used in the present study was remarkably lower than that used in the previous study (298.0 ± 101.0 mg daily versus 1,085 ± 330 mg daily).

For all groups, more than 60% of the trough levels were in the therapeutic range, which is consistent with the findings of Stelzer et al. (4). In the CFLT group, a third of the concentrations were less than 0.7 mg/liter. However, the dosage was significantly higher in the CFLT group than in the other groups, and a dosage greater than 300 mg was necessary almost exclusively in the CFLT group.

PSZ concentrations were lower in the CFLT group than in the NCFLT group. Changes in pharmacokinetics in the CF population can indeed lead to decreased drug exposure and to the need for an increased drug dose (16). The CF patients were also significantly younger than the other patients. It has been demonstrated that CF and the age of the patient significantly influence azole concentrations in lung transplant recipients (4). The upper threshold in a clinical trial was defined to be 3.75 mg/liter. This concentration was exceeded in 4% of the patients in a previous study (10) and 3% of hematological patients treated with oral tablets in another study (21) and was exceeded in 4.9% of the patients in our study.

The PSZ OSF increased the maximum blood concentration and the area under the concentration-time curve for TRL by 121% and 358%, respectively, after 14 days (22). The TRL C₀/D was increased with PSZ tablets. One could assume that this is likely due to the higher levels of exposure achieved with the tablet formulation. Confronted with the values previously registered for the same CF patient cohort, a quantitative difference in the drug-drug interaction intensity can be described upon treatment with TRL and proton pump inhibitors: the reference C₀/D were 7.8 ± 4.5 (5-fold) and 6.5 ± 3.4 (4-fold) for itraconazole (ITZ) and VRZ, respectively. In this scheme, PSZ acted as an inhibitor as severe as VRZ and ITZ. In a recent study (23), the variation in TRL concentration between that at the baseline and that after azole therapy was, on average, 4.4 ± 2.6 (range, 0.9 to 18.0) with posaconazole, but the study was performed between 2007 and 2015 and the PSZ formulation was not considered.

In contrast to the findings with sirolimus (SRL), in which the concomitant use of PSZ tablets resulted in the inhibition of CYP3A4 of a greater magnitude than the concomitant use of the PSZ OSF (24), the ERL C₀/D was similar with both formulations.

The level of TRL exposure was significantly increased when the level of PSZ exposure was high, whereas the level of ERL exposure was not significantly different. The metabolism of both ERL and TRL is mediated by cytochrome P450. P-glycoprotein is known to play an important role in the intestinal absorption of TRL (25). The intestinal absorption of ERL is also affected by the different activities of the drug efflux pump P-glycoprotein (26). Mechanisms other than solely P-gp-mediated efflux might limit the intestinal bioavailability of SRL and ERL (27). It could be assumed that the difference in the levels of exposure to TRL and ERL is due to those other mechanisms, resulting in a saturable interaction between PSZ and ERL. Because of the small number of patients in our study, the evaluation of a larger cohort would be interesting to confirm this hypothesis. However, particular precautions must be made with the TDM of TRL because of its immunosuppressive properties and toxicity.

Although PSZ is well tolerated (28, 29), monitoring of the level of PSZ exposure is important in CFLT patients because, despite the use of dose adjustment strategies, 34.4% of our lung transplant patients experienced transient supratherapeutic tacrolimus levels.

As shown previously (30, 31), the PSZ concentration was also not significantly different in lung transplant patients, including CF patients, according to whether the patient was receiving a PPI.

Conclusion.

PSZ tablet administration enables a satisfactory exposure, even in CFLT patients, with a 3-fold lower dosage than that of PSZ in the OSF. The once-a-day administration of the tablet formulation was not impacted by the coadministration of PPI, which are extensively used by CF patients. More than 60% of the concentrations were in the therapeutic range of 0.7 to 3 mg/liter. Almost all the patients had a concentration in the therapeutic range within the first month after treatment introduction. Despite the use of a higher PSZ dosage but one that was still in the 300-mg range, PSZ concentrations were lower in the CFLT group than in the NCFLT group.

PSZ acts as significant an inhibitor of TRL as VRZ and ITZ, considering the C₀/D of 7.4 ± 4.4, and a significant correlation between TRL and PSZ concentrations was observed.

Although PSZ is well tolerated, monitoring of PSZ exposure is very important to manage the drug-drug interaction with immunosuppressive therapy in NCFLT patients, especially CFLT patients receiving PSZ.

MATERIALS AND METHODS

We conducted a prospective study among LT patients in two French centers. The study included all patients of the European Hospital Georges Pompidou (Paris, France) and Foch Hospital (Suresnes, France) receiving PSZ tablets under TDM evaluation between June 2015 and December 2016. PSZ TDM was routinely performed, without any program ensuring regularity, according to the clinician's decision. Data collection was approved by the French National Commission of Informatics and Liberty in decision number 1896480v0. The target populations were LT patients, including CF patients with a lung transplant (CFLT patients) and non-CF patients with a lung transplant (NCFLT patients), and nontransplant (NT) patients in the Pneumology Department of each center. PSZ quantitative plasma trough concentrations (C₀) were determined using a liquid chromatography-tandem mass spectrometry assay (Acquity TQD; Waters Corporation, Milford, MA, USA). Indicative thresholds of interest were based on usual levels: 0.7 mg/liter for prophylaxis and 1 to 3 mg/liter for cure (6).

Data were collected from the tracking sheets used in the daily routine by the pharmacology laboratory for patients of the European Hospital Georges Pompidou and from the patients' electronic medical records (from DxCare [version 10.2.0.4.0; Medasys, Clamart, France] and from hospitalization reports from Foch Hospital).

The primary outcome was the PSZ trough concentration, which was compared between the groups (NCFLT, NT, and CFLT patients).

Secondary outcomes included the drug-drug interaction with immunosuppressive agents, such as TRL and ERL. For this purpose, the TRL and ERL trough blood concentrations measured during PSZ exposure were collected when available. Doses were not kept constant during the study, with variable exposure, but linear pharmacokinetics, also justifying consideration of the trough concentration-versus-dose ratio (C₀/D). The TRL and ERL C₀/D were calculated by dividing the blood concentration of TRL or ERL (expressed in nanograms per milliliter) by the total daily dose (in milligrams). The ERL C₀/D under treatment with the PSZ OSF was determined for patients in whom the ERL concentration was monitored when the patients were concomitantly receiving PSZ before commercialization of the PSZ tablet formulation (unpublished data obtained between 2006 and 2011). Finally, the interaction with proton pump inhibitors (PPI) was evaluated using a comparison of the PSZ concentration between patients receiving a PPI and patients not receiving a PPI.

Statistical analysis was performed using Excel 2010 software for Windows (Microsoft Corporation, Redmond, WA, USA) and the R program (version 3.2.3). Quantitative variables were expressed as means and standard deviations and were compared using the t test or the Welch test (depending on the difference between variances) and analysis of variance or the Kruskal-Wallis test (after checking for the homogeneity of variances by the Bartlett test). Categorical variables were expressed as number and percentage and were compared by the Pearson chi-square test.