Graft-Versus-Host Disease

Pharmacokinetics of CsA during the switch from continuous intravenous infusion to oral administration after allogeneic hematopoietic stem cell transplantation

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Abstract

We investigated the serial changes in the blood CsA concentration during the switch from continuous intravenous infusion to twice-daily oral administration in allogeneic hematopoietic stem cell transplant recipients (n=12). The microemulsion form of CsA, Neoral, was started at twice the last dose in intravenous infusion in two equally divided doses. The area under the concentration–time curve during oral administration (AUCPO) was significantly higher than the AUC during intravenous infusion (AUCIV) (median 7508 vs 6705 ng/ml × h, P=0.050). The median bioavailability of Neoral, defined as (AUCPO/DOSEPO) divided by (AUCIV/DOSEIV), was 0.685 (range, 0.45–1.04). Concomitant administration of oral voriconazole (n=4) significantly increased the bioavailability of Neoral (median 0.87 vs 0.54, P=0.017), probably due to the inhibition of gut CYP3A4 by voriconazole. Although the conversion from intravenous to oral administration of CsA at a ratio of 1:2 seemed to be appropriate in most patients, a lower conversion ratio may be better in patients taking oral voriconazole. To obtain a similar AUC, the target trough concentrations during twice-daily oral administration should be halved compared with the target concentration during continuous infusion.

Introduction

CsA is the most widely used immunosuppressive agent for the prophylaxis of GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). It is usually administered by intravenous infusion for at least several weeks after allogeneic HSCT because of the damage done to the oral and gastrointestinal mucosa by the conditioning regimen. However, the dose, target blood level, and schedule of administration vary among protocols and have not been optimized.1 It has been shown that the blood concentration of CsA affects the incidences of acute GVHD and adverse events,2 and an increase in the target blood concentration from 300 to 500 ng/ml in the continuous infusion of CsA significantly decreased the incidence of acute GVHD.3 On the basis of these results, we are currently administering CsA by continuous infusion with target concentrations of 500 ng/ml for standard-risk patients and 300 ng/ml in high-risk patients. When patients can tolerate oral intake, CsA is switched from intravenous to oral administration at a dose ratio of 1:2. Neoral, a microemulsion formulation of CsA, has improved bioavailability and is the most commonly used oral product.4 However, the appropriateness of this conversion rate has been inconsistent among earlier studies.5, 6 Parquet et al. reported that doubling the last intravenous dose provided the best therapeutic range concentration, whereas the concentration/dose ratio was similar in intravenous administration and oral administration and thus, 1:1 conversion seemed appropriate in the McGuire's study. In addition, no data are available regarding the detailed pharmacokinetics in allogeneic HSCT recipients. Therefore, in this study, we investigated the serial changes in the CsA blood concentration during the switch from intravenous to oral administration and assessed the bioavailability of Neoral.

Patients and methods

Patients

Patients who underwent allogeneic HSCT with GVHD prophylaxis consisting of the continuous infusion of CsA and short-term MTX were included. This single-center prospective study was approved by the Institutional Review Board of Jichi Medical University, and each patient provided their written informed consent to be enrolled in the study.

Transplantation procedure

The conditioning regimen was mainly a combination of cyclophosphamide (60 mg/kg for 2 days) and TBI (2 Gy twice daily for 3 days) (n=8). Patients with severe aplastic anemia (n=3) were prepared with fludarabine, cyclophosphamide, and anti-thymoglobulin with or without a low dose of TBI at 2 Gy.7 A reduced-intensity regimen with fludarabine and melphalan was used for a 58-year-old patient with acute lymphoblastic leukemia (n=1). GVHD prophylaxis consisted of the continuous infusion of CsA with a starting dose of 3 mg/kg/day and short-term MTX (10–15 mg/m2 on day 1 and 7–10 mg/m2 on days 3 and 6, and optionally on day 11 in HSCT from a donor other than an HLA-matched sibling). The dose of CsA was adjusted to maintain the blood CsA concentration between 450 and 550 ng/ml in standard-risk patients (n=9) or 250 and 350 ng/ml in high-risk patients (n=3) according to the disease status.3 Acute GVHD was graded as described earlier.8 Prophylaxis against bacterial, fungal, and Pneumocystis jiroveci infection consisted of levofloxacin, fluconazole (FLCZ), and sulfamethoxazole/trimethoprim (ST) or inhalation of pentamidine. In three patients, micafungin (MCFG) was used instead of FLCZ because of persistent fever despite broad-spectrum antibiotic therapy, development of Candidemia, and high risk for invasive aspergillosis, respectively. As prophylaxis against herpes simplex virus infection, acyclovir (ACV) was given from days −7 to 35, followed by a long-term low-dose administration of ACV for varicella zoster reactivation.9 Pre-emptive therapy with ganciclovir for cytomegalovirus infection was performed by monitoring cytomegalovirus antigenemia.10

Study schedule

When patients were able to tolerate oral intake, CsA was switched from continuous infusion to oral administration. Intravenous infusion was stopped just before the first oral administration. The initial dose of Neoral was twice the last daily dose of continuous infusion, and was given in two equally divided doses based on the reported bioavailability of Neoral of about 0.4 (40%) in allogeneic HSCT recipients.5 On the last day of the continuous infusion of CsA (day −1), the serum CsA concentration was measured at 9:00, 15:00, and 21:00. After the patient was switched to Neoral, the CsA concentration was measured just before (C0), and 1 (C1), 2 (C2), 3 (C3), 4 (C4), 6 (C6), and 12 (C12) hours after the oral administration of Neoral on the first day (day 0) and between day 3 and day 5. The CsA concentration was measured using the CYCLO-Trac SP-whole blood kit (DiaSorin, Inc., Stillwater, MN, USA).11 In brief, 200 μl of whole blood sample was mixed with 800 μl of methanol and centrifuged at 1600 g for 5 min. The methanolic supernatant (50 μl in duplicate) was mixed with 100 μl of 125I-ligand and 1 ml of anti-CYCLO-Trac Immune Sep (pre-mixed mouse monoclonal antibody, donkey anti-mouse serum, and normal mouse serum). After centrifuging, the ligand was discarded by decanting and the amount of radioactivity of the pellet was determined. Data were analyzed by logit-log reduction. The standard curve was obtained using the CsA standard sera provided in the kit. The intra-assay coefficient of variance was <15%. The inter-assay coefficient of variance was <14%. The limit of detection was 4.0 ng/ml. The results of this assay showed good correlation with those obtained by high-performance liquid chromatography (r=0.98).

During the study, the dose of CsA could be modified at the discretion of each physician. Vital signs and laboratory variables including renal and liver function tests were evaluated on days 0, 3, 7, and 14. Concomitant medications that could potentially interact with CsA were recorded.

Statistical considerations

The area under the concentration–time curve (AUC) (0–12 h) of CsA was calculated by the trapezoidal method. We estimated the bioavailability of Neoral by dividing (AUCPO/DOSEPO) by (AUCIV/DOSEIV). Toxicities after switching from intravenous to oral administration were evaluated compared with the baseline data on day 0. Renal toxicity was defined as an elevation of the creatinine (Cr) level above × 1.5 the baseline value. Liver dysfunction was defined as an elevation of alanine aminotransferase (ALT) above × 2 the baseline value, or elevation of the total bilirubin (T-bil) level by 2 mg per 100 ml compared with the baseline value. Comparisons were made using the Wilcoxon signed-rank test for continuous variables. The Pearson correlation coefficient was used to analyze the correlation between AUC and the CsA concentration at each measurement point after logarithmic transformation. The effect of concomitant medications on CsA pharmacokinetics was first analyzed by a univariate analysis with the Mann–Whitney U-test, and then those with at least borderline significance (P<0.10) were subjected to a multivariate analysis using multiple regression modeling. A P-value of <0.05 was considered to be significant.

Results

Patients

Between January 2008 and April 2009, 12 patients were enrolled in the study. There were 7 males and 5 females with a median age of 34.5 years (range, 16–58). Underlying diseases included acute myeloblastic leukemia (n=4), acute lymphoblastic leukemia (n=3), severe aplastic anemia (n=3), chronic myelogenous leukemia (n=1), and myelodysplastic syndrome (n=1). Five patients received bone marrow graft from an unrelated donor, whereas 1 and 6 patients, respectively, received bone marrow and peripheral blood stem cell graft from a related donor. There was an HLA mismatch in three donor-recipient pairs.

Pharmacokinetic analysis

The median duration from transplantation to the switch from intravenous to oral administration was 40 days (range, 27–60). The dose of CsA and the pharmacokinetic parameters during intravenous and oral administration are shown in Table 1. Neoral was started at approximately twice the last dose of intravenous infusion, except that 1 patient (No. 8) received Neoral at the same dose as in intravenous infusion, as the mean CsA concentration on the last day of intravenous infusion was >700 ng/ml. In three patients (Nos. 1, 2, and 3), the dose of CsA was reduced on day 1 due to the high CsA concentration on day 0 (the day when Neoral was started).

Table 1 Dose of CsA and pharmacokinetic parameters during the intravenous and oral administration of CsA

The median AUC value was 6705 ng/ml × h (AUCIV; range, 3090–8730) before the conversion from intravenous to oral administration (day −1), 8493 ng/ml × h (AUCIV−PO; range, 3375–12 555) on day 0, and 7508 ng/ml × h (AUCPO; range, 2860–12420) on days 3–5, respectively. AUCPO was considered to be the AUC of Neoral in the steady state, as AUCIV−PO was affected by the intravenous administration of CsA and at least 3 days are required for the CsA concentration to stabilize after a change in the administration route. As a result, not only AUCIV−PO but also AUCPO was significantly higher than AUCIV (P=0.050), even though the dose of Neoral was reduced in three patients and the conversion ratio was 1:1 in another patient. The median bioavailability of Neoral was 0.685 (range, 0.45–1.04).

Relationship between AUC and the CsA concentration at each measurement point

Although the CsA concentration at each measurement point significantly correlated with AUCPO after logarithmic transformation, the strongest correlation was observed between C3 and AUCPO (Figure 1a and Table 2, correlation coefficient 0.984, P<0.001). The AUCPO could be predicted from the trough concentration (C0 or C12), which is widely measured in daily practice, by the following formula based on the linear regression model: Log (AUCPO)=1.020 × Log(C12)+1.344 (Figure 1b). Accordingly, each trough concentration between 50 and 250 ng/ml corresponds to the CsA concentration during the continuous intravenous infusion of CsA with the same AUC, calculated by dividing the predicted AUC by 12, between 99 and 514 ng/ml (Table 3). Thus, when the continuous intravenous administration of CsA with a target concentration of 500 ng/ml was switched to twice-daily oral administration, the target trough level should be about 250 ng/ml to obtain the same AUC. Also, the target blood concentration of 300 ng/ml during continuous infusion corresponds to the target trough concentration at 150 ng/ml during twice-daily oral administration. This estimation was different from that in kidney transplantation by Nakamura et al. (Table 3).12

Figure 1
figure1

Correlation between the AUC and the CsA peak (a: C3) and trough (b: C12) levels.

Table 2 Correlation coefficients between the AUC and the cyclosporine concentration at each measurement point
Table 3 Target cyclosporine concentration during continuous infusion to obtain a similar AUC during twice-daily oral administration with each target trough concentration

Influence of possible confounding factors on the bioavailability of Neoral

With regard to laboratory data, there were no statistically significant correlations between the bioavailability of Neoral and the serum Cr level, ALT level, and T-bil level (P=0.867, P=0.159, and P=0.770, respectively). Four patients had developed acute GVHD before the change in the route of CsA administration, but all of them had stage 1 skin GVHD that was successfully controlled by topical steroid. None of the patients had gastrointestinal involvement and thus the influence of gut GVHD on the bioavailability of Neoral could not be evaluated.

With regard to drug interactions, the effects of the following drugs on the bioavailability of Neoral were evaluated; antifungal agents including FLCZ, itraconazole (ITCZ), voriconazole (VRCZ), and MCFG, antibacterial agents including ST, vancomycin, fluoroquinolones (FQ), and cefepime, antiviral agents including ACV and ganciclovir (DHPG), and other drugs including amlodipine, sulpiride, gabapentin, and prednisolone (PSL) (Table 4). FLCZ (n=3), ITCZ (n=3), and VRCZ (n=4) were exclusively administered orally. These agents had been started at least 7 days before the change in the route of CsA administration. By the Mann–Whitney U-test, VRCZ, FQ, and ST were shown to have significant effects with at least borderline significance (P=0.048, P=0.061, and P=0.100, respectively). Among these, only VRCZ was identified as an independent significant factor by a multivariate analysis (P=0.017). The median bioavailability of Neoral in patients taking VRCZ was 0.87 (range, 0.76–1.04), whereas it was only 0.54 (range, 0.45–0.94) in those without VRCZ.

Table 4 Clinical and laboratory data at the conversion that could influence the cyclosporine pharmacokinetics

Clinical course after the change in the route of CsA administration

One patient (No. 2) developed liver dysfunction with an elevation of ALT from 28 IU/l at baseline to 300 IU/l 2 weeks after the conversion. The AUC of CsA was rather lower after conversion, and thus CsA was not considered to be the causative agent of liver dysfunction. Otherwise, no notable changes in laboratory and clinical data were observed (Table 5).

Table 5 Serial changes in laboratory data and blood pressure after the change in the route of CsA administration

Four patients had developed grade I acute GVHD of the skin before the change in the route of CsA administration. During the 2 weeks after the switch, 3 of the 4 patients had persistent grade I skin GVHD, whereas GVHD was improved in 1 patient. Among the eight patients who did not have acute GVHD at the switch, one patient developed grade I acute GVHD of the skin, which was well controlled by topical steroid, and the other seven patients did not develop acute GVHD during the observation period. No clinically significant changes in vital or biological parameters occurred in the study patients. One patient (No. 9) developed nausea soon after conversion. An excessive increase in the CsA concentration was considered to be the cause of nausea and this symptom was improved after the dose of Neoral was reduced.

Discussion

Neoral is a microemulsion formulation of CsA that has improved bioavailability and reduced variability in pharmacokinetic parameters within and between patients compared with a conventional CsA formulation (Sandimmun).4 Its bioavailability has been reported to be 0.38 (38%) in healthy volunteers.13 However, allogeneic HSCT patients have complications that could influence the CsA pharmacokinetics, such as damaged gastrointestinal mucosa and multiple drug interactions. The results of this study showed that the median value of the bioavailability of Neoral was 0.685 (range, 0.45–1.04). Detailed analyses revealed that the oral administration of VRCZ strongly affected the bioavailability of Neoral (0.87 vs 0.54). Therefore, although the switch from intravenous to oral administration of CsA at a ratio of 1:2 seemed to be appropriate in most patients, a lower conversion ratio such as 1:1.1 or 1:1.2 may be better in patients taking oral VRCZ.

The drug interactions between CsA and azole antifungal agents including FLCZ, ITCZ, and VRCZ have been well recognized.14 Azole antifungal agents are metabolized through the cytochrome P450-3A (CYP3A4) enzyme system, interfere with the metabolism of CsA, and thereby increase the exposure to CsA. Therefore, careful monitoring of the blood CsA concentration is recommended when these agents are added during CsA administration. On the other hand, there are considerable differences among azole antifungals with regard to their ability to inhibit CYP3A4.14 Interestingly, the concomitant use of oral VRCZ significantly increased the bioavailability of Neoral. We confirmed that VRCZ was started at least 7 days before the switch from intravenous to oral administration of CsA and was continued at the same dose after the switch. Therefore, the drug interaction between CsA and VRCZ seemed to be stronger during oral administration than during the intravenous infusion of CsA. We hypothesized that this stronger interaction can be explained by the presence of the P450 enzyme system in the gastrointestinal mucosa. The CYP3A4 isoenzymes are the most abundant isoforms of CYP and it has been postulated that CsA is also metabolized in the intestine by gut CYP3A4 isoenzymes.15 The administration of VRCZ might have inhibited the gut metabolism of CsA and increased the bioavailability of CsA. However, a prospective controlled study is required to confirm this hypothesis.

ITCZ, another strong inhibitor of CYP3A4, did not increase the bioavailability of Neoral. As the ratio of AUCIV/DOSEIV was higher not only in patients taking VRCZ but also in patients taking ITCZ compared with other patients (median 47.5, 55, and 41), ITCZ might have inhibited liver CYP3A4 similar to VRCZ, but inhibited gut CYP3A4 less strongly than VRCZ. This might have been affected by the different bioavailable dose of these agents, as the bioavailability of ITCZ is lower than that of VRCZ, in addition to the fact that the dose of ITCZ was lower than that of VRCZ (200 vs 400 mg/day).

With regard to the route of VRCZ, it was exclusively administered orally in this study. Therefore, we could not conclude whether the intravenous administration of VRCZ would similarly affect the bioavailability of CsA. In earlier reports, the extent of drug interaction between CsA and azole antifungals varied according to the route of administration and the dose or kind of antifungal agent. Numerous reports have shown a significant interaction (>84%) between oral FLCZ with a dose of 200 mg/day or greater and oral CsA.16, 17 On the other hand, Osowski et al.18 evaluated the drug interaction between intravenous FLCZ at 400 mg/day and intravenous CsA in HSCT recipients and there was a statistically significant but smaller increase (21%) in the serum CsA concentration. Mihara et al.19 reported that the mean steady-state whole-blood level of CsA significantly increased after the route of FLCZ administration was switched from intravenous to oral. These data suggest that the drug interaction between CsA and FLCZ was stronger when FLCZ was administered orally. With regard to other azole antifungal agents, not only oral but also intravenous administration of ITCZ significantly affected the blood concentration of CsA.20, 21, 22 Concerning the interaction between VRCZ and CsA, Mori et al.23 reported that the administration of VRCZ to patients receiving CsA resulted in a significant increase in the concentration/dose ratio of CsA, but the route of VRCZ administration did not affect the changes in the concentration/dose ratio. If we consider these findings together, it may be reasonable to suggest that the interaction between azole antifungal agents and CsA is stronger when the antifungals are given orally, but the difference becomes unclear with ITCZ and VRCZ, as the interactions of these agents are stronger than that of FLCZ and can be detected even when they are given intravenously. Therefore, when we interpret pharmacokinetic data of CsA, we must be cautious not only about concomitantly used agents but also the route of administration of both CsA and the other drugs. For example, Parquet et al. reported that a ratio of 1:2 in the switch from intravenous to oral administration was appropriate,5 whereas a 1:1 ratio seemed to be appropriate in the study by McGuire et al.6 In the former study, oral FLCZ was used concomitantly and thus their conclusion was consistent with our data. In the latter study, information on the use of antifungal agents was not described, and thus the data were difficult to interpret.

When we switch the route of CsA administration from continuous infusion to twice-daily oral administration, the target blood concentration should also be changed. Nakamura et al.12 reported that the CsA blood concentration during continuous infusion was estimated to be 2.55 times the trough level during twice-daily oral administration of Neoral to obtain an equal AUC of CsA in kidney transplant patients. In this study, we concluded that the CsA concentration during continuous infusion should be doubled compared with the trough concentration during twice-daily oral administration in allogeneic HSCT recipients. Although the calculation method was different, the conclusion was consistent (mean 2.01) when we applied their methods. Although the reason for the difference between these studies remains unclear, it may have been due to the differences in the use of concomitant drugs or the status of the gastrointestinal tract.

In conclusion, when switching CsA from continuous infusion to oral administration, concomitant medications that could affect the bioavailability of CsA, especially azole antifungal agents, should be taken into account. Although a 1:2 ratio on switching may be appropriate in most patients, a lower conversion ratio is recommended in patients taking oral VRCZ.

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Acknowledgements

This research was supported in part by grants from the Ministry of Health, Labor and Welfare of Japan.

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Correspondence to Y Kanda.

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Keywords

  • CsA
  • pharmacokinetics
  • bioavailability
  • drug interaction

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