Similar Trough Levels Research Articles

Sublingual Administration of Tacrolimus is Safe and Provides Similar Drug Exposure to Per-oral Route in Liver Transplant Recipients During Early Postoperative Period–A Large, Retrospective, Observational Study

BackgroundPer-oral(PO) administration of Tacrolimus(TAC) results in inadequate trough levels in early post-operative period in liver-transplant(LT) recipients who undergo Roux-en-Y hepaticojejunostomy for biliary reconstruction. Sublingual administration(SL) of tacrolimus provides an alternative route in such patients. ObjectiveTo assess feasibility and safety of SL tacrolimus in adult LT-recipients in early post-operative period and to compare therapeutic efficacy of SL administration of tacrolimus vs.PO route. Patients and MethodSingle-centre, retrospective, observational study carried out in adult living donor liver transplant(LDLT) recipients between January 2022 till December 2022. Recipients who underwent Roux-en-Y hepaticojejunostomy for biliary reconstruction, received tacrolimus through SL route till post-operative day(POD)5 as they were kept nil per oral constituted the study group while recipients who underwent duct-to-duct(D-D) anastomosis for biliary reconstruction were allowed orally from POD1 and received PO-tacrolimus were chosen as controls. Feasibility and safety of SL-Tacrolimus was assessed in terms of patient acceptance, need to discontinue SL-Tacrolimus, incidence of local adverse effects and systemic adverse events like neurotoxicity and nephrotoxicity. Therapeutic efficacy was evaluated by comparing median trough levels(TAC level) achieved and incidence of graft rejection between two groups. Results212 patients underwent LT during the study period of which 125 were included(58 in SL-group and 67 in PO-group). Both groups had comparable baseline characteristics. In SL-group, all patients tolerated SL-Tacrolimus well and no local adverse events were observed. Patients with SL-Tacrolimus administration achieved higher median TAC level(ng/ml) vs.PO route(5.85 vs 5(p=0.06)) despite similar median cumulative tacrolimus dose before assessing TAC-level. 50% patients achieved TAC level ≥6ng/ml in SL-group vs. 35.8% in PO-group(p=0.14). Incidence of neurotoxicity, nephrotoxicity and graft rejection during hospital stay were similar in both the groups(p=0.56,0.82 and 0.28 respectively). ConclusionSL-tacrolimus is safe and provides similar trough levels to PO-tacrolimus and may be considered as viable alternative whenever inadequate TAC-levels are anticipated through per-oral route.

Tacrolimus Dose Requirements in Lung Transplant Recipients on Systemic Azole Antifungals: The Influence of Race

<h3>Purpose</h3> The <i>CYP3A5*1</i> polymorphism, predominant in African Americans (AAs), and drug interactions with CYP3A inhibitors/inducers significantly impact tacrolimus metabolism. Minimal data evaluating tacrolimus dose requirements (TDRs) in lung transplant recipients (LTRs) on concurrent strong CYP3A inhibitors exists. We sought to assess the effect of race on TDRs and transplantation outcomes in a cohort of LTRs initiated on a fixed tacrolimus dose and antifungal prophylaxis with a systemic azole after transplant. <h3>Methods</h3> All adult LTRs transplanted from 1/2015-10/2019 initiated on an equivalent tacrolimus dose posttransplant per institutional protocol were included and stratified by race. TDRs, tacrolimus levels, systemic azole use, biopsy proven acute rejection (BPAR), patient survival, and graft survival for the first year posttransplant were evaluated. <h3>Results</h3> 68 LTRs were included (10 AA, 58 non-AA); the majority were on a systemic azole at 1 (90.8%) and 3 (90.3%) months posttransplant. TDRs were significantly higher in AAs at the first therapeutic level, discharge, and months 1, 3, 12 posttransplant (Figure 1); tacrolimus levels and time within therapeutic range (55% AA vs 40.5% non-AA, p=0.13) were similar. AAs had a similar time to first therapeutic level (11.2 days AA vs 7.8 days non-AA, p=0.10) and number of dose adjustments to achieve this level (4 vs 2.6, p=0.08). The majority of LTRs did not achieve a therapeutic tacrolimus level prior to discharge (80% AA vs 69% non-AA, p=0.48). No differences in BPAR (20% AA vs 25.9% non-AA, p=0.69), patient survival (100% AA vs 86.2% non-AA, p=0.21), or graft survival (100% for both) within 12 months posttransplant were observed. <h3>Conclusion</h3> While AA LTRs had significantly higher TDRs to maintain similar trough levels compared to non-AAs, this did not influence transplantation outcomes. Further research is needed to determine the optimal dosing strategy in LTRs immediately posttransplant.

Tailored Immunosuppression Using CYP3A5 Metaboliser Status in Heart and Lung Transplant Cases - An Indian Study

CYP3A5 enzyme allele status affects metabolism of Calcineurin inhibitors . There is data on influence of Polymorphism in CYP alleles on Tacrolimus levels in Caucasian and Afro - American patients, but little data available for Indian patients METHODS: We studied 93 Heart, lung and Combined Heart plus lung transplant patients from our Hospital with 6 months Followup . The age range was 12 yrs to 72 yrs (70 M, 23 F) .Pattern of expression of 2 alleles CYP3A 5 *1 and * 3 were analysed to classify the patients in Two groups - Group A Poor metabolisers (*3*3) and Group B made of intermediate metaboliser (*1*3) or Extensive metaboliser (*1*1) . The Initial tacrolimus drug dosages were Planned according to the metaboliser status ie Lower doses started for group A and Higher doses started for Group B. Out of 93 patients 37 patients (39 %) were found to be Poor metabolisers, 9 patients (9.6 %) extensive metabolisers and 47 patients (50.5 %) Intermediate metabolisers . Statistical analysis was done using One way Analysis of variance for independent variables (ANOVA) . The Average time taken to reach Optimal Tacrolimus trough levels was 8.9 days in Group A versus 14.6 days in group B (p< 0.0001), Average tacrolimus Trough levels at 1 month after Transplantation was 9.7 ng/ml in group A versus 7.8 ng/ml in group B (p=NS), Average tacrolimus dose was 1.8 mg in group A and 4.07 mg in group B at 1 month (P > 0.0001) and Incidence of renal dysfunction (upto 6 months) was 18 cases out of which 8 patients were poor metabolisers (44. 5 %) . Clinical rejection episodes were seen in 9 patients . The Incidence of CYP poor metaboliser Status in Indian Patients were Found to be Midway between Caucasians and Africans. We find that Poor metabolisers Take a Shorter time to achieve Optimal tacrolimus levels after thoracic organ transplants and Similar Trough levels seen in all Patients if the Initial Tacrolimus Dose is tailored as per the CYP3A5 status, thus reducing chances of renal dysfunction, drug related side effects and Rejection .

22 CHANGE IN FECAL CALPROTECTIN AND LACTOFERRIN PREDICT CLINICAL REMISSION FOLLOWING INDUCTION THERAPY WITH INFLIXIMAB IN PEDIATRIC CROHN’S DISEASE (CD)

Abstract Background The fecal biomarkers, calprotectin and lactoferrin are noninvasive biomarkers for mucosal inflammation in IBD. While prior cross-sectional studies showed a correlation between these measures, less is known about the relationship of these measurements with treatment response over time. We aimed to assess the correlation between and utility of fecal calprotectin and lactoferrin on treatment response with infliximab (IFX). Methods We analyzed fecal calprotectin (FCP) and lactoferrin (LCT) as part of a multicenter, prospective anti-TNF induction cohort. IFX induction between 5-10mg/kg occurred at 0, 2 and 6 weeks. Stool and serum were collected prior to IFX treatment (baseline) and during follow-up. We evaluated FCP, LCT and trough IFX levels prior to the first and at subsequent infusions up to infusion 4. The primary outcome was the correlations between FCP, LCT, and outcomes at maintenance. Clinical outcomes were assessed by the wPCDAI measured at each infusion. Clinical remission was defined as wPCDAI &amp;lt;12.5. Spearman correlation was used to assess the relationship between FCP and LCT. Predictive outcomes were calculated by receiver operating characteristics (ROC) with Youden-J statistic. Results Among 57 CD patients, 54 (95%) had FCP and LCT measured at both baseline and infusion 4. There was a strong correlation between calprotectin and lactoferrin with data at all time points (R = 0.82, P &amp;lt; 0.0001). The correlation was even stronger at infusion 4 (R = 0.88, P &amp;lt; 0.0001). A delta score for FCP and LCT was calculated by the proportional change between baseline levels to infusion-4 levels. There was a strong correlation between the FCP delta and LCT delta (R = 0.7, P &amp;lt; 0.0001), suggesting similarities in quantifiable change over time. At Infusion 4, an FCP &amp;lt; 378 μg/g predicted sustained clinical remission between week 14 and 6 months with a sensitivity (sens) of 71% and specificity (spec) of 58% (AUC 0.708; P = 0.01). LCT &amp;lt;20.5 μg/g predicted sustained clinical remission between week 14 and 6 months with a sens of 68% and spec of 45% (AUC 0.627; P = 0.117). FCP &amp;lt; 639 μg/g at infusion 4, had a sens of 75% and spec of 75% for achieving an infusion 4 trough level ≥ 5μg/ml (AUC 0.758; P = 0.005). LCT &amp;lt; 34.2 μg/g had a sens of 69% and spec of 54% (AUC 0.692; P = 0.036) for similar trough levels. FCP &amp;lt; 213.6 μg/g at infusion 4, had a sens of 56% and spec of 88% for achieving a infusion 4 trough level &amp;gt; 8μg/ml (AUC 0.744; P = 0.007). LCT &amp;lt; 6.0 μg/g had a sens of 44% and spec of 92% (AUC 0.675; P=0.05) for similar trough levels. Discussion This study demonstrates that both noninvasive biomarkers can be used to predict sustained clinical remission during IFX therapy. It also provides further evidence for the utilization of fecal calprotectin and lactoferrin as predictors to achieve IFX infusion 4 trough level targets for ≥ 5μg/ml and &amp;gt;8μg/ml.

P674 Monitoring posologic change in adalimumab intensification dosing regimen from 40 mg every week to 80 mg every other week

Abstract Background The previous usual adalimumab (ADA) intensification regimen was 40 mg every week (ew)). Recently the original laboratory commercialised the 80 mg injection pen, with pharmacokinetic studies indicating an alternative intensification dose of 80 mg every other week (eow) similar to 40 mg ew, even though interchangeability has not been assessed in clinical practice. In the biosimilars era, this pen was sold to many Hospitals at the same price as the 40mg pen. For this fact and for patient comfort, we proposed our stable-intensificated-ADA IDB patients on a 40 mg ew regimen, to change the dose to 80 mg eow (clinical practice). Methods In this setting, we designed an observational study to monitor clinical, analytical and pharmacokinetic outcomes through this posologic change, for patients who signed the Informed Consent. Clinical (Harvey–Bradshaw index (HBI), partial Mayo score), analytic parameters and ADA trough levels were prospectively obtained at baseline, 4 and 8 months after posologic change. We describe the evolution of this cohort and calculate savings. Results 12 from 18 patients initially evaluated for new dose regimen were finally changed. All of them agreed to participate in the study. Eighty-three per cent were CD patients, 58% males, median age 51 years old (intecuartil range (IQR) 42–55). Median age at IBD diagnosis was 34 years (IQR 24–44). In 9 patients ADA was the first-line biologic. Median IBD duration before starting ADA was 6 years (IQR 5–8). Median time from ADA initiation to intensification was 31 months (IQR 14–55). The median time of ADA intensification was 37 months (IQR 30–66). Seventy per cent of patients were on immunosuppressors (IS) at the start of the study. Table 1 shows the results of clinical, analytical variables and ADA trough levels at baseline, 4 and 8 months. No differences were found. At 4 months, all patients maintained ADA 80 mg eow. Two patients referred mild worsening, (HBI from 3–4 to 5–6) without significant changes in CRP, calprotectin or ADA levels. They recovered after restoring the previous regimen (ADA 40mg ew). At 8 months, ADA was stopped in one patient in remission with undetectable ADA levels and positive ATI. Total savings in the first 8 months were 59022 €. Conclusion in IBD patients with stable response to ADA intensification regimen of 40 mg ew, changing to 80mg eow seems to maintain response and similar trough levels, although some patients may perceive mild symptoms. Economic savings are 50% per patient.

Impact of Protease Inhibitor-Based Anti-Retroviral Therapy on Outcomes for HIV+ Kidney Transplant Recipients.

Excellent outcomes have been demonstrated among select HIV-positive kidney transplant (KT) recipients with well-controlled infection, but to date, no national study has explored outcomes among HIV+ KT recipients by antiretroviral therapy (ART) regimen. Intercontinental Marketing Services (IMS) pharmacy fills (1/1/01-10/1/12) were linked with Scientific Registry of Transplant Recipients (SRTR) data. A total of 332 recipients with pre- and posttransplantation fills were characterized by ART at the time of transplantation as protease inhibitor (PI) or non-PI-based ART (88 PI vs. 244 non-PI). Cox proportional hazards models were adjusted for recipient and donor characteristics. Comparing recipients by ART regimen, there were no significant differences in age, race, or HCV status. Recipients on PI-based regimens were significantly more likely to have an Estimated Post Transplant Survival (EPTS) score of >20% (70.9% vs. 56.3%, p=0.02) than those on non-PI regimens. On adjusted analyses, PI-based regimens were associated with a 1.8-fold increased risk of allograft loss (adjusted hazard ratio [aHR] 1.84, 95% confidence interval [CI] 1.22-2.77, p=0.003), with the greatest risk observed in the first posttransplantation year (aHR 4.48, 95% CI 1.75-11.48, p=0.002), and a 1.9-fold increased risk of death as compared to non-PI regimens (aHR 1.91, 95% CI 1.02-3.59, p=0.05). These results suggest that whenever possible, recipients should be converted to a non-PI regimen prior to kidney transplantation.

Two-Year Results of Envarsus (Once-Daily MeltDose Tacrolimus Tablets) vs Prograf (Twice-Daily Tacrolimus Capsules): A Phase 3, Double-Blind, Double-Dummy, Multi-Center, Prospective, Randomized Study.

In this Phase 3, double-blind, double-dummy, multi-center, prospective, randomized study, 543 kidney transplant recipients (KTR) (Mean age 56 yrs; 65% male; 77% White, 5% Black; 51% deceased donor) were randomly assigned to Envarsus (N=268 patients [pts]) or Prograf (N=275). 517 pts (95%) completed 1 year followup; to date, 83% of patients (451) have completed the 2 year visit. For the entire two year study only 12 (2%) pts were lost to followup; only 3 pts between year 1 and 2. One year results showed noninferiority to Prograf based on the composite treatment failure primary endpoint (Envarsus 18%, Prograf 20%). Three month failure rates were 10% and 14% respectively. One year analyses of adverse events showed no statistically significant differences. Envarsus patients attained targeted troughs within 1 day of first dose; Prograf levels were achieved within 4 to 7 days. From month 3 onward, Envarsus KTR required a lower daily dose vs. Prograf KTR with similar trough levels, suggesting Envarsus' improved bioavailability. Two year data on estimated glomerular filtration rate of Envarsus and Prograf pts show a steady improvement in renal function over the two year study. Database lock will be in March 2014 and full two year efficacy and safety data on all unblinded pts will be available April 2014. Patient retention was excellent in this large, well-controlled, 2 year trial. Data to date show excellent efficacy and safety with both tacrolimus formulations and a gradual improvement in renal function over the course of two years. Pending the imminent completion of the study, the full two-year followup efficacy and safety results will be available for presentation.Figure: No Caption available.DISCLOSURES:Rostaing, L.: Other, Chiesi, Advisory Board. Bunnapradist, S.: Grant/Research Support, Veloxis, Genentech, Novartis, Speaker's Bureau, Novartis, Other, Veloxis, Advisory Board. Budde, K.: Grant/Research Support, AiCuris, Astellas, BmT GmbH, Bristol-Myers Squibb, speaker's fees, honoraria, travel expenses, Chiesi, Hexal, Novartis, Roche, Pfizer, Siemens, speaker's fees, honoraria, travel expenses, Veloxis, speaker's fees, honoraria, travel expenses, Other, Bristol-Myers Squibb,, Consultant, Chiesi, Effimune, Hexal, Veloxis, Novartis, Consultant.

Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukemia: A Children’s Oncology Group (COG) report.

3055 Background: The COG trial ANHL01P1 was undertaken to determine pharmacokinetics (PK) and safety following the addition of rituximab (R) to FAB/LMB 96 chemotherapy in children and adolescents with stage III/IV mature B-NHL and B-ALL±CNS disease. Methods: Patients received R (375mg/m2) on day -2 and 0 of two induction cycles and day 0 of two consolidation cycles. R levels were measured prior to any antibody infusion, during induction cycles (1 hour prior and 30-60 minutes after each R dose) and following consolidation cycles (1, 3, 6 and 9 months after last R dose). R was measured by ELISA with goat anti-rituximab antibody as the capture reagent and goat anti-mouse IgG-conjugated to horseradish peroxidase as the detection reagent. R terminal half-life (t½) was calculated if at least 3 time points after the last dose were measurable in an individual subject. Results: Serum R levels are reported in the Table. Highest peak levels were achieved following the second dose of each induction cycle with sustained troughs and a t½ of 26-29 days. Group C patients tended to have lower R levels than Group B. Patients with LDH ≥2xULN were noted to have lower R levels during induction 1 compared to those with LDH &lt;2xULN. Children (&lt;13 years) exhibited higher peak concentrations, similar trough levels and a shorter t½ than adolescents (≥13 years). None of these differences reached significance after adjusting for multiple comparisons. Conclusions: R can be safely added to FAB chemotherapy with high early R peak/trough levels and a long terminal half-life. The efficacy of R combined with FAB chemotherapy is currently being investigated in an ongoing international intergroup trial. Clinical trial information: NCT00057811. [Table: see text]

Pretransplantation Pharmacokinetic Curves of Tacrolimus in HIV-Infected Patients on Ritonavir-Containing cART

Ritonavir is an extremely strong inhibitor of P450 cytochrome 3A, which is the main metabolizing enzyme of tacrolimus. Subsequently, the pharmacokinetics of tacrolimus are affected to a large extend by the coadministration of ritonavir in HIV-infected transplant recipients. Therefore, to prevent overexposure directly posttransplantation in HIV-infected patients on ritonavir-containing cART, the predictive value of a pretransplantation pharmacokinetic curve of tacrolimus was explored. A pretransplantation pharmacokinetic model of tacrolimus in these patients was developed, and a posttransplantation dosing advice was established for each individual patient. The pharmacokinetic population parameters were compared with HIV-negative patients, and predictive value of the pretransplantation curves was assessed in patients after the transplantation procedure. No significant difference was found between the model-predicted and actual posttransplantation 24 h-tacrolimus levels (14.6 vs. 17.8 ng/mL, P=0.19). As the simulated pharmacokinetic curves lacked an absorption peak every 12 h, the mean 12 h-AUC was approximately 40 % lower compared with AUC's reported in HIV-negative recipients, when similar trough levels were targeted. In conclusion, pretransplantation curves of tacrolimus seem a promising tool to prevent overexposure directly posttransplantation in patients on ritonavir-containing cART and raising trough levels to achieve an exposure equivalent to HIV-negative recipients is suggested.

Cyclosporine: A Commentary on Brand versus Generic Formulation Exchange

The evidence for conversion from brand name to generic equivalent cyclosporine is conflicting. Cyclosporine is a narrow therapeutic-range drug for which small variations in exposure may have severe clinical consequences for transplant patients. There is currently a lack of comparative outcome data relating to the pharmacokinetics of the reference formulation, Neoral, and generic formulations in transplant recipients. A major common concern is the potential inability to attain similar trough levels, an issue that can be easily corrected by ongoing therapeutic drug monitoring to ensure that the new steady state falls within an intended target range. Prospective clinical studies investigating the efficacy and safety of generic formulations in both de novo and long-term transplant patients are also awaited. Until further evidence is available on the conversion of transplant patients to or between generic formulations of cyclosporine, any transfer to a different cyclosporine formulation should be undertaken with close supervision. The best available information to date, however, does not support the frequently held but unsubstantiated belief that generic preparations of immunosuppressive drugs are not as effective as brand names or that conversion from brand to generic is associated with significant danger. This paper attempts to initiate a discussion of these issues.

De Novo Kidney Transplant Recipients Need Higher Doses of Advagraf Compared With Prograf to Get Therapeutic Levels

Advagraf is a new modified-release once-daily formulation of tacrolimus with a similar efficacy and safety profile to twice-daily tacrolimus (Prograf) according to clinical trials. Few data are published about its use in clinical practice, outside of sponsored clinical trials. We compared efficacy and basic pharmacokinetics of once-daily and twice-daily tacrolimus in de novo renal transplantation. The Advagraf group included 26 de novo renal cases who had received initial immunosuppression with once-daily tacrolimus (0.2 mg/kg from day 1 posttransplantation) combined with mycophenolic acid, steroids, and anti-CD25 monoclonal antibodies (2 doses). We compared them with a Prograf group of 26 transplants performed immediately before, who received equivalent immunosuppression with twice-daily tacrolimus (0.2 mg/kg from day 1). We did not observe significant differences between groups in demographics, efficacy, and basic pharmacokinetics, namely, tacrolimus trough levels at 7, 15, 30, 60, or 90 days. We found that recipients on Advagraf needed significantly higher tacrolimus doses per kg up to 6 months post-transplantation than those on Prograf: 0.16 vs 0.11; 0.14 vs 0.08; and 0.12 vs 0.08 mg/kg at 1, 3, and 6 months. No patient suffered severe liver dysfunction. There were no differences between groups in the administration of drugs interacting with CYP3A4 or prokinetics, which could alter tacrolimus pharmacokinetics. Among de novo renal cases, the new once-daily formulation of tacrolimus offered a similar short-term efficacy profile as the twice-daily tacrolimus. But it was necessary to use up to a 50% higher dose of Advagraf than Prograf to achieve similar trough levels during the first 6 months.

Pharmacokinetics of once-daily dosing of gentamicin in neonates

In a prospective, randomized trial of once-daily versus twice-daily intravenous or intramuscular dosing with gentamicin, 11 neonates received 5.0 mg/kg once daily and 15 received 2.5 mg/kg twice daily for 2 or 3 days. The once-daily intravenous dosing group and the twice-daily intravenous or intramuscular dosing group, respectively, had mean steady-state gentamicin peak concentrations of 10.7 versus 6.6 μg/ml ( p < 0.05), 6-hour postdosing concentrations of 4.7 versus 2.8 μg/ml ( p < 0.05), trough concentrations of 1.7 versus 1.7 μg/ml, elimination half-life of 8.8 versus 5.4 hours ( p < 0.05), and volume of distribution at steady state of 0.57 versus 0.46 L/kg. No nephrotoxic effects were identified in any group. Once-daily gentamicin therapy with 5.0 mg/kg in neonates achieves peak serum levels that are more suitable for optimal bacterial killing than those which traditional regimens achieve. Similar trough levels suggest that even larger doses and longer dosing intervals may be ideal in term neonates. (J Pediatr 1997;131:76-80)

Long-term cyclosporin A pharmacokinetic profiles in pediatric renal transplant recipients

Abstract To study the long-term effect of cyclosporin A (CyA), 94 6-h and 29 12-h pharmacokinetic profiles were evaluated in 32 children at least l year after renal transplantation. Children weighing less than 25 kg needed significantly higher doses of CyA than those weighing more than 25 kg(9.8 vs 5.3 mg/kg per day; P < 0.001) to achieve similar trough levels (TL). The average dose of CyA required to achieve the target TL declined gradually with time after transplantation. The average area under the curve over 6 h (AUC/6) correlated strongly with the AUC/12 (r = 0.967; P< 0.001). The AUC/6 of patients with biopsy-proven CyA toxicity was significantly higher than for those without toxicity (Mann-Whitney U-test P< 0.05) despite similar TL. We conclude that AUC monitoring for 6 h provides valuable information not only on TL but also on the absorption and elimination characteristics of CyA as well as on the potential for CyA toxicity.

Long-term cyclosporin A pharmacokinetic profiles in pediatric renal transplant recipients.

To study the long-term effect of cyclosporin A (CyA), 94 6-h and 29 12-h pharmacokinetic profiles were evaluated in 32 children at least 1 year after renal transplantation. Children weighing less than 25 kg needed significantly higher doses of CyA than those weighing more than 25 kg (9.8 vs 5.3 mg/kg per day; P < 0.001) to achieve similar trough levels (TL). The average dose of CyA required to achieve the target TL declined gradually with time after transplantation. The average area under the curve over 6 h (AUC/6) correlated strongly with the AUC/12 (r = 0.967; P < 0.001). The AUC/6 of patients with biopsy-proven CyA toxicity was significantly higher than for those without toxicity (Mann-Whitney U-test P < 0.05) despite similar TL. We conclude that AUC monitoring for 6 h provides valuable information not only on TL but also on the absorption and elimination characteristics of CyA as well as on the potential for CyA toxicity.