CsA AUC Research Articles

Limited sampling strategies for estimating intravenous and oral cyclosporine area under the curve in pediatric hematopoietic stem cell transplantation.

The optimal monitoring strategy for cyclosporine (CsA) in pediatric hematopoietic stem cell transplantation (HSCT) patients remains unclear. Although there is a growing interest in the use of the area under the concentration-time curve (AUC), measurement of AUC in clinical settings is often impractical. The objective of this study was to identify and validate limited sampling strategies (LSSs) for the prediction of CsA AUC after intravenous (IV) and oral (PO) administration in this population. Sixty-eight pediatric patients who underwent HSCT and received CsA were investigated. Twelve-hour pharmacokinetic profiles (n = 138) performed per standard of care were collected. Weighted multiple linear regression was used to investigate all possible LSSs consisting of 4 or less concentration-time points. Their predictive performance was evaluated by leave one out cross validation and external validation by measuring the root mean squared relative error (RMSE%) and the 95th percentile of the absolute relative error (AE%). Values less than 20% were considered clinically acceptable. Nine LSSs (4 IV and 5 PO) convenient for clinical application proved to have clinically acceptable performance. Notably, LSS based on C0, C2, and C4 was found to be accurate for estimation of CsA exposure after both IV and PO administration with the 95th percentile of AE% of 19.7% and 17.5%, respectively. LSSs using 3 or 4 concentration-time points obtained within 4 hours postdose provide a convenient and reliable method to estimate CsA exposure in this population. These LSSs may facilitate future research aiming at better defining the relationship between AUC and clinical outcomes.

Best Single Time Point Correlations With AUC for Cyclosporine and Tacrolimus in HIV-Infected Kidney and Liver Transplant Recipients

Interactions between antiretrovirals (ARVs) and transplant immunosuppressant agents (IS) among HIV-infected transplant recipients may lead to lack of efficacy or toxicity. In transplant recipients not infected with HIV, tacrolimus (TAC) trough levels (C0) or cyclosporine (CsA) drawn at C0 or 2 hours after dosing (C2) correlate with drug exposure (area under the curve [AUC]/dose) and outcomes. Because of ARV-IS interactions in HIV-infected individuals, and the high rate of rejection in these subjects, this study investigated the correlations between IS concentrations and exposure to determine the best method to monitor immunosuppressant levels. This study prospectively studied 50 HIV-infected transplant recipients undergoing kidney or liver transplantation evaluating the pharmacokinetics of the IS in 150 studies over time after transplantation (weeks 2 to 4, 12, 28, 52, and 104). IS levels were measured with liquid chromatography-tandem mass spectrometry and AUC calculated using WinNonlin 9.0. Correlation analyses were run on SAS 9.2. CsA concentration at C4 correlated better with AUC than C0 or C2, and over time TAC concentration correlated better at C0 or C2. It is suggested that C0 is acceptable for TAC monitoring, but poor predictability will occur at C0 with CsA. The low correlation of C0 with CsA AUC could be responsible for the higher rejection rates on CsA that has been reported in these subjects.

CsA exposure is associated with acute GVHD and relapse in children after SCT

CsA is commonly used after haematological SCT (HSCT) as GVHD prophylaxis. In solid organ transplantation, area under the blood concentration vs time curve (AUC) correlates with clinical outcome. However, in HSCT, it has not been determined whether the AUC is superior to trough level monitoring to optimize clinical efficacy of CsA therapy. Therefore, the aim of this study was to investigate the relationships between CsA trough levels and/or AUC early after HSCT with clinical outcome. A total of 91 children (1.1-17.3 years) were treated consecutively with HSCT for a haematological malignancy. CsA trough levels were obtained and were used to estimate the AUC, retrospectively, with a NONMEM (Non-Linear Mixed Effects Modelling) method. Subsequently, these exposure parameters were correlated to the occurrence of acute GVHD, relapse risk (RR) and OS. Low CsA trough levels were found to correlate with the occurrence of acute GVHD. In addition, a CsA AUC over 3000 mcg h/l in AML patients was associated with a higher RR and a reduced OS. This was not the case for ALL patients. Thus, monitoring CsA exposure early after HSCT and adjusting the CsA dose to a predefined target trough level and AUC may provide a tool to influence GVHD/GVL balance.

Cyclosporine and sirolimus pharmacokinetics and drug‐to‐drug interactions in kidney transplant recipients

This study was conducted to evaluate the pharmacokinetics (pk) and drug interactions between cyclosporine (CsA) and sirolimus (SRL) in kidney transplant recipients. The morning (a.m.) and evening (p.m.) pk of CsA (4-5 mg/kg/dose) and SRL (2 mg, n = 20; 5 mg, n = 33) were evaluated on day 7 (n = 53). CsA showed circadian variation when comparing a.m. and p.m. administration [AUC: 8066 vs. 6699, P < 0.001 (CI 970.9; 1763.6); C0: 272 vs. 245, P = 0.007 (CI 7.5; 46.1)]. SRL showed dose-proportional pk. Significant and drug-to-drug concentration-dependent pk interactions were observed within a narrow concentration range for both drugs. A fivefold increase in SRL AUC (from a mean of 130 to 538 ng h/mL) was associated with a 25% increase in mean a.m. CsA AUC [7021 to 8811 ng h/mL, P = 0.037, CI (-3461.2; -118.9)] and with a 42% increase in mean p.m. CsA AUC [5386-7639, P = 0.024, CI (-4164.4; -340.7)]. A twofold increase in a.m. CsA AUC (from 5860 to 10 974 ng h/mL) was associated with a 70% increase in mean SRL AUC [223 to 380 ng h/mL, P = 0.0026, CI (-291.7; -22.8)]. A twofold increase in p.m. CsA AUC (from 4573 to 9692 ng h/mL) was associated with a 63% increase in mean SRL AUC [246 to 400 ng h/mL, P = 0.032, CI (-290.7; -16.6)]. CSA shows circadian pk regardless of sirolimus dose or blood concentration. Significant drug-to-drug interactions occur within narrow blood drug concentrations. The magnitude of the effect of CsA on SRL blood concentration is higher than that of SRL on CsA blood concentrations. These findings emphasize the need for therapeutic drug monitoring using this drug combination.

The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

Trough- or 2-h post-dose (C2) blood cyclosporine (CsA) concentrations are used for prediction of efficacy and toxicity of CsA in transplant recipients concomitantly treated with antiproliferative agents, but information on utility of blood CsA levels in patients treated with proliferation signal inhibitors (PSIs), such as everolimus, is sparse. Because of the inhibitory effect of PSIs on the P-glycoprotein drug efflux pump present in lymphocytes, we hypothesized that CsA pharmacokinetics in blood and lymphocytes were dissociated in patients concomitantly treated with everolimus. Twelve-hour pharmacokinetic studies of whole-blood and intralymphocytic CsA concentrations were conducted in long-term heart-transplant recipients treated with mycophenolate mofetil (MMF) + CsA (n = 8) and everolimus + CsA (n = 9). There was a highly significant correlation between blood CsA C2 levels and blood CsA AUC(0-12) in groups of patients treated with MMF or everolimus (R(2) 0.93 and 0.96, respectively; P < 0.001 for both). Whereas blood CsA C2 levels were closely associated with lymphocyte CsA AUC(0-12) in patients treated with MMF (R(2) = 0.98), there was poor correlation between whole-blood C2 and lymphocyte AUC(0-12) in patients treated with everolimus (R(2) = 0.24). Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus.

Pharmacokinetics and Pharmacodynamics in Renal Transplant Recipients Under Treatment With Cyclosporine and Myfortic

Introduction Efficacious prophylaxis of acute rejection episodes (ARE) requires adequate exposure to each component of the immunosuppressive treatment from the first days after renal transplantation. The aim of the present study was to evaluate the correlation between cyclosporine (CsA) and mycophenolic acid (MPA) exposure based upon pharmacokinetics (PK) and pharmacodynamics (PD) and 6-month biopsy-proven acute rejection (BPAR) episodes and chronic allograft nephropathy on 6 month protocol biopsies. Patients and methods We examined twenty-two first or second de novo renal transplant recipients treated with steroids, Sandimmune Neoral (CsA) and Myfortic (720 mg twice a day). PK (C0, C2, and AUC 0–12h) for both drugs were determined on days 7, 90, and 180. Calcineurin activity, interleukin-2 and interferon-γ synthesis as well as %CEM were tested at days 7 and 180. CsA dosages were adjusted by C2 monitoring. Collected data included: BPAR during the first 6 months and Banff histological parameters on the 6-month protocol biopsies. Results Eighteen of 22 patients completed 1 year follow-up under treatment. The 6-month BPAR was 18% (4/22). Six-month protocol biopsies in 50% of 14 recipients showed chronic allograft nephropathy 1. At day 7, CsA C2 and AUC median values were 138 ng/mL and 6377 ng × h/mL, while C0 MPA was 1.0 μg/mL and AUC = 23.9 μg × h/mL. CsA C2 medians at 3 and 6 months were 1468 and 1720 ng/mL. MPA-AUC reached therapeutic targets at 3 months (32.3 μg × h/mL) and was 48.3 μg × h/mL at 6 months. Patients with BPAR showed lower CsA AUC ( P = .06) and a significantly lower baseline inhibition of calcineurin activity ( P < .005) than patients with no BPAR. An increase in mesangial matrix in 6-month protocol biopsies correlated with higher CsA C2 ( P = .01). All biomarkers evaluated were significantly inhibited compared with the standard population. Conclusions When Myfortic is administered together with CsA, it is advisable to begin with higher doses (720 mg × 3 days) to reach adequate PK targets and improve BPAR rates. To prevent chronic allograft nephropathy, lower CsA C2 should be targeted from 3 months.

Relationship Between Acute Rejection and Cyclosporine or Mycophenolic Acid Levels in Japanese Heart Transplantation

Cyclosporine (CsA), Mycophenolate mofetil (MMF) and prednisolone (PSL) are widely used for the prevention of acute rejection after heart transplantation. Recently, the serum concentration - time curves (AUC) of CsA and MMF have been demonstrated to be precise predictors of acute rejection. Fourteen heart transplant patients were treated concomitantly with CsA, MMF, and PSL between May 1999 and November 2005 at the National Cardiovascular Center and of them 3 had acute rejection episodes [International Society for Heart & Lung Transplantation grade 3a]. Two patients (man in his 30 s; woman in her 40 s) had acute rejection with a mycophenolic acid (MPA) AUC(0-12 h) <30 microg x h x ml(-1) and low CsA AUC (AUC(0-4 h); 2,408 ng x h x ml-1, 1,735 ng x h x ml-1). However, 1 patient (man in his 30 s) with a high CsA AUC(0-4 h) (4,019 ng x h x ml-1) did not develop cardiac allograft rejection even if the MMF was temporarily stopped. These 3 patients were investigated to evaluate the relationship between acute rejection and pharmacokinetic parameters, including the CsA C0, C2, AUC(0-4 h) and MPA AUC(0-12 h). The findings suggest that a high CsA AUC(0-4 h) may prevent rejection of a cardiac allograft, even if MMF is stopped or drastically reduced.

MDR1 C3435T Polymorphisms Correlate With Cyclosporine Levels in De Novo Renal Recipients

Background Single nucleotide polymorphisms (SNPs) in the multidrug resistance (MDR1) gene correlate with the intestinal function of P-glycoprotein (PGP). PGP serves as a hydrophobic export pump that extrudes cyclosporine (CsA) across the luminal membrane thus preventing CsA absorption. These genetic variants may predict CsA exposure levels in the early posttransplantation period. Methods CsA absorption profiles were established in 75 renal transplant patients using total daily dose and body weight adjusted 4-hour area under the time-concentration curve, AUC (0–4)/mg dose/kg body weight, on posttransplant day 3. These patients were subsequently genotyped for C3435T and G2677T polymorphisms using real-time polymerase chain reaction. An analysis was conducted to assess the independent impact of C3435T and G2677T SNPs on CsA bioavailability. Results C3435T polymorphisms were found to be an independent predictor of CsA AUC (0–4)/mg dose/kg levels on postoperative day 3. An inverse correlation was found between the number of T alleles and AUC values such that every T allele was associated with an approximate 15% decrement in AUC (0–4)/mg dose/kg ( P = .034). A similar nonsignificant trend was observed for G2677T polymorphisms. Conclusions MDR1 SNPs are correlated with CsA exposure in the early post-transplant period. Polymorphisms, in conjunction with other criteria, may become a useful tool to optimize initial drug dosing in renal transplantation.

Decision Support Tool to Individualize Cyclosporine Dose in Stable, Long-term Heart Transplant Recipients Receiving Metabolic Inhibitors: Overcoming Limitations of Cyclosporine C 2 Monitoring

Monitoring of the 2-hour post-dose sample (C(2)) for cyclosporine (CsA) has gained favor; however, choosing a single-point surrogate marker of therapeutic effect for a drug with extensive pharmacokinetic variability is problematic and has limitations. A Bayesian decision support tool was developed using published pharmacokinetic information implemented using ABBOTTBASE pharmacokinetic software. The model was evaluated in 47 stable heart transplant recipients who received concomitant administration of drugs known to inhibit CsA metabolism: diltiazem; ketoconazole; and a combination of diltiazem and ketoconazole. A 3-point feedback strategy with samples collected at 0, 1 and 2 hours after an oral CsA dose was used to predict area under the concentration-time curve in the first 12 hours post-dose (AUC(0-12)). In Group A, patients who received CsA alone showed a good correlation between observed and model-predicted CsA AUC(0-12) (r(2) = 0.871, p < 0.001, precision of 12%, accuracy of 13%). Furthermore, the Bayesian model provided acceptable predictions in patients who received CsA with metabolic inhibitors: Group B (diltiazem), r(2) = 0.791, p < 0.001, precision of 19%, accuracy of 22%; Group C (ketoconazole), r(2) = 0.761, p < 0.001, precision of 4%, accuracy of 12%; and Group D (diltiazem plus ketoconazole), r(2) = 0.818, p < 0.001, precision of 14%, accuracy of 17%. A Bayesian decision support tool is described that can predict CsA AUC(0-12) in a cohort of patients with variable CsA absorption who received metabolic inhibitors. Bayesian modeling offers a number of advantages over single point metrics that are used to adjust CsA dose and may provide another refinement to optimize CsA therapy.

Pharmacokinetic Study and Limited Sampling Strategy of Cyclosporine in Japanese Heart Transplant Recipients

The purpose of this study was to characterize the pharmacokinetics of cyclosporine (CsA) in Japanese heart transplant patients, and to optimise the monitoring strategy based on measurements of the area under the curve of plasma concentration absorption phase or 2 h post-dose concentrations (C(2)). At defined time periods during the first year after transplantation, the area under the curve for the CsA serum concentration from 0 to 4 h (AUC(0-4 h)) was evaluated. Pharmacokinetic parameters and renal function at 1 month and 12 months after transplantation were compared in 7 Japanese patients. The highest coefficient of determination between CsA AUC(0-4 h) and a single concentration was observed using C2 (r2 =0.838). For CsA pharmacokinetics, the mean measurement of whole blood trough levels value at 12 months was significantly lower than at 1 month after transplantation (p=0.026). The mean serum creatinine level at 12 months was significantly higher than at 1 month (1.00 mg/dl vs 0.73 p=0.0194). A single-time-point model that includes C2 is useful for predicting CsA AUC(0-4 h) in Japanese heart transplant patients. Mean C2 values >1,000 ng/ml were obtained in patients with no rejection at 1 month and 12 months after transplantation; however, renal impairment may occur.

Association Between Cyclosporine Concentrations at 2 Hours Post-dose and Clinical Outcomes in De Novo Lung Transplant Recipients

The objective of this study was to investigate the relationship between cyclosporine (CsA) pharmacokinetic parameters and clinical outcomes after lung transplantation. Data from 48 lung or heart/lung transplant recipients originally recruited to a randomized, prospective clinical trial of Sandimmune vs Neoral and followed for 12 months were included in this study. CsA dosing was based on the trough concentration. CsA concentrations at 0 (C0), 2 (C2), and 6 (C6) hours post-dosing were obtained at 1, 2, 3, 4, 13, 26, 39, and 52 post-operative weeks. Based on their average C2 levels in the first post-transplant month, patients were stratified retrospectively into Low C2 (<1,000 microg/liter, n = 18), Intermediate C2 (1,000-1,500 microg/liter, n = 16) and High C2 (>1,500 microg/liter, n = 14) Groups. Cyclosporine C2 was the best single-point determinant (r2 = 0.934) for area-under-the-concentration-time curve (AUC(0-6 hours)) compared with C0 (r2 = 0.267) or C6 (r2 = 0.304). The mean +/- SD values of CsA C2 and AUC(0 to 6 hours) in the first year post-transplant were significantly lower in patients with >2 rejection episodes compared with those with < or =2 rejection episodes (C2: 875 +/- 546 microg/liter vs 1,114 +/- 633 microg/liter, p = 0.01; AUC(0-6 hours): 4,036 +/- 1,904 microg x hour/liter vs 4,870 +/- 2,182 microg x hour/liter; p = 0.01) whereas C0 and C6 did not differ. Patients in the Intermediate C2 Group were free from rejection episodes for a significantly longer duration (p < 0.001) and had significantly higher predicted forced expiratory volume in 1 second (%) values (p < 0.001) compared with the Low and High C2 Groups. The percentage of increase in serum creatinine concentration by the end of first month post-transplant was significantly higher in the Intermediate C2 Group (p < 0.003). CsA C2 concentrations correlated better with the incidence of multiple rejections after lung transplantation than did C0 or C6. C2 concentrations between 1,000 and 1,500 microg/liter within the first post-operative month may be associated with better graft outcomes and improved pulmonary function and worsened renal function.

Best Single Time Points to Predict the Area-Under-the-Curve in Long-Term Heart Transplant Patients Taking Mycophenolate Mofetil in Combination with Cyclosporine or Tacrolimus

The use of C2 levels for therapeutic drug monitoring (TDM) of cyclosporine microemulsion (CsA) has been clinically validated. Routine TDM of tacrolimus and mycophenolate mofetil (MMF) is based on trough (C0) levels and side effects, respectively. The purpose of the present study was to determine the best single time points to assess the area-under-the-curve (AUC(0-12 hours)) in long-term heart transplant patients being treated with MMF in combination with CsA or tacrolimus. We studied the AUC(0-12 hours) in long-term (>1 year), adult heart transplant patients being treated with CsA and MMF (14 patients) and with tacrolimus and MMF (9 patients). C2 is the best surrogate (r2 = 0.87) of CsA AUC(0-12 hours). Tacrolimus C1 (r2 = 0.78), C2 (r2 = 0.83), C3 (r2 = 0.89) and C4 (r2 = 0.92) correlate better than C0 (r2 = 0.51) with the AUC(0-12 hours). When MMF is combined with CsA, there is poor correlation (r2) of MPA at all measured time points (C0 = 0.49, C2 = 0.09, C3 = 0.23, C4 = 0.44, and C6 = 0.60). When MMF is combined with tacrolimus, MPA C2 (r2 = 0.72), C4 (r2 = 0.86), C6 (r2 = 0.85), and C8 (r2 = 0.93) are better surrogates of the AUC(0-12 hours) compared with C0 (r2 = 0.69). Our results suggest that in long-term heart transplant patients, the calcineurin inhibitor used in combination with MMF affects the correlation between MPA single time points and the AUC(0-12 hours). Future studies should determine the clinical benefit of TDM of tacrolimus and MPA with C2 or C4 compared with C0 and determine the therapeutic ranges. As for CsA-treated patients, CsA TDM should be performed with C2, and the TDM of MMF may be clinically irrelevant.

Cyclosporine-sparing effect of basiliximab in renal transplant recipients with mycophenolate mofetil

O284 Aims: Cyclosporine (CsA) or corticosteroids withdrawal from conventional immunosuppressive regimens has thus far been associated with increased risk of acute rejection episodes (AR). In this study, basiliximab (BA) added to a maintenance regimen consisting of CsA microemulsion and mycophenolate mofetil (MMF) was studied for its effectiveness in allowing early steroid withdrawal in renal allograft recipients. Furthermore, the CsA-sparing effects between the groups with and without BA induction therapy were compared. Methods: Between September 2001 and March 2003, 80 patients underwent renal transplantation (RTx) with CsA-based immunosuppression at our department. Nine of the 80 cases were of cadaveric RTx, and the remaining 70 cases were of living donor RTx including 17 cases of ABO-incompatible RTx. Immunosuppression consisted of CsA, MMF, and methylprednisolone (MP), (Group 1; n = 25), and BA was given during the induction phase in the latter half of the study (Group 2; n = 55). In Group 2, MP was completely withdrawn on postoperative day 14. Results: All patients survived after the RTx, but one patient in Group 2 died with a functioning graft. Outcomes, CsA doses and CsA AUC levels in both groups are summarized in the table.FigureConclusions: The use of BA, together with MMF, allowed for a significant reduction in the CsA dose without increasing the risk of AR. Although further follow-up is necessary to prove the effect, the regimen may attenuate CsA nephrotoxicity which is one of the non-immunologic factors affecting the long-term outcome after RTx.

Analysis of variability of drug exposure and blood concentration during Neoral absorption phase in Chinese adult liver transplant recipients

目的 通过分析中国成人肝移植受体中Neoral吸收期血药浓度与药物暴露量的变异性,为临床上发展新的Neoral治疗药物监测方法提供理论依据.方法通过定期测定22例中国成人肝移植受体口服Neoral前及服药后1、2、3、4 h的血药浓度,采用个体及群体药代动力学的方法计算出个体内和个体间变异系数(CV).结果 Neoral血药浓度和AUC0～4的个体内和个体间变异系数均在服药头2 h达到高峰,此后逐渐下降.术后10～11 d个体间的浓度及AUC变异系数均最高.结论 Neoral吸收期的变异性主要集中在服药后头2 h.服药后1 w左右是变异性最大的时期。

Achieving adequate cyclosporine exposure in liver transplant recipients: a novel strategy for monitoring and dosing using intravenous therapy.

It has been demonstrated that achieving therapeutic levels of cyclosporine (CsA) exposure in the first days posttransplant is critical for effective prevention of rejection. In patients receiving oral CsA, it has been shown that C(2)-monitoring is superior to trough (trough level [C(0)]) measurement. Intravenous administration may overcome the problem of CsA absorption dysfunction seen in some patients. Currently, little evidence is available concerning CsA exposure after intravenous application. Twenty de novo liver transplant recipients were given twice-daily 4-hour infusions of intravenous CsA, with full pharmacokinetic profiles undertaken during the first postoperative week. The greatest CsA exposure occurred during the period 2 to 4 hours after the start of infusion. The correlation between C(0) and area under the curve (AUC(0-12)) was r(2) = 0.18; the correlation between C(2) and AUC(0-12) was r(2) = 0.82. The best 2-point predictive model included both C(2) and C(4) (r(2) = 0.90). There was a poor correlation between CsA dose per kilogram of body weight and AUC(0-12) (r(2) = 0.19); total CsA dose also showed a weak relationship to exposure (r(2) = 0.37). When patients were divided according to initial or delayed graft function, there was good correlation between total CsA dose and AUC(0-12) (initial function, r(2) = 0.71; delayed function, r(2) = 0.86). In conclusion, previous discouraging results with intravenous CsA in liver transplant patients may have been due to a limited understanding of CsA pharmacokinetics. Our results show that C(2)-monitoring during 4 hour infusion provides a reliable indication of CsA exposure. Calculation of starting dose based on initial graft function is more precise than use of body weight. Using C(2)-monitoring to individualize dosing and function-based calculations of starting dose could be expected to improve clinical outcomes in patients receiving intravenous CsA.

Cyclosporin assays, metabolite cross-reactivity, and pharmacokinetic monitoring.

The range of cyclosporin (CsA) immunoassays has become the mainstay in many therapeutic drug monitoring laboratories for delivering CsA concentration data to support clinical care of patients after transplantation. However, these assays have been criticized because of the varying degree of CsA-metabolite interferences that introduce analytical errors. The introduction of another such CsA assay (on the AXSyM analyzer) has been considered, as the manufacturer has represented it as having a low CsA-metabolite cross-reactivity profile compared with chromatographic methods. A case is presented to question how this apparent result was obtained in view of the method using the same antibody as another CsA method from the same manufacturer (fluorescence polarizaton immunoassay on the TDx analyzer) which is well known to have poor performance in regard to CsA-metabolite cross-reactivity. The implications for this problem may be even more serious as more patients are monitored using the CsA AUC strategies, rather than the traditional trough concentration approach. Such issues reinforce the need for the clinical laboratory to be critical of methods offered commercially based on scientific/pharmacologic skills.

COMPARISON OF MICROEMULSION FORMULATION WITH OIL BASED CYCLOSPORINE IN CARDIAC TRANSPLANT PATIENTS

625 Extent and variability of oral cyclosporine (CsA) bioavailability correlates with incidence of acute and chronic rejection in renal transplant(txp) patients. The goal of this single center double-blinded, two arm pharmacokinetic (PK) study was to determine and compare relative bioavailability AUC), Cmax & Tmax of Neoral (NL) with oral Sandimmune(SM) in de novo cardiac txp recipients at three time periods (1, 12 & 52 weeks post-txp). Intrapatient variability (%CV) of PK values were determined between the NL and SM groups. Correlations (r2) were measured between CsA troughs (Co) & AUC's. Methods: Adult first-time txp candidates were enrolled pre-txp & randomized to receive either de novo NL or SM in blinded capsules. At 1 week post-txp (T1), at three months (T2) and 1 year (T3) PK profiles (12 whole blood samples per AUC) were obtained from a non-compartmental model. Results: 35 subjects completed T1, 31 for T2 and 26 for T3. There were no differences in demographics or CsA doses between the NL and SM groups. Dose normalized AUC (ng.hr/ml) & Cmax (ng/ml), & Tmax (hr) group means are: Table Improvements in CsA absorption for NL vs SM were greatest at 1 week (+35% in AUC & +54% in Cmax) and improvements persisted at T-2 and T-3. Mean intrasubject %CV for NL AUC was 15% vs 26% for SM for T-1 & T-2 (p < .05). Cmax: %CV for NL was 21% vs 29% for SM (p < .05). Correlations between Co and AUC for NL& SM at T-1 (0.82 vs 0.63), T-2 (0.62 vs 0.28) and T-3 (0.83 vs 0.68) also reflected the more consistent and reliable PK for NL vs SM.Conclusions: This blinded PK study in de novo cardiac txp patients documents significant improvements in AUC & Cmax at 1 and 12 weeks post-txp. Also, there was an improvement in both intrapatient variability of PK and in Co-AUC correlations with NL for all three profiling periods. These results reflect the improvement in CsA absorption patterns and lower intrapatient variability with NL vs SM which are documented in renal and liver txp studies.

COMPARISON OF MICROEMULSION FORMULATION WITH OIL BASED CYCLOSPORINE IN CARDIAC TRANSPLANT PATIENTS

625 Extent and variability of oral cyclosporine (CsA) bioavailability correlates with incidence of acute and chronic rejection in renal transplant(txp) patients. The goal of this single center double-blinded, two arm pharmacokinetic (PK) study was to determine and compare relative bioavailability AUC), Cmax & Tmax of Neoral (NL) with oral Sandimmune (SM) in de novo cardiac txp recipients at three time periods (1, 12 & 52 weeks post-txp). Intrapatient variability (%CV) of PK values were determined between the NL and SM groups. Correlations (r2) were measured between CsA troughs (Co) & AUC's. Methods: Adult first-time txp candidates were enrolled pre-txp & randomized to receive either de novo NL or SM in blinded capsules. At 1 week post-txp (T1), at three months (T2) and 1 year(T3) PK profiles (12 whole blood samples per AUC) were obtained from a non-compartmental model. Results: 35 subjects completed T1, 31 for T2 and 26 for T3. There were no differences in demographics or CsA doses between the NL and SM groups. Dose normalized AUC (ng.hr/ml) & Cmax (ng/ml), & Tmax(hr) group means are: TableImprovements in CsA absorption for NL vs SM were greatest at 1 week (+35% in AUC & + 54% in Cmax) and improvements persisted at T-2 and T-3. Mean intrasubject%CV for NL AUC was 15% vs 26% for SM for T-1 & T-2 (p<.05). Cmax:%CV for NL was 21% vs 29% for SM (p <.05). Correlations between Co and AUC for NL & SM at T-1 (0.82 vs 0.63), T-2 (0.62 vs 0.28) and T-3 (0.83 vs 0.68) also reflected the more consistent and reliable PK for NL vs SM. Conclusions: This blinded PK study in de novo cardiac txp patients documents significant improvements in AUC & Cmax at 1 and 12 weeks post-txp. Also, there was an improvement in both intrapatient variability of PK and in Co-AUC correlations with NL for all three profiling periods. These results reflect the improvement in CsA absorption patterns and lower intrapatient variability with NL vs SM which are documented in renal and liver txp studies.

The kinetics of cyclosporine and its metabolites in bone marrow transplant patients.

1. The pharmacokinetics of cyclosporine (CsA) and the time course of CsA metabolites were studied in five bone marrow transplant patients after intravenous (i.v.) administration on two separate occasions and once after oral CsA administration. 2. Cyclosporine and cyclosporine metabolites were measured in whole blood by h.p.l.c. 3. Cyclosporine clearance after i.v. administration decreased from 3.9 +/- 1.7 ml min-1 kg-1 to 2.0 +/- 0.6 ml min-1 kg-1 after 14 days of treatment. The mean +/- s.d. absolute oral bioavailability of cyclosporine was 17 +/- 11%. 4. Hydroxylated CsA (M-17) was the major metabolite in blood. There were no significant differences in the mean metabolite/CsA AUC ratios between the first and second i.v. studies. 5. After oral administration, the metabolite to CsA AUC ratios were higher for most metabolites compared to those observed in the second i.v. study, suggesting a contribution of intestinal metabolism to the clearance of CsA.