Comparison of Neoral and Sandimmun cyclosporin A pharmacokinetic profiles in young renal transplant recipients

A major factor influencing whole blood cyclosporin A levels in young children with renal transplants is the variable absorption of Sandimmun (SIM). Neoral (NEO) is a new microemulsion of cyclosporin A (CYA) that has been reported to have better absorption characteristics. We compared the pharmacokinetics of SIM and NEO in nine renal transplant recipients aged less than 11 years (range 4.8 – 10.9 years) and observed clinical parameters during 6 months of NEO therapy. Median CYA dosage was 149 mg/m² per day (range 98 – 226). We observed an increase in the maximum CYA concentration (C_max) of 114%, an increase in area under the curve (AUC) of 71% and the time to reach C_max was reduced from 1.75 h to 1.25 h with NEO, while 12-h trough levels (C12 h) did not change significantly. AUC correlated with C12 h for SIM (r ² = 0.833) and NEO (r ² = 0.699) and also C1.5 h for NEO (r ² = 0.775). During 24 weeks’ follow-up, the coefficient of variation of CYA levels was lower for NEO (13%) than for SIM (20%). Although CYA dosages at the start and the end of 6 months on NEO were similar, only one patient was maintained on a constant dose. Four patients had acute reversible rises in plasma creatinine which responded to a 11% reduction in NEO dose; their increase in AUC was greater than those patients not showing a rise in plasma creatinine. Overall, median plasma creatinine was unchanged at the end of the study. NEO was well tolerated by the patients; temporary nausea and headache were experienced by three patients and one of them stopped NEO after 20 days. Other biochemical parameters were not significantly different on NEO. Received May 28, 1996; received in revised form and accepted October 24, 1996     

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( ± SD) of C_max, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 ± 9 ng kg/mg ml, 210 ± 70 ng h kg/mg ml and 2.6 ± 0.9 ng kg/mg ml, respectively. For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rejection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/kg–150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mg/kg–100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ng/ml and 700 ng/ml. Received: 1 October 1997 Revised: 20 April 2001 Accepted: 7 June 2001     

Pharmacokinetics of a new microemulsion formulation of cyclosporin A (Neoral) in young patients after renal transplantation

Pharmacokinetics of the new galenic formulation of cyclosporin A, Neoral, (Sandoz) was examined in 12 stable young patients after renal transplantation. Six of these patients were tested before and 4 weeks after switching from the standard formulation Sandimmun to Neoral. No significant changes were observed in trough levels, t_max, C_max, and AUC_0–12h, but the absorption rate constant (K_a) increased (P=0.003). Glomerular filtration rate, as assessed by inulin clearance, increased by more than 10% in three patients and decreased in two, and was usually associated with a respective drop and rise in C_max and AUC_0–12h of cyclosporin A. The large interindividual variability in the response to the conversion to the new formulation points to a need for close monitoring of cyclosporin A trough levels and renal function after switching from Sandimmun to Neoral in this age group in order to avoid nephrotoxicity.     

Abbreviated cyclosporine AUCs on Neoral – the search continues!

 Cyclosporine is a powerful immunosuppressant with a narrow therapeutic window and considerable inter- and intrapatient variability. The pre-dose trough concentration (C_min) is commonly used for therapeutic drug monitoring. With the new microemulsion (Neoral), intrapatient variability was reduced. However, the usefulness of Neoral C_min was questioned. Firstly, because of the improved and more-rapid absorption, accidental intake before blood sampling has a greater impact on C_min than with classic cyclosporine. Secondly, C_min may be low despite high drug exposure, due to rapid clearance in children. A full pharmacokinetic (PK) profile with determination of the area under the curve (AUC) is expensive and cumbersome, and therefore a search for an abbreviated AUC began. Here, we present a retrospective analysis of 84 PK profiles from 78 pediatric renal transplant recipients. By analysis of rejection episodes and toxicity, we estimated a target AUC above 5,000 ng×h/ml in the early post-transplant period and 3,900 ng×h/ml beyond 100 days. The abbreviated AUC using the 2- and 6-h concentrations (C2 and C6) and a simple estimate derived from the 3-h concentration (C3) were equally well correlated with the AUC. From our data, we recommend a target C3 at approximately 800 ng/ml early after transplantation and 450–550 ng/ml beyond 100 days. Received: 28 January 1998 / Revised: 10 June 1998 / Accepted: 15 June 1998     

Safety and tolerability of a new oral formulation of cyclosporin A, Sandimmun Neoral, in renal transplant patients

Abstract The current therapy with Sandimmun has been improved by the development of a new oral formulation of its active ingredient, Cyclosporine A and which is called Sandimmun Neoral. This new galenical formulation is based on the microemulsion technology and offers consistent oral absorption and pharmacokinetic predictability. In two studies of a 12 weeks duration each and including 466 stable renal transplant patients and 86 new renal transplant patients it was shown that Sandimmun Neoral is as well tolerated and as safe as Sandimmun. Stable renal transplant patients currently receiving Sandimmun can safely be switched to Sandimmun Neoral on a 1:1 dose level basis. However, as a result of the more consistent absorption of Sandimmun Neoral, poor absorbers with Sandimmun will become normal absorbers and than will need a considerable dose reduction to reach the same Cyclosporine A exposure. In new renal transplant patients kidney function seems to improve better and faster when Sandimmun Neoral is given as shown by creatinine and creatinine clearance values. In the Sandimmun Neoral group less patients experienced a rejection episode and time free of rejection was longer, this may reflect a better maintenance of immunosuppression. In addition, considerably lower doses (16% on average) are required for Sandimmun Neoral to achieve comparable cyclosporine A blood trough levels and these patients are also sooner stabilized in terms of Cyclosporine a therapy.     

Pharmacokinetics of cyclosporine in pediatric long-term liver transplant recipients converted from Sandimmun to Neoral

Absorption of cyclosporin from the microemulsion formulation Neoral is less variable than from Sandimmun. Because of a lack of data in pediatric liver transplant recipients, the pharmacokinetic profiles with Sandimmun and Neoral were compared in a conversion study. Thirty-eight children with stable graft function were converted 2–12.3 years post-transplant at a 1:1 ratio. The trough-level (C_min) with Neoral was 123 ± 39 ng/ml versus 134 ± 29 ng/ml with Sandimmun (P = NS), the area under the time-concentration curve (AUC) was 3325 ± 1125 ng_*h/ml versus 2423 ± 846 ng_*h/ml (P < 0.001), the peak concentration (C_max) was 650 ± 280 ng/ml versus 337 ± 142 ng/ml (P < 0.001), and the median time to C_max was 2 h (range 0.5–3 h) versus 4 h (range 1–8 h; P < 0.05). The weak correlation between C_min and AUC with Sandimmun (r = 0.5; P = NS) was improved by using Neoral (r = 0.7; P < 0.001). The best predictor of AUC was the 2-h concentration (C_{2 h}) of Neoral (r = 0.9; P < 0.001). Increased absorption and a more predictable pharmacokinetic profile with Neoral permit safer therapeutic monitoring in children. The exclusive measurement of Neoral-C_{2 h} allows one to estimate drug exposure with high precision ( > 90 %). Received: 12 February 1997 Received after revision: 16 May 1997 Accepted: 5 June 1997     

Variable effect of ursodeoxycholic acid on cyclosporin absorption after orthotopic liver transplantation

The acute effects of administering a single dose of ursodeoxycholic acid (UDCA) on cyclosporin pharmacokinetics were recorded during paired studies in twelve liver transplant recipients, six of whom were cholestatic. Cyclosporin was measured using monoclonal selective antibodies (for parent drug) and nonselective antibodies (for cyclosporin plus metabolites). UDCA resulted in more rapid absorption of cyclosporin in 8 of 12 cases (67%) but had no effect in two patients with and two patients without cholestasis. Median t_max did not change significantly after UDCA (3.0vs 4.0 h without UDCA) and only 7 of 12 patients (58%) showed a rise in the amount of cyclosporin absorbed over 24 h with the AUC not having changed significantly (median 4527 vs 4979 g·h·1^-1 without UDCA). Median C_max and C₂₄ also increased only marginally following UDCA administration (616 vs 587 g·1^-1 and 87 vs 58 g·1^-1 without UDCA, respectively). In the cholestatic patients, median AUC was 50% smaller (3223 vs 6439 g·h·1^-1) and median t1/2a was 100% longer (1.58 vs 0.8 h) than in patients without cholestasis. There was no consistent improvement in cyclosporin pharmacokinetics in the cholestatic patients following UDCA, although the significantly elevated ratio of non-selective:selective AUC measurements (median 4.8 vs 2.7) fell markedly in the two most severely affected, possibly as a result of an increased clearance of cyclosporin metabolites by choleresis.     

Pre-transplant pharmacokinetic profiling and tacrolimus requirements post-transplant

Aim: To determine the proportion of patients achieving tacrolimus whole‐blood concentrations of ≥10 ng/mL within 3 days of kidney transplantation, after randomization either to standard dosing (control group) or post‐transplantation dosing guided by a 2‐hour (C₂) level following a preoperative tacrolimus dose (T2 group). Methods: The first postoperative tacrolimus dose was given either according to standard care (control group) or 0.15 mg/kg b.d. if the pre‐transplant C₂ level was ≤20 ng/mL, 0.1 mg/kg b.d. if the C₂ level was 21–59 ng/mL or 0.05 mg/kg b.d. if the C₂ level was ≥60 ng/mL (T2 group). Subsequent dosing in both groups was based upon tacrolimus trough level monitoring. Participants received concomitant mycophenolate mofetil and steroids. Results: Ninety patients were recruited, of which 84 were included in the analysis (control group n = 43; T2 group n = 41). There was no difference in the proportion of subjects achieving tacrolimus trough levels ≥10 ng/mL (82.9% Control vs 93.0% T2; P = 0.19) or between 10 and 15 ng/mL (41.5% Control vs 41.9% T2; P = 0.97) at day 3 post transplant. The T2 group achieved tacrolimus trough levels of ≥10 ng/mL significantly faster than the control group (100% achievement in 14 days (Control) versus 4 days (T2); P = 0.01). Conclusion: Performing a pre‐transplant tacrolimus C₂ does not significantly increase the high proportion of subjects achieving 10 ng/mL tacrolimus concentrations by day 3 using routine protocols. However, compared with standard care, performing a pre‐transplant tacrolimus C₂ does lead to patients achieving a whole‐blood concentration of ≥10 ng/mL sooner.     

Clinical pharmacokinetics of Neoral in pediatric recipients of primary liver transplants

Pediatric liver transplant recipients constitute a population characterized by a particularly unpredictable and poor bioavailability of cyclosporin (CyA). Even though several adult studies show that the new oral formulation of CyA, Neoral (NEO), produces better bioavailability and blood level predictability, few data describe its pharmacokinetics in children. We performed a complete analysis of the pharmacokinetics of NEO in ten small children after primary liver transplantation. Three pharmacokinetic profiles were set up with data obtained from tests taken during i. v. administration of CyA, after the first oral NEO dose, and after the last NEO dose before discharge from the hospital. The mean half-lives obtained were 8.1, 7.7, and 6.9 h, respectively, and the bioavailabilities were 22 % and 21 % for the first and last NEO doses. A large interpatient variability was observed. This was due, in part, to episodes of diarrhea that interfered with the pharmacokinetic evaluation and, in part, to the variability of post-transplant hepatic function. There was a good correlation between CyA trough levels and their related AUCs for both NEO profiles (r = 0.93 and r = 0.74, respectively). We conclude that, even though the pediatric OLT population remains more unpredictable than that of adults, NEO has a relatively rapid half-life and a remarkably improved bioavailability. Received: 29 November 1996 Received after revision: 10 April 1997 Accepted: 15 May 1997     

Neoral induction in pediatric renal transplantation

Neoral was instituted in pediatric renal transplant patients with the hypothesis it would have more predictable kinetics than Sandimmun. However, significant questions have arisen concerning potential toxicity and dosing interval related to its rapid absorption with subsequent high initial peak. This is compounded by the fact that children appear to metabolize cyclosporine at a greater rate than adults. This combination of a rapid peak and rapid absorption may then result in lower trough levels at 12 h. We compared the trough cyclosporine levels of nine children who received Neoral with nine who received Sandimmun at the time of initial transplantation. More frequent dosing (every 8 h) was required in the Neoral population compared with the Sandimmun population for the 1st month in order to obtain comparable trough levels. Beyond the initial 4–6 weeks, trough levels were similar for Neoral and Sandimmun. Whereas 1-month creatinine levels and blood pressures were similar, the number of blood pressure medications was significantly higher in the Neoral group. At 5.5 ± 1.1 months’ followup, a single patient in the current Neoral group and in the retrospective Sandimmun group each experienced a single OKT3 allograft-treated rejection. We suggest that the area under the curve is different in Neoral than Sandimmun, and the initial dosing frequency may need to be adjusted accordingly. Received August 21, 1996; received in revised form June 27, 1997; accepted June 30, 1997     

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.     

Blood alcohol concentrations rise rapidly and dramatically after Roux-en-Y gastric bypass

BackgroundThis study provides new information on how rapidly and extensively alcohol is absorbed after Roux-en-Y gastric bypass (RYGB). Previous alcohol pharmacokinetic research in RYGB patients has not reported blood alcohol concentrations in this early time period after ingestion. The objective of this study was to examine the rate and extent of alcohol absorption, particularly in the first 10 minutes after a dose of alcohol.MethodsFive female participants who had undergone RYGB 3 to 4 years previously completed the study. Participants were given .3 g/kg of actual weight of ethanol. After the dose of alcohol, blood samples were collected through an indwelling intravenous catheter every minute for the first 5 minutes and at 7.5, 10, 20, and 60 minutes.ResultsThe observed mean C_max was 138.4±28.6 mg/dL (range 98.0–170.0 mg/dL), and the observed mean T_max was 5.4±3.1 minutes (range 2–10 minutes) after alcohol consumption.ConclusionsWithin minutes after consumption of a beverage containing a modest amount of alcohol, post-RYGB patients achieve disproportionately high blood alcohol concentrations. All 5 participants in this study reached blood alcohol concentrations>.08%, the legal driving limit in the United States, within 10 minutes after a dose of alcohol. Clinicians are encouraged to educate patients about the marked changes in alcohol pharmacokinetics that are they are likely to experience after RYGB and to guide patients in making modifications to alcohol intake after surgery accordingly.     

Phase I study of single‐dose pharmacokinetics and pharmacodynamics of belatacept in adolescent kidney transplant recipients

Belatacept is an intravenously infused selective T cell costimulation blocker approved for preventing organ rejection in renal transplant recipients aged ≥18 years. This phase I trial examined the pharmacokinetics and pharmacodynamics (percentage CD86 receptor occupancy [%CD86RO]) of a single dose of belatacept (7.5 mg/kg) administered to kidney transplant recipients aged 12‐17 years receiving a stable calcineurin inhibitor–based immunosuppressive regimen. Nine adolescents (mean age 15.1 years) who were seropositive for Epstein‐Barr virus were enrolled; all completed the 6‐month study. Pharmacokinetics suggested relatively low variability of exposure (coefficients of variation for maximum observed serum concentration [C_max] and area under the serum concentration‐time curve from time zero extrapolated to infinity [AUC_0‐INF] were 20% and 25%, respectively). Mean half‐life (T_1/2) occurred 7.2 days postinfusion. Belatacept total body clearance was 0.48 mL/h/kg, and volume of distribution at steady‐state (V_ss) was low at 0.09 L/kg. Compared with historical data from healthy adult volunteers administered a single dose of belatacept 10 mg/kg and adult kidney transplant recipients administered multiple doses of belatacept 5 mg/kg, pharmacokinetic values for adolescents were similar, indicating consistency across adolescent and adult populations. Mean %CD86RO increased with increasing belatacept concentration, indicating a direct relationship between pharmacokinetics and pharmacodynamics. Four patients reported 7 serious adverse events; none was considered related to belatacept. These data will inform belatacept dose selection in future studies of adolescent kidney transplant recipients.     

Sotrastaurin single‐dose pharmacokinetics in de novo liver transplant recipients

Sotrastaurin is a protein kinase C inhibitor in development for prevention of rejection after liver transplantation. In a pharmacokinetic study, 13 de novo liver transplant recipients received 100 mg sotrastaurin once between days 1–3 and once between days 5–8 post‐transplant. Sotrastaurin absorption based on the area under the concentration‐time curve (AUC) of total drug in blood (3544 ± 1434 ng·h/ml) was similar to that of healthy subjects in a previous study (4531 ± 1650 ng·h/ml). However, the sotrastaurin binding protein, α1‐acid glycoprotein, was nominally higher in patients (1.07 ± 0.28 vs. 0.87 ± 0.16 g/l, P = 0.13) yielding a 60% lower AUC based on free drug versus that in healthy subjects (27 ± 13 vs. 62 ± 15 ng·h/ml, P < 0.0001). There was minor excretion of sotrastaurin in drained bile (1% of dose) consistent with the fact that sotrastaurin is extensively metabolized leaving little unchanged drug to excrete. In the first week after liver transplantation, sotrastaurin is bioavailable after oral administration. However, patients with elevated α1‐acid glycoprotein levels may have lower free drug concentrations. Whether a higher dose of sotrastaurin is needed to compensate for this in the short‐term after surgery will be addressed in future clinical trials.     

INTRA- AND INTERINDIVIDUAL VARIATION IN THE PHARMACOKINETICS OF TACROLIMUS (FK506) IN KIDNEY TRANSPLANT RECIPIENTS—IMPORTANCE OF TROUGH LEVEL AS A PRACTICAL INDICATOR

Background: Tacrolimus (FK506) is currently used as the primary immunosuppressant in clinical kidney transplantation in some centers. The purpose of this study was to evaluate the pharmacokinetics of this drug and to see if trough level, which has been used widely in therapeutic drug monitoring, can be used as an appropriate substitute for other pharmacokinetic measurement tests. Methods: The blood concentration-time curve was studied in 10 kidney transplant recipients on 26 Occasions after oral dosage of 2 to 18 mg every 12 hours. Whole blood concentration was measured by two-step irnmunoabsorption assay. Methylprednisolone was used as a concomitant immuno-suppressive drug. Results: The blood concentration-time curves showed remarkable interindividual variation. lntraindividual variation was also found, but the degree of variation was slight compared with interindividual variation. On 17 occasions of measurement in one patient, the dose was significantly correlated with trough (r = 0.684). C_max (r = 0.838) and AUC_0–12 (r = 0.817). In nine patients on nine occasions, however, the dose was not significantly correlated with trough (r = 0.351), C_max (r = 0.270) or AUC_0–12 (r = 0.355). t_max ranged from one to four hours (mean + SD; 2.8 + 1.3) and fluctuated in both intra- and interindividual measurements. In spite of a wide variation in the blood concentration-time-curve patterns, a highly significant linear relationship between trough and C_max or AUC_0–12 was observed in both intraindividual (C_max, r = 0.876; AUC_0–12, r = 0.926) and interindividual (C_max, f = 0.943; AUC_0–12, r = 984) measurements. Concluslons: We conclude that trough level is a practical acceptable indicator of the blood levels of tacrolimus, and can be used to monitor blood concentration.     

Impact of late conversion from C0 to C2 monitoring of microemulsified cyclosporine in pediatric living donor liver transplant recipients

The efficacy and feasibility of 2-h post-dose level (C2) monitoring of cyclosporine in long-term living donor liver transplantation (LDLT) is not clear. The aim of this study was to investigate the impact of late conversion from conventional trough-level (C0) monitoring to C2 monitoring of a microemulsion form of cyclosporine (Neoral) in pediatric LDLT recipients. From June 1994 to August 2002, we performed 116 LDLTs in 115 patients. Initially, we adapted conventional C0 monitoring of Neoral, which was converted to C2 monitoring starting in January 2002. The 60 patients who were enrolled in the study had the following characteristics: they were younger than or equal to 15 yr at transplantation, and they had survived LDLT, and they had received a Neoral-based immunosuppression regimen, and they underwent conversion to C2 more than 1 month after transplantation. We evaluated the impact of conversion on doses, blood levels, rejection, adverse effects, and patient/graft outcome. In the long-term patients, the mean C2 levels immediately after conversion were higher than the target levels at any time point selected after transplantation; thus, 34 patients (57%) finally required a dose reduction of Neoral. The current mean C2 level was significantly lower than that observed immediately after conversion (584.6 +/- 262.8 ng/ml vs. 893.1 +/- 260.2 ng/ml, mean +/- SD, p < 0.0001) with a mean follow-up period of 7.4 +/- 0.6 months (range: 5-8 months) after conversion. Only one patient encountered rejection after conversion (1.7%), and no de novo infection or adverse effects were observed. Traditional C0 monitoring of Neoral was safely replaced by C2 monitoring without an increase in the rejection rate or any adverse effects in pediatric LDLT patients. C2 monitoring contributed to the dose reduction of Neoral, which may lead to the avoidance of long-term complications due to immunosuppression.     

Effect of grapefruit juice on Sandimmun Neoral absorption among stable renal allograft recipients.

BACKGROUND: The oral formulation of cyclosporin A (CsA)-Sandimmun-has a highly variable absorption. The development of a CsA microemulsion-Sandimmun Neoral-resulted in increased bioavailability, and decreased variability of absorption. The first oral formulation (Sandimmun) interacted with numerous other drugs and grapefruit juice. Several of these interactions might be explained by decreased pre-systemic metabolism by a cytochrome-enzyme (e.g. CYP3A4) located in the enteral mucosa, and/or via the P-glycoprotein-mediated decreased transport of CsA back from enterocytes into the gut lumen. The purpose of this pharmacokinetic study was to investigate the interaction between Sandimmun Neoral and grapefruit juice. METHOD: Eight stable renal transplant recipients were studied during two 8-h sessions in a randomized cross-over design with 4 weeks interval. Following an overnight fast the patients ingested their habitual morning dose of Neoral either with water or with grapefruit juice. During the 8-h study period 10 blood samples were taken for determination of CsA concentration. These results formed the basis for calculation of area under curve (AUC), and half-life (t(1/2)). Maximum concentration (C(max)) and time until C(max) (t(max)) were obtained from the concentration-time profile. RESULTS: The median AUC increased by 38% (12-194%) (P<0.05) following co-administration of Neoral with grapefruit juice. There were no significant changes in C(max), t(max), and t((1/2)). CONCLUSION: Co-administration of Sandimmun Neoral with grapefruit juice resulted in an increased bioavailability of CsA, indicating unchanged pre-systemic enterocyte first-pass metabolism as compared to Sandimmun. There was no impact of an oral grapefruit juice load on systemic clearance of CsA. It seems prudent to advise renal allograft recipients treated with Sandimmun Neoral not to ingest their medication with grapefruit juice.     

Factors that affect concentrations of cyclosporine during the induction period of kidney transplantation: multivariate analysis

Objective

The pharmacokinetics of cyclosporine (CsA) depend on numerous factors over the transplantation course. The aim of this study was to evaluate the impact of several clinical variables on CsA concentrations during the induction period after kidney transplantation.

Methods

Potential variables were contrasted with CsA concentrations at 2 hours postdose (C₂) and with the area under the concentration curve of CsA (AUC) at days 3 and 10 after transplantation. Evaluated variables were: recipient age, gender, body mass index (BMI), type/duration of previous dialysis, pretransplant serum creatinine (sCr), donor type, CsA dose, cold ischemia time, reduction of sCr, and use of other immunosuppressive drugs.

Results

This series included 112 patients who displayed an average age of 43 ± 13 years, including 62 men and 31 recipients of living donor organs. The induction dose of CsA was 8.36 ± 1.53 mg/kg. On day 3, the C₂ was related to the reduction of sCr (P = 0.034) and to the BMI (P = 0.033). There was an inverse correlation with pretransplant sCr (P = 0.012). The AUC correlated with BMI (P = 0.027) and living donor category (P = .002). Patients receiving rapamycin or a locally procured kidney showed a trend toward higher AUC values. On day 10, the CsA dose and use of rapamycin showed a trend to higher values of C₂; the AUC was related to the CsA dose (P = .034). None of the other variables showed significant effects. Analysis between variables showed that time on dialysis correlated with the pretransplant sCr (P = .002) and that the CsA dose was negatively associated with BMI (P = .009).

Conclusion

Pretransplant sCr, BMI, living donor kidney category, better functional recovery, and the dose of CsA were predictors of CsA concentrations of clinical interest during this induction period. The effect of BMI was not related to higher doses of CsA.     

Decreased cyclosporine exposure during the remission of nephrotic syndrome

In this paper, we report the pharmacokinetics changes observed in seven children with steroid-resistant nephrotic syndrome (SRNS). They received cyclosporine A (CsA) microemulsion 6 mg/kg/day and, one week later, they were admitted to perform a 12-h pharmacokinetic profile with eight time sample points. The pharmacokinetic profile was repeated at 24 weeks of treatment, when all patients achieved remission. Blood concentration against time curves were constructed for each patient at weeks 1 and 24 of CsA treatment. Peak concentrations (C _max) and the time needed to reach peak concentrations (t _max) were directly determined from these plots. The area under the curve (AUC) was estimated by the trapezoidal rule. There was a statistically significant difference of the AUC, trough levels, and t _max between weeks 1 and 24, with a decrease of AUC from 5,211 ng*h/ml in week 1 to 3,289 ng*h/ml in week 24, the trough levels decreased from 157 ng/ml to 96 ng/ml, and the t _max decreased from 1.85 h to 1.00 h. The higher CsA bioavailability during the nephrotic state has to be considered when managing patients, since the target AUC cannot be the same throughout the treatment.     

环孢素新剂型Neoral在肾移植中的应用

对10例肾移植患者作山地明转换Neoral试验进行药效动力学对比研究，30例新移植患者应用Neoral进行临床观察。结果表明，Neoral最高血浓度（Cmax）较山地明高282±84ng／ml，达峰时间（Tmax）短0．79±0．29h，CSA暴露（AUC）大1533±169ng／（h·ml）（P＜0．05）。提示Neoral有较好地抗排斥反应作用，但由于吸收迅速，血药浓度易超过治疗窗水平而引起毒副反应。本组肝中毒达20％。认为Neoral与山地明转换比例应为1：0．8～1：0．9，以避免毒副作用发生；Neoral服药量可较山地明常规剂量减少25％。