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.     

Impact of early cyclosporin average blood concentration on early kidney transplant failure

This retrospective study served to examine the correlation between the degree of cyclosporin (CyA) exposure, as estimated by a single pharmacokinetic (PK) profile performed at 1 week post-transplant, and the outcome of 290 consecutive renal transplants performed over a 6-year period. For this retrospective analysis patients were stratified into four historical groups based on 12- versus 24-h PK studies and on the use of radioimmunoassay versus fluorescence polarization immunoassay methods for estimates of CyA concentrations. Four PK measures – trough concentration (C₀), average concentration values (C_av; i. e., the dosing interval-corrected area under the concentration-time curve), maximum concentration (C_max), and time to maximum concentration (t_max) – were examined as predictors of patient, graft, and rejection-free survival rates for each of the four groups individually and for all groups combined. Patients with an initial C_av≥ 550 ng/ml had higher 1-year (88 %) and 6-year (66 %) graft survival rates than patients with C_av < 550 ng/ml, who had 1- and 6-year graft survival rates of 80 % and 59 %, respectively (P = NS). Statistically significant differences were observed in graft survival rates between patients with C_av < 550 versus C_av≥ 550 ng/ml at 30 (88 % vs 96 %; P < 0.02), 60 (85 % vs 94 %; P < 0.007), 90 (85 % vs 94 %; P < 0.02), and 180 (83 % vs 92 %; P < 0.05) days. Moreover, patients with C_av < 550 ng/ml displayed more severe rejection episodes, as judged by Banff classification, than patients who displayed C_av≥ 550 ng/ml (grades II and III; 71 % vs 50 %; P = 0.036). In contrast, the C₀, C_max, and t_max values did not correlate with patient, graft, or rejection-free survival rates. The pharmacokinetic parameter of C_av correlated strongly with early graft survival and may, therefore, be a useful predictor of those renal transplant patients who may require more intensive post-transplant monitoring of CyA concentrations by serial PK studies to improve graft survival. Received: 27 May 1997 Received after revision: 8 August 1997 Accepted: 21 August 1997     

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.     

Cyclosporin A blood levels during use of cyclosporin as oral solution or in capsules: comparison of pharmacokinetic parameters

Recently cyclosporin A (CsA) capsules have been introduced to meet a number of disadvantages associated with the use of the oral solution. We compared the pharmacokinetics of the oral solution and the capsules in a group of nine renal transplant patients during the first 3 weeks after transplantation. After a morning dose of CsA, whole blood concentrations were measured at regular intervals for 12 h. Subsequently, a cross-over was made to the alternative form of administration, and 3 or 4 days later a second pharmacokinetic profile was obtained. Comparison of the trough level, the maximum concentration, the time to reach the maximal concentration and the area under the blood concentration curve, showed no significant differences. Our findings thus suggest a similar bioavailability of CsA administered as oral solution or in capsules in the early post-transplant period.     

Glomerular filtration rate after liver transplantation with a low-dose cyclosporin protocol

Cyclosporin nephrotoxicity is a well-known complication in organ transplantation. In successful liver transplantation, a moderate degree of renal impairment is accepted. Whether this impairment is continuously progressive, stabilizes with time, or is reversible is not known. We have prospectively evaluated the glomerular filtration rate (GFR) using ⁵¹CrEDTA plasma clearance in 29 liver transplant patients (11 males and 18 females) with a mean age of 49 years (range 22–62 years). The ⁵¹CrEDTA plasma clearance measurements were performed preoperatively and at 3, 6, 12, 24, and 36 months after the liver transplantation. All but six patients were given sequential, quadruple drug therapy with antithymocyte globulin, azathioprine, steroids, and cyclosporin. Intravenous cyclosporin was avoided and oral cyclosporin started when renal function was stable. Cyclosporin was started in a dose of 8 mg/kg body weight, aiming at whole blood trough levels (specific monoclonal technique) of 200 g/l in the postoperative period; thereafter, the dosage was rapidly tapered down, aiming at whole blood trough levels of less than 100 g/l at 3 months (1.5–2 mg/kg body weight). From a mean preoperative GFR of 89±3 ml/min per 1.73 m², all patients declined in renal function after transplantation to a mean of 64±4 ml/min per 1.73 m² 3 months after transplantation, and starting in the 3rd month the renal function was stable at about 70% of the preoperative value. No correlations were found between cyclosporin weak level or accumulated cyclosporin dose and renal impairment. We conclude that liver transplantation with cyclosporin immunosuppression will induce renal impairment even if cyclosporin blood levels are carefully monitored and kept low. However, with a low-dose regimen, a progressive decline can be avoided.     

Two-hour post-dose cyclosporin A levels in adolescent renal transplant recipients in the late post-transplant period

Although the success of renal transplantation is closely linked to the immunosuppression provided by cyclosporin A (CsA), the best way to monitor the blood levels of CsA is still not clear. Trough CsA levels (C₀) are commonly used, but the 2-h post-dose CsA levels (C₂) are reported to correlate better with area under the curve. The aim of this study was to evaluate the correlation of C₂ levels with allograft function in adolescent renal transplant recipients in the late post-transplant period (6 months after transplantation) compared with C₀ levels. The data of 17 adolescent renal transplant recipients (12 males, 5 females) were evaluated retrospectively. The mean age at the time of transplantation was 15.212±2.918 years and the mean follow-up period was 53.172±34.090 months. C₀ levels correlated with oral CsA and diltiazem doses, while C₂ levels exhibited no correlation. When C₂ levels were classified as 0–400, 401–800, and 801–1200 ng/ml, no statistically significant difference was found between these groups with respect to glomerular filtration rate (P=0.830). Although 82% of the patients had C₂ beneath the therapeutic level (<800 ng/ml), none had an acute rejection episode. In conclusion, optimum C₂ levels could be different from levels in the adult population. Furthermore, the correlation of C₂ levels with CsA dose seems to be weaker than in the adult population. Thus, further studies are needed to determine a more reliable predictor for CsA dose monitoring and target blood CsA levels in adolescent patients.     

Influence of bile on cyclosporin absorption from microemulsion formulation in primary liver transplant recipients

We analysed the absorption, after oral application, of a new galenic form of cyclosporin A (CyA-NOF) in liver-grafted patients (n=12) during the 1st week (days 2–4) after transplantation. Pharmacokinetic profiling was performed with an open or clamped T tube in situ or with the T tube absent. The pharmacokinetic parameters of CyA-NOF were influenced by T tube clamping and bile diversion. The highest AUC, C_max and earliest T_max values were found in patients without a T tube in situ, indicating that absorption of CyA-NOF in patients during the early course after liver transplantation is not bile-independent. CyA-NOF, at a dose of 7.5 mg/kg, was enterally absorbed with appropriate AUC and C_max levels. Patients receiving a starting dose of 7.5 mg/kg were successfully maintained on CyA-NOF during the subsequent clinical course.     

No rise in renal Doppler resistance indices at peak serum levels of cyclosporin A in stable kidney transplant patients.

BACKGROUND: The measurement of intrarenal resistance indices by duplex ultrasound plays an important role in the follow-up care of renal transplant patients. Increasing resistance indices indicate rejection episodes, but may also occur e.g. in parenchymal renal diseases. As calcineurin inhibitors induce vasoconstriction both in vivo and in vitro, we studied whether peak serum levels of cyclosporin A led to an acute rise in renal resistance indices via the induction of intrarenal vasoconstriction. METHODS: The acute impact of peak serum levels of cyclosporin A on intrarenal resistance indices was studied in 36 patients after allogeneic renal transplantation. All patients were transplanted for > 6 months and received an immunosuppressive treatment comprising cyclosporin A. Intrarenal resistance indices were measured by duplex ultrasound immediately before (trough serum level) and 2 h after (peak serum level) the oral intake of cyclosporin A at the individual maintenance dose. RESULTS: Compared with renal resistance indices measured at trough serum levels [resistive index (RI) 0.72 +/- 0.07; pulsatility index (PI) 1.40 +/- 0.27], values remained unchanged at peak serum levels of cyclosporin A (RI 0.72 +/- 0.08; PI 1.43 +/- 0.31). Renal resistance indices correlated with the age of the patients, but not with mean arterial pressure or time since transplantation. CONCLUSIONS: The oral intake of cyclosporin A does not induce an acute rise in intrarenal resistance indices in stable transplanted patients. Thus, timing of duplex ultrasound examinations with regard to the intake of cyclosporin A is not necessary in these patients.     

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     

Effect of cyclosporin on lung diffusing capacity in renal transplant patients

A prospective lung function study pre- and postrenal transplantation was performed on 21 patients in order to evaluate whether cyclosporin decreased the lung diffusing capacity due to lung toxicity. Initial inclusion criteria were absence of respiratory symptoms and normal findings in both chest X-ray and pulmonary function tests. Participants had to be nonsmokers. We determined spirometry including lung volumes, arterial blood gases, carbon monoxide diffusing capacity by the single breath method (D_LCO_SB), and rate of CO uptake per unit of lung volume (KCO) before and 3, 6, and 12 months after transplantation. Immunosuppression consisted of prednisone and cyclosporin, maintaining total blood levels between 100 and 250 ng/ml. Spirometric and blood gases data remained within reference levels during the follow-up. Hemoglobin (Hb) pretransplant concentrations remained low, returning to their normal levels posttransplantation. Pretransplant D_LCO_SB levels were slightly decreased but fell within the therapeutic range after correction for Hb concentration, unlike the mean KCO levels which remained slightly diminished despite their correction. In post-transplant controls, the values obtained for both D_LCO_SB and KCO were significantly higher at the different post-transplant intervals (P<0.005) than pretransplantation but only when compared without Hb correction. No significant differences for D_LCO_SB were found when corrected values were compared, and an improvement in the KCO appeared to be significant at 12 months posttransplantation. Based on these findings, we feel that when serum levels are within the therapeutic range, cyclosporin fails to alter the respiratory function or the pulmonary diffusing capacity of the lung.     

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.     

Improving the therapeutic monitoring of cyclosporin A

The narrow therapeutic window of cyclosporin A (CsA) and the variable pharmacokinetics of the traditional preparation, CsA-SIM (Sandimmune), have made it difficult to establish its optimal use. The introduction of a microemulsion preparation, CsA-ME (Neoral), with less variable pharmacokinetics, has made it possible to attempt to define its use more closely. One hundred and one renal allograft recipients were converted from CsA-SIM to CsA-ME. Absorption was monitored using a standard pharmacokinetic 'profile' measuring 'whole blood' CsA levels at several time points following drug administration. Areas under the resulting time-versus-CsA concentration curve (AUC) were calculated. Surprisingly, many patients showed very little fluctuation in 'whole blood' levels after administration of the conventional preparation: 31% had a difference between trough (to) and maximal levels of < 100 micrograms/L. On microemulsion cyclosporin, there was much better correlation between AUC and several parameters incorporating elements of trough and peak values. The best correlation was with t0 + (t1/4), where t1 represents the concentration at 1 h following administration, (r2 = 0.779 for microemulsion cyclosporin). The use of this parameter is a practical possibility in an out-patient setting. The very common, but under-recognised, pattern of almost flat absorption profiles in patients on conventional CsA suggests that the use of CsA in numerous clinical contexts should be reviewed, since CsA immunosuppression may previously have been inadequately monitored.     

A Steady‐State Head‐to‐Head Pharmacokinetic Comparison of All FK‐506 (Tacrolimus) Formulations (ASTCOFF): An Open‐Label,Prospective, Randomized,Two‐Arm,Three‐Period Crossover Study

This two‐sequence, three‐period crossover study is the first pharmacokinetic (PK) study to compare all three innovator formulations of tacrolimus (twice‐daily immediate‐release tacrolimus capsules [IR‐Tac]; once‐daily extended‐release tacrolimus capsules [ER‐Tac]; novel once‐daily tacrolimus tablets [LCPT]). Stable renal transplant patients were dosed with each drug for 7 days, and blood samples were obtained over 24 h. Thirty subjects were included in the PK analysis set. A conversion factor of 1:1:0.80 for IR‐Tac:ER‐Tac:LCPT was used; no dose adjustments were permitted during the study. The median (interquartile range) total daily dose was 6.0 (4.0–8.0) mg for IR‐Tac and ER‐Tac and 4.8 (3.3–6.3) for LCPT. Significantly higher exposure on a per milligram basis, lower intraday fluctuation and prolonged time (T_max) to peak concentration (C_max) were found for LCPT versus IR‐Tac or ER‐Tac. ER‐Tac showed no differences versus IR‐Tac in exposure, C_max, T_max or fluctuation. The observed exposure of IR‐Tac was used to normalize exposure for LCPT and ER‐Tac, resulting in the following recommended total daily dose conversion rates: IR‐Tac:ER‐Tac, +8%; IR‐Tac:LCPT, ?30%; ER‐Tac:LCPT, ?36%. After exposure normalization, C_max was ~17% lower for LCPT than for IR‐Tac or ER‐Tac; C_min was ~6% lower for LCPT compared with IR‐Tac and 3% higher compared with ER‐Tac.     

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     

Substitution of conventional cyclosporin with a new microemulsion formulation in renal transplant patients: results after 1 year

BACKGROUND: A new galenic form of cyciosporin A has been developed, basedon microemulsion technology. The bioavailability of the compoundis reiativeiy independent of food intake and bile flow. It wasthe purpose of this prospective clinical trial to study thesafety of the microemulsion form of cyclosporin A. METHODS: Three hundred and two renal transplant patients, stratifiedaccording to transplant age, were switched from the conventionalto the new micro-emulsion formulation of cyclosporin A. A 1:1conversion ratio was used. Measurements included CsA levels,S-creatinine, liver enzymes, uric acid, and blood pressure.Measurements were performed at baseline and on days 4, 8, 15,29 and months 3, 6 and 12 after conversion. Dose adjustmentswere performed to achieve trough levels of 80–120 ng/ml. RESULTS: Within the 12-month observation period the cyclosporin dosewas reduced by 14.7% (from 204±60 mg/day at baselineto 174±51 mg/day after conversion, P<0.001). Acutely,i.e. by day 8, a 1:1 dose conversion resulted in a modest increaseof mean drug trough levels (from 114 ng/ml at baseline to 120ng/ml, P<0.01). This increase was accompanied by an increasein serum creatinine concentration, a decrease in calculatedcreatinine clearance, and an increase in uric acid values (P0.05).Liver enzymes remained unchanged while systolic and mean arterialblood pressure decreased (P<0.05). After 1 month, drug troughlevels had decreased to baseline (112 ng/ml) and remained thereuntil month 6. They were significantly lower after 12 months(102±33 ng/ml, P<0.001). Creatinine clearance valuesincreased to above baseline at 6 and 12 months. Within the 1-yearperiod there occurred 24 (=8%) episodes of biopsy-proven rejectionand seven episodes of cyclosporin-attributed nephrotoxicity. CONCLUSIONS: The 1:1 conversion from conventional cyclosporin A to the microemulsionformulation is efficacious and safe, but an initial dose reductionof 10% is advised in patients with trough levels in the high-normalrange.     

Acute effect of cyclosporin on renal function following the initial changeover to a microemulsion formulation in stable kidney transplant patients

Potential differences in the acute effect of cyclosporin on renal function when dosed orally as the current market formulation or following a milligram-to-milligram conversion to a new microemulsion formulation were investigated in 14 stable kidney transplant patients. The study consisted of three sequential periods of 2 weeks duration each. Patients entered (period I) and completed (period III) the investigation with the market formulation and received the microemulsion formulation in period II; individualized cyclosporin doses remained unchanged throughout the study. Over one steady-state dosing interval at the end of each study period, whole blood cyclosprin pharmacokinetic profiles were assessed in parallel with endogenous creatinine clearances over sequential 1-to 2-h intervals. The rate and extent of cyclosporin absorption were significantly greater (P<0.01) from the microemulsion formulation with average increases of 73% in peak concentration and 44% in area under the curve compared to the market formulation. Sequential creatinine clearances exhibited a transient decrease with the nadir occurring on average between 4 and 6h post dose followed by a rapid return to baseline. Specifically in period I on the market formulation, clearances decreased from a baseline of 71.7±20.6 to a minimum of 51.1±17.9 ml/min per 1.73 m² (similar values in period III) and from 76.8±24.8 to 53.5±17.5 ml/min per 1.73 m² in period II on the microemulsion. Neither the baseline nor minimum clearances were significantly different among the study periods. Hence, the pharmacokinetic differences between the formulations did not acutely influence the pattern of glomerular filtration rate following the initial milligramto-milligram changeover in stable renal transplant patients.     

Contribution of cyclosporin metabolites to immunosuppression in liver-transplanted patients with severe graft dysfunction

The aim of this study was to analyse the immunosuppressive contribution of cyclosporin metabolites in liver-grafted patients. Therefore the immunosuppressive potency of 17 metabolites, alone and in combination, was tested in human mixed lymphocyte cultures, and the results were correlated with metabolite blood levels in liver-grafted patients. Of the 17 metabolites tested only six highly lipophilic metabolites showed a detectable immunosuppressive activity of up to 10% of the activity of cyclosporin; the effect of combining metabolites was additive. For calculation of the in vivo activity, blood levels of seven major cyclosporin metabolites were determined in liver-grafted patients with normal liver function (group A, 43 episodes) and with severe hyperbilirubinaemia (group B, 66 episodes). Both patient groups had comparable levels of parent drug (122.9±17.4 vs. 111.1±23.5 ng/ml by HPLC) and similar blood levels of the highly lipophilic metabolites 17, 1 and 18. By contrast, blood levels of the less lipophilic metabolites 8, 9, 26 and 203–218 were substantially increased in group B (P<0.05). High overall metabolite blood levels in group B were also indicated by a non-specific monoclonal RIA (520±199 ng/ml for group A vs. 1318±407 ng/ml for group B). Despite the very high levels in group B, however, the overall contribution of the metabolites to immunosuppression was similar in both groups (12.6±5.0% for group A vs. 13.8±5.6% for group B). These findings indicate that, despite a marked accumulation of cyclosporin metabolites in patients with severe cholestatic liver dysfunction, their immunosuppressive contribution remains low. This suggests that for assessment of the immunosuppressive potency of cyclosporin therapy monitoring of parent drug levels is necessary and sufficient. Since a variety of non-immunological effects of high metabolite levels cannot be excluded, however, additional non-specific measurements may, nevertheless, be useful in patients with severely disturbed liver graft function.     

Renal fibrosis in cyclosporin A-treated renal allograft recipients: morphological findings in relation to renal hemodynamics

Nineteen nondiabetic kidney graft patients treated with cyclosporin A for 2 years underwent percutaneous renal allograft biopsy as well as renal hemodynamic examination. Renal allograft fibrosis was quantitatively evaluated as the relative volume of the renal cortical interstitium (V_v%) and as the intersttium/tubuli ratio (I/T ratio). The histological changes were then classified into four groups, depending on the degree of interstitial fibrosis. The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and fractional clearance of sodium, potassium, phosphate, chloride, osmoles, and free water clearance were determined in all patients and in 13 healthy controls. Kidney graft recipients had significantly lower GFR, lower RPF, and lower RBF than the healthy controls (P<0.001 for all comparisons) while FF was similar in patients and controls. Transplant recipients had a significantly higher fractional excretion of sodium, potassium, chloride, and phosphate than controls. All except one patients had clearly increased V_v values, indicating increased interstitial fibrosis. The mean V_v in renal allograft patients was 35%±10% (normal <16%±5%) and the I/T ratio was 1.07±0.60 (normal <0.24±0.08). No correlation was found between the quantitative or semiquantitative biopsy analysis and any renal hemodynamic parameter measured. We conclude that renal function is significantly decreased in kidney graft recipients, but that adaptive tubular changes occur in the graft. Interstitial renal fibrosis was common but did not correlate to any renal functional parameter.     

Safety and steady-tate pharmacokinetics of a new oral formulation of cyclosporin A in renal transplant patients

Abstract The steady-tate pharmacokinetics of a new oral formulation of cyclosporin A (Sandimmun Neoral, NOF, a microemulsion) was compared with those of the market formulation (Sandimmun, SIM) in stable renal transplant patients. Both formulations were administered as soft gelatin capsules every 12 h with doses adjusted to provide comparable trough concentrations ( C ^ssmin). Whole blood samples were obtained over a steady-tate dosing interval (τ), and the cyclosporin A level was determined by a specific monoclonal RIA. Both formulations were well tolerated. The mean doses were 139 ± 27 mg (SIM) vs. 120 ± 19mg (NOF), indicating a milligram doseconversion factor of approximately 1:1 to yield comparable troughs. NOF exhibited a stronger correlation between AU C ^ss and C ^ssmin ( r ²= 0.821) compared with SIM ( r ²= 0.288), due in part to less variability in the NOF profiles. Average increases of 39% in C ^ssmax and 15% in AU C ^ssT during treatment with NOF were not associated with any safety concerns over the 4-week exposure to Sandimmun Neoral, as evidenced by the absence of changes in blood pressure, hematologic and biochemical parameters (including serum creatinine and blood urea nitrogen, BUN) and ultrasound of the transplanted kidney.