Reduced intrapatient variability of cyclosporine pharmacokinetics in renal transplant recipients switched from oral Sandimmune to Neoral.

Sixty-six renal transplant patients maintained on Sandimmune, the traditional formulation of cyclosporine, participated in an open-label, sequential trial to compare intrapatient variability in drug exposure before and after a switch to Neoral. Three 12-hour cyclosporine pharmacokinetic profiles were obtained over approximately 6 weeks while patients were receiving Sandimmune. Patients were then switched to Neoral, with the dose adjusted as necessary to maintain target trough blood cyclosporine concentrations. At approximately 4 and 6 weeks postconversion, 2 additional pharmacokinetic profiles were obtained. Key pharmacokinetic variables analyzed were area under the concentration-time curve (AUC), maximum concentration (Cmax), and predose trough concentration (C0). Intrapatient variability in drug exposure for dose-normalized mean AUC, Cmax, and C0 was significantly reduced with Neoral, with 50 (76%), 57 (86%), and 45 (68%) patients experiencing reduced variability in AUC, Cmax, and C0, respectively (P < 0.001). Additionally, the total exposure to cyclosporine was more predictable from the trough level of cyclosporine with Neoral; the relationship between AUC and C0 was 0.81 for Neoral at both pharmacokinetic profiling time points but ranged from 0.49 to 0.69 for the 3 Sandimmune time points. The large reductions in intrapatient variability of pharmacokinetic variables for cyclosporine provided by Neoral indicate an improvement in the consistency of drug exposure, which may translate into important clinical benefits.

Improved cyclosporine bioavailability in black pediatric liver transplant recipients after administration of the microemulsion formulation.

Black transplant recipients are associated with low cyclosporine bioavailability, which may contribute to the poorer clinical outcomes observed with these patients. In this analysis, we compared cyclosporine exposure in black (n = 9) and nonblack (n = 18) pediatric maintenance liver transplant recipients by using steady-state pharmacokinetic profiles obtained after administration of the original and microemulsion formulations of cyclosporine. Treatment with the original cyclosporine formulation resulted in lower mean dose-normalized, area under the concentration-versus-time curve values for black compared with nonblack pediatric liver transplant recipients. On conversion to the microemulsion formulation of cyclosporine, black and nonblack patients experienced increases in cyclosporine bioavailability of 102% and 39%, respectively (P =.009 and P =.001). Because the increase in mean bioavailability was substantially greater for blacks, area under the concentration-versus-time curve values for this pediatric subpopulation became similar to those levels obtained for nonblacks receiving the microemulsion formulation for cyclosporine. When patients were further stratified by age, ethnic differences in bioavailability with the original formulation of cyclosporine were most apparent in the 1- to 5-year age group. Conversion to the microemulsion formulation resulted in a 164% increase (P =.05) in bioavailability for black patients within this age group such that, again, these levels became similar to area under the concentration-versus-time curve values obtained for young nonblacks receiving cyclosporine for microemulsion. Improvements in cyclosporine bioavailability after administration of the microemulsion formulation of cyclosporine may translate to improved long-term graft and patient outcomes for black pediatric liver transplant recipients.

Reduced cyclosporine absorption preceded acute allograft rejection in a child with a liver transplant.

This case report correlates impaired cyclosporine absorption from the traditional oral formulation in a 9-year-old liver transplant recipient with subsequent acute allograft rejection. Although impaired absorption in this patient was documented by cyclosporine pharmacokinetic profiling (steady-state area under the cyclosporine concentration-time curve or AUC), no indication was evident from the pre-dose cyclosporine trough level, which was within the typical target range of blood concentrations. However, when the subject received the microemulsion formulation of cyclosporine the AUC value reflected an adequate absorption pattern. We recommend that if malabsorption is suspected in the de novo pediatric liver transplant patient, then single-sample pre-dose trough cyclosporine levels should not be relied on as an indicator of sufficient immunosuppression and that a limited sampling strategy be used to confirm or rule out impaired absorption.

Cyclosporin pharmacokinetics in paediatric transplant recipients.

Cyclosporin is an essential component of the antirejection drug protocol used in the long term management of paediatric organ transplant recipients. This article looks at the pharmacokinetics of cyclosporin in paediatric kidney, heart, liver and bone marrow transplant recipients and critically evaluates its relationship to pharmacokinetic data in adult transplant recipients. There are limited data on the pharmacokinetics of cyclosporin in paediatric transplant recipients (14 publications provide the database) as compared with the adult transplant population. Study design, analytical methodology and age ranges of the individuals differ between studies, making comparative interpretation of pharmacokinetic data difficult. However, significant trends are noteworthy and these may influence dose administration guidelines and therapeutic monitoring standards for cyclosporin in the paediatric organ transplant recipient. The bioavailability of the oral formulations of cyclosporin is highly variable as with the adult population, but there appears to be a correlation between cyclosporin bioavailability and age with both the traditional oral formulation (Sandimmun) and the new microemulsion formulation (Neoral) in young liver transplant patients. Bowel length, presystemic metabolism in the gut wall, type of transplant and time since transplant are contributing factors in the variation of bioavailability patterns in paediatric transplant patients. The volume of distribution of cyclosporin does not appear to differ between paediatric and adult transplant recipients, but systemic clearance is comparatively higher in the paediatric population. In general, paediatric patients require higher doses of cyclosporin to achieve target blood concentrations of the drug which are equivalent to the values used in the adult population. Younger patients (less than 8 years of age) may be managed more effectively with a 3 times daily administration schedule rather than the twice daily schedule which is universally used for cyclosporin in the transplant population. The comparatively higher doses and more frequent administration schedule used in paediatric transplant recipients are the consequence of age-related differences in bioavailability and the possibility of increased metabolic clearance of the drug in younger patients.

Comparison and validation of limited sampling equations for cyclosporine area-under-the-curve monitoring calculations in pediatric renal transplant recipients.

Therapeutic monitoring of cyclosporine (CsA) by using area-under-the-concentration-time-curve (AUC) values in renal transplant recipients has been previously demonstrated to predict posttransplant clinical outcome. Two previous studies also reported that limited sampling equations could accurately determine the AUC of CsA using one to six blood concentration determinations in adults. The purpose of this study was to validate the accuracy of these equations in a pediatric population. In 18 pediatric patients who received renal allografts, three limited sampling equations, which used one, four, or five concentration time points, accurately estimated CsA AUC when compared with an actual 7- to 9-point curve. An equation that used a single concentration time point at 5 hours was unbiased and provided the best precision in calculating a 12-hour interval AUC. This equation had a mean absolute percentage error of 5.8% (95% confidence interval, 3.3 to 8.3). Equations using four or five concentration time points were found to provide estimates of AUC for a 24-hour interval AUC, with less than 10% error. These findings suggest that limited sampling models using as few as one to four concentration time points provide accurate estimations of CsA AUC in pediatric patients. The use of these limited sampling models provides the clinical advantage of lower blood sampling requirements and reduced costs associated with the monitoring of cyclosporine.

Sequestration of vecuronium bromide during extremity surgery involving use of a pneumatic tourniquet.

BACKGROUND: We hypothesized that sequestration of a neuromuscular blocking agent could occur during surgery involving use of an extremity tourniquet and cause changes in neuromuscular function after tourniquet release. METHODS: Sixteen patients scheduled for total knee replacement were randomized to one of two groups. In Group I, 10 patients were administered 0.1 mg/kg of vecuronium 5 minutes prior to inflation of a pneumatic tourniquet; in Group II, 6 patients were administered 0.1 mg/kg of vecuronium after inflation of the tourniquet. The twitch (T1) and train-of-four (TOF) were analyzed before and after release of the tourniquet, as was the rate of recovery of T1 and TOF. Serial vecuronium plasma levels were drawn during the study. RESULTS: The T1 and TOF responses and the T1 and TOF recovery rates were not significantly different between groups at tourniquet deflation. In Group I, after release of the tourniquet, T1 and TOF recovery rate decreased significantly over a 10-min period (10% +/- 3 to 4% +/- 4 and 0.12 +/- 0.06 to 0.06 +/- 0.04, mean +/- SD, respectively); in Group II, T1 and TOF recovery rate increased significantly over a 10-min period following deflation of the tourniquet (10% +/- 6 to 14% +/- 7 and 0.10 +/- 0.03 to 0.18 +/- 0.02, respectively). Changes in pharmacodynamics were temporally associated with transient but statistically significant changes in vecuronium plasma levels. Overall pharmacokinetics during the study period were comparable between groups. After administration of neostigmine 30-40 micrograms/kg i.v. all subjects in both groups showed complete TOF recovery within 15 min. CONCLUSIONS: Sequestration of a bolus dose of vecuronium, by a pneumatic tourniquet, causes transient changes in pharmacokinetics and pharmacodynamics. These changes are of limited clinical importance and do not affect reversibility of neuromuscular block.

Absorption characteristics of a microemulsion formulation of cyclosporine in de novo pediatric liver transplant recipients.

In pediatric liver transplant recipients, oral cyclosporine (CsA) therapy may be complicated by impaired or delayed absorption during the initial weeks posttransplant. Neoral (NL) is a microemulsion preconcentrate formulation of CsA expected to increase the rate and extent of absorption of CsA and have less pharmacokinetic variability. The absolute bioavailability (F) of CsA from NL was compared with that of the currently marketed Sandimmune (SM) formulation in a double-blind, crossover study conducted in 9 pediatric liver transplant recipients (age 6 months to 11 years) between 8 and 20 days posttransplant. After determination of CsA pharmacokinetics for a steady-state intravenous dose, patients were randomized to receive a single oral dose of NL or SM in period I and the alternative formulation in period II. Clearance (Clt) and volume of distribution (Vss) values (mean +/- s.d.) calculated from the i.v. dose were similar to that previously reported for pediatric patients (Clt = 12.0 +/- 1.3 ml/min/kg; Vss = 2.2 +/- 0.2 L/kg). Mean F (+/- SD) for NL was significantly higher than SM (NL = 37.6 +/- 14.6%; SM = 24.7 +/- 8.0%; P = 0.05). Although not reaching statistical significance, the observed maximum blood concentration (Cmax) was higher, and the time to Cmax (Tmax) was shorter for NL in 8 or 9 patients. There were no significant correlations between age and any pharmacokinetic parameter for the group as a whole--however, there were statistically significant correlations between age and F for NL (r = 0.87; P = 0.02), and for age and Vss (r = 0.91; P = 0.01) for the 6 patients aged 2 years or less. In this pediatric liver transplant population, Neoral demonstrated improved absorption (% increase in F) compared to Sandimmune. In liver transplant recipients aged 2 years or less, absorption of Neoral may be a function of age and/or bowel length.

Comparison of three methods for cyclosporine area under the curve monitoring calculations.

A method of therapeutic monitoring of cyclosporine by using area under the curve (AUC) has been previously proposed. However, different mathematical methods of calculating AUC may produce different results. We compared three methods of calculating whole blood 12-h AUC of cyclosporine A (CsA) at steady state in 16 pediatric renal allograft recipients. The linear trapezoidal method tended to significantly overestimate AUC when compared with a method combining linear and log trapezoidal methods, or the Lagrange technique combined with the logarithmic trapezoidal method, producing mean differences of 13.8 ng*h/ml [95% confidence interval (CI), 7.3-20.3] and 12.8 ng*h/ml [95% CI, 7.3-18.3], respectively. However, these differences appear to be of little clinical significance because they comprised < 1% of the calculated AUC value. The calculated AUCs by the three methods produced values with similar means and overlapping 95% CI. These data suggest that use of any of these three mathematical methods, when used to calculate CsA AUC for the determination of average steady-state concentrations and dose rate calculations, will produce similar results.

Effects of carbamazepine on cyclosporine metabolism in pediatric renal transplant recipients.

This study documents a pharmacokinetic interaction between carbamazepine and cyclosporine (CsA) in pediatric renal transplant recipients. Noncompartmental steady-state CsA pharmacokinetics were determined in three pediatric renal transplant recipients who were receiving both CsA and carbamazepine as long-term therapy (carbamazepine group) and in three matched renal transplant subjects who were not receiving carbamazepine (control group). Even though the mean daily dosage of CsA was consistently higher in the carbamazepine group than in the control group (16.2 mg/kg/24 hrs vs 10.8 mg/kg/24 hrs, respectively), the predose trough CsA blood concentrations were significantly lower in the carbamazepine group (57 ng/ml vs 162 ng/ml, respectively; p = 0.0023). Mean average steady-state blood concentrations of CsA (Cav) per mg of CsA administered were less than 50% in the carbamazepine group compared with the control group. This reflects either an induction of CsA hepatic metabolism or a reduced systemic bioavailability (possible induction of pre-hepatic metabolism) by concurrent use of carbamazepine.

Utility of pretransplantation cyclosporine pharmacokinetic studies.

Pretransplant cyclosporine (CsA) pharmacokinetic analysis of an individual patient is advocated as a more accurate method of determining the optimal dose schedule of CsA for immediate posttransplant patients than traditional mg/kg dosing methods. Eight adult renal transplant candidates (age range 28-69 years) were studied. CsA whole blood analysis was done with a monoclonal fluorescence polarization immunoassay (mFPIA) and high-performance liquid chromatography HPLC. Noncompartmental modeling methods were used to derive CsA pharmacokinetic values. At 1 and 3 months posttransplant CsA pharmacokinetic analyses were completed on five subjects and the average steady state CsA concentration for the dosing interval, Cav, was compared to predicted values calculated from pretransplant pharmacokinetic parameters for each subject. At 6 months posttransplant, actual and predicted Cav were compared in three subjects. Correlation between predicted and actual Cav at 1 month posttransplant was poor (mean actual Cav = 365 ng/ml versus mean predicted Cav = 238 ng/ml; r2 = 0.361). At 3 months posttransplant, the discrepancy between predicted and actual Cav was greater for all five subjects (r2 = 0.039) and this trend persisted for three subjects at 6 months posttransplantation. The mFPIA analysis overestimated the parent CsA concentration when compared to HPLC analysis; the degree of overestimation ranged from 118 to 180%. The mFPIA assay variability may have contributed to the poor correlation between pre- and posttransplant Cav values. There appears to be little or no basis for subjecting transplant candidates to sophisticated pharmacokinetic tests in order to develop specific CsA dosing guidelines for the posttransplant phase.

Absolute bioavailability and absorption characteristics of aerosolized tobramycin in adults with cystic fibrosis.

Administration of antibiotics by the inhalational route has become part of standard protocols for treatment of and prophylaxis for Pseudomonal pneumonias in patients with cystic fibrosis. For tobramycin, however, limited data are available on the aerosol absorption patterns, and no absolute bioavailability data for tobramycin exist. The purpose of this study was to measure the absolute bioavailability and systemic absorption characteristics of tobramycin when administered in high doses by a nebulizer. Multiple serum concentrations of tobramycin were measured after administration of an intravenous dose (mean, 2.9 mg/kg every 6 hours) and after an inhalational dose (5.6 mg/kg over 1 hour). Inhalational doses were superimposed over the "tail" of a steady-state intravenous dose to improve the sensitivity of the assay procedure (Abbott-TDX). Absolute bioavailability (F) was determined from AUC ratios normalized for dose. Model-independent pharmacokinetic parameters (volume of distribution [Vss] and total clearance [CLt]) were determined for each subject. Absorption characteristics (absorption rate constant [Ka] and mean absorption time [MAT]) were assessed after calculation of the cumulative fraction of drug absorbed, amount of bioavailable drug, and percent remaining to be absorbed per unit time using the Loo-Riegelman method. Three men and three women completed the study, and all received concurrent doses of ceftazidime. Mean absolute bioavailability (+/- standard deviation) was 9.13% (+/- 3.82), and the rate of absorption into the systemic circulation was consistent with a zero-order model profile for all subjects. Mean absorption time values reflected a wide degree of subject variability and ranged from approximately 15 to 150 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)