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Case Reports Indian Pediatrics 2001; 38: 911-914 |
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Cyclosporine Pharmacokinetics in a Renal Allograft Recipient |
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Transplantation has become a common practice in children with end stage renal disease. With advances in tissue matching, surgical techniques, postoperative care and immunosuppressive regimens, the one-year graft survival rate reported by the North American Pediatric Renal Transplant Co-operative Study (NAPRTCS) has improved to 76% for the cadaver and 90% for the living related donor transplants(1). Episodes of acute rejection and a high percentage of panel reactive antibody are considered to be risk factors for chronic allograft nephropathy (CAN), which still remains the main cause of graft loss(2). Evaluation of immuno-suppressive protocols demonstrates that cyclosporine A is an important medication for both induction and maintenance treatment for renal transplant recipients(3). Pediatric renal transplant recipient pose a unique set of challenges and problems includ-ing heightened immune responsiveness, vari-able cyclosporine absorption and pharmaco-kinetics, and inhibited growth relative to their healthy peers as a result of immunosuppressive drugs in typical post-transplant protocols. There is a weak but significant positive correlation between age and dose per body surface area and normalized area under curve (AUC), indicating that the younger the child the larger the required dose(4). Microemulsion forms of cyclosporine, e.g., Neoral have been developed to give better absorption and bioavailability, particularly in children(3,5). Because children metabolize and eliminate cyclosporine A at a faster rate than adults, they may require frequent dosing of the drug to prevent rejection(3,6). AUC, the gold standard for evaluating cyclosporine exposure, is expensive and difficult due to the number of blood samples required, trough levels are commonly used although their correlation with AUC is unsatisfactory(7,8). Here we describe the full pharmacokinetic profile of Neoral with determination of AUC in a 11-year-old girl who had undergone renal transplantation. Case Report An 11-year-old girl, weighing 21 kg with end stage renal disease due to an unknown cause underwent a renal transplantation from her mother in August 1995. The mother was 30 years old and had one mismatch of the class I antigen. Pre-operative investigations includ-ing a micturating cystourethrogram was normal but the ultrasound abdomen showed left hydroureteronephrosis. She underwent left sided nephrectomy at the time of transplanta-tion, which showed a calcium oxalate stone in the left ureter. The initial immunosuppresion consisted of prednisolone 30 mg, azathioprine 50 mg and Neoral 100 mg twice daily (9.5 mg/kg). Other medications included oral cotrimoxazole one tablet thrice a week, dilitiazem 30 mg three times a day, prazosin 1 mg thrice daily and atenolol 50 mg. On the third post-operative day, the serum cretinine was 0.8 mg/dl and blood urea nitrogen 7 mg/dl. Neoral was reduced to 8.3 mg/kg on the fifth day. Whole blood trough cyclosporine level (12 hours after the last dose) was 80.83 ng/ml on the eighth day (monoclonal antibody method TDx). The dose of Neoral was increased to 9.5 mg/kg. A cyclosporine pharmacokinetic study was done estimating the whole blood cyclosporine level using high performance liquid chromatography (HPLC) every 90 minutes for 24 hours (Fig. 1). During the first 12 hours the AUC was 3,487 ng/ml/h, with an average AUC of 35.5 ng/ml/h/mg dose. During the second 12 hours the AUC was 3,615 ng/ml/h. This showed the child to be at the lower end of the AUC range seen in this group of patients. Trough level at end of the first 12 hours interval was 108 ng.ml. The trough level at the end of second 12 hours interval was 170 ng/ml. As this trough level was considered to be very low in the early post transplant period the child was switched over to an 8 hourly Neoral regimen in equal divided doses of 9.5 mg/kg/day. While following up the child after 4 months she weighed 32 kg, blood pressure was 110/84 mm Hg. Investigations showed a blood urea nitrogen level of 18 mg/dl and creatinine 0.9 mg/dl. The immunosuppressive medications included prednisolone 10 mg every other day, azathioprine 50 mg once daily and Neoral 50 mg thrice daily. She had one episode of biopsy proven acute cellular rejection in January 1996, which was successfully treated with three 250 mg pulses of methylprednisolone. At the end of 1 year, diltiazem was discontinued and she was switched over to nifedipine retard 10 mg thrice daily. In February 2000, she is 16 years old, weighs 63 kg with serum cretinine level of 1.2 mg/dl, blood urea nitrogen of 12.1 mg/dl and blood pressure of 120/80 mm Hg. Her current immunosuppressive medications are predni-solone 5 mg alternating with 2.5 mg, Neoral 125 mg daily (in three divided doses) and oral trimethoprimsulfamethoxazole one tablet twice weekly prophylaxis for PCP. Discussion Neoral was instituted in pediatric renal transplant patients with the hypothesis that it would have more predictable kinetics than other generic forms of cyclosporine A. A decrease in rejection rate has been observed with Neoral, although this was questioned(8). The combination of rapid absorption and a rapid peak may result in lower trough levels at 12 hours in the early post-transplant period in children, which can lead to increased incidence of rejection(2). Neoral is considered to have better bio-availability but a narrow therapeutic window. Any change in cyclosporine formula-tion should be made cautiously with follow up laboratory test under physician’s supervision because it may result in the need for dosage adjustment(6). Current data from NAPRTCS show that at one-year post transplant the mean cyclosporine dosage varies from 5.6 to 8 mg/kg(9). In a study of 78 pediatric renal transplant recipients, a target level of 800 ng/ml at 2 hours after ingestion during the first 100 days following transplantation and 450-500 ng/ml thereafter, was found to prevent rejection(6). Trough levels <100 ng/ml at one month post-transplant had 2.24 and 2.73 times the risk of biopsy proven rejection episodes at 1 and 6 months respectively(2). In order to obtain the target trough levels of cyclosporine A, one may increase the dose or change the dosing frequency(10). The t½ for cyclosporine in this child was found to be 3 hours, which was lower than the Caucasian patients of the same age and weight. It has been found that 3-5% less of cyclosporine A can be prescribed by decreasing the Neoral dose using the child’s previous serum cretinine as the measure of adequacy and toxicity of the drug(9). Data from the NAPRTCS have demonstrated that higher cyclosporine A dosing has positive impact on post-trans-plantation allograft survival(1). Diltiazem may have a dual effect; controlling blood pressure is beneficial in enchancing blood cyslosporine levels and hence reducing episodes of rejection. This is independent of the dosage of diltiazem used(11). Although, our experience is limited to one patient, we suggest that a pharmacokinetic profile using an abbreviated AUC in the second, third and sixth hour should be done in all children who have undergone renal transplantation instead of doing 12 hour trough level as practised(6,10). Higher doses of Neoral, administered at frequent intervals, result in better availability of cyclosporine. Better bioavailability of the drug is expected to prevent episodes of acute rejection thereby improving long term graft function. Contributors: GC and JVR co-ordinated the case management and co-drafted the paper. GA and PS helped in drafting and supervising. GA will act the guarantor for the report. Funding: None. Competing interests: None stated.
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