| | Modifications in cyclosporine (CsA) microemulsion blood concentrations by olestra☆☆☆★Abstract Objective: Determine whether olestra alters the absorption of cyclosporine microemulsion in pediatric renal transplant recipients. Design: Prospective, open-label, crossover pharmacokinetic study. Setting: General clinical research center in a university medical setting providing tertiary care. Participants: Seven pediatric-adolescent renal transplant recipients, ages 9 to 18, 5 to 24 months post-transplant with mean serum creatinine of 0.9 mg/dL (range, 0.7-1.6 mg/dL). Methodology: Patients participated in 2 study periods: 1. Patients were given their usual dose of Neoral (Novartis Pharmaceuticals Corporation, East Hanover, NJ) without olestra, 2. patients were given their usual dose of Neoral combined with 0.35 g/kg (maximum of 16 g of olestra or approximately 2 ounces of Lays WOW [Frito Lay, Plano, TX] potato chips). The 2 study periods were separated by a minimum 7-day washout period. CsA blood concentrations were obtained at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration. Results: Each patient in the study had a consistent decrease in area under the curve (AUC) when given olestra along with their usual dose of Neoral, compared with giving Neoral alone (5,018 ng*hr/mL versus 4,086 ng*hr/mL; P < .001). There also was a decrease in maximum concentration (Cmax) when Neoral was given with olestra compared with giving Neoral alone (1,202 ng/mL versus 876 ng/mL; P = .015). There was no statistical difference in the mean elimination rate or the trough values for both regimens (half-life 4.767 hours versus 4.771 hours and trough levels of 143 ng/mL versus 124 ng/mL). Conclusion: Olestra decreases total CsA exposure in pediatric renal transplant recipients. The noted decrease in AUC was not adequately predicted by CsA trough values which could lead to rejection episodes in the clinical setting. © 2003 by the National Kidney Foundation, Inc.
It is estimated that in the United States alone there are greater than 60,000 renal transplant recipients and many more liver, heart, lung, and pancreas transplant recipients.1 Although organ transplantation generally increases the quality and length of life, it is associated with significant morbidity. Post-transplant rejection episodes, obesity, nephrotoxicity, hypertension, diabetes mellitus, infection, and hyperlipidemia are not uncommon.2, 3, 4, 5 Because of the complexity of transplantation, it is difficult to determine if post-transplant complications are related to the disease state or are the result of post-transplant drug therapy. Most post-transplant morbidity, in fact, appears to be a combination of disease pathology and toxic drug effect. Thus, to decrease post-transplant complications it is therefore necessary to minimize disease progression while optimizing drug therapy.
Two post-transplant complications that can be positively impacted by appropriate dietary changes and exercise are obesity and hyperlipidemia. However, compliance to a low fat, low cholesterol diet can be difficult, particularly if intensive dietary advice and follow-up are not available. Pediatric and adolescent kidney transplant patients may be at increased risk for dietary nonadherence because of their desire to eat high-fat snack foods similarly to their peers. Olestra (Olean; Procter and Gamble, Cincinnati, OH), a palatable, nontoxic, nonabsorbable, saturated fat substitute currently being used in common snack foods such as potato chips and corn chips may help transplant patients comply with a lower fat, lower calorie diet. Chemically, olestra is composed of 6 to 8 fatty acid chains attached to a sucrose core.6, 7 The tight molecular confirmation of olestra prevents its hydrolysis by pancreatic lipases, thus it can not be absorbed or digested by humans.6, 7 Because olestra is not absorbed, it is a nonfat, zero-calorie cooking oil. Because snack foods made with olestra are lower in fat, it may be more healthful for pediatric renal transplant recipients to eat these foods instead of triglyceride-containing snacks. However, there is some evidence that olestra alters fat-soluble vitamin absorption and may interfere with medication absorption when consumed on a daily basis.8, 9
There is a theoretic potential that olestra could decrease the absorption of fat-soluble medications. Cyclosporine microemulsion (CsA) is a fat-soluble immunosuppressive medication commonly prescribed after kidney transplantation. Because there is evidence that olestra alters fat soluble vitamin absorption and preliminary studies in rats indicate olestra decreases blood cyclosporine levels, it is necessary to examine the potential effects of olestra on CsA absorption in pediatric renal transplant recipients.
This study investigated the impact of olestra on CsA blood levels in pediatric and adolescent kidney transplant patients. The goal was to determine if, and to what extent, olestra alters CsA pharmacokinetecs and if its consumption could potentially contribute to organ rejection as a result of decreased cyclosporine absorption and suboptimal blood levels.
Methods  The study was a prospective, open-label, crossover pharmocokinetic study and involved two regimens. For regimen A, the subject received their usual oral dose of CsA (Neoral) and in regimen B, the subject received their usual oral dose of Neoral in combination with 0.35 g/kg/d olestra (not to exceed 16 g). Venous blood samples were obtained at 1, 2, 3, 4, 6, 8, and 12 hours post-Neoral administration. Whole blood venous cyclosporine concentrations were assessed using Abbott TDX Immunoassay methodology. There was at least a 7-day washout period between regimens. Eligibility for the study included subjects between the ages of 5 and 21 years, with weight greater than 13 kg, a normal physical examination, normal electrolytes, liver function tests and blood counts, stable CsA dose for at least 7 days, and a serum creatinine less than 2.5 mg/dL. Patients were excluded if they had a recent acute rejection, hypoalbuminemia, elevated liver enzymes, or elevated bilirubin. They were excluded also if they had changes in doses of any other medication within 7 days of the study that could alter cyclosporine pharmacokinetics. Area under the curve (AUC) represents the total exposure to drug in a given time period and was calculated with the trapezoidal rule for a 12-hour dosing interval. The Cmax, which is the maximum level of drug in the subject's blood during the 12-hour dosing interval, was determined by visual inspection of the subject's blood cyclosporine concentration versus time curve. Half-life, which is the time required for the total blood concentration of a drug to decrease by 1 half, was calculated using the following equation:
Half-life = 0.693 ÷ (elimination rate constant for cyclosporine). The elimination rate constant for cyclosporine was calculated with 2 concentration-time points with the following equation:
k = lnC1 − lnC2 where c = concentration, t = time point (t2 - t1). This equation allows the elimination and half-life to be calculated for each study subject without a direct measurement of metabo elimination or clearance. CsA trough level is the minimum amount of drug in the body 12 hours after oral administration. Statistic analysis The AUC, Cmax, and half-life for cyclosporine alone and in combination with olestra were calculated and then compared using a paired t-test with a predetermined significance level of α = 0.05. All values are expressed as absolute or mean values plus or minus standard deviations. A change of 20% in pharmacokinetic parameters between the 2 regimens was considered clinically significant for the purposes of this study. Results A summary of the patient demographics can be seen in Table 1.
| | |  | Subject | Age (yrs) | Gender | Wt (kg) | CsA Dose (mg/kg/d) | sCr (mg/dL) | Primary Disease | |
|---|
| 1 | 13 10/12 | M | 38.9 | 5.36 | .7 | Focal segmental glomerulosclerosis | |
| 2 | 14 11/12 | F | 45.0 | 5.0 | .9 | P-ANCA Positive syndrome | |
| 3 | 14 2/12 | M | 42.0 | 4.16 | 1.6 | Obstructive uropathy, solitary dysplastic kidney | |
| 4 | 10 10/12 | F | 33.5 | 5.97 | .7 | Vesicoureteral reflux, renal dysplasia | |
| 5 | 18 11/12 | M | 53.6 | 7.46 | 1.5 | Prune belly syndrome | |
| 6 | 9 5/12 | M | 26.0 | 9.62 | .8 | Obstructive uropathy, prune belly variant | |
| 7 | 16 3/12 | M | 65.5 | 3.44 | 1.0 | Focal segmental glomerulosclerosis | |
| | | | | |
A total of 7 subjects were enrolled with an average age of 15.3 years (9-18 years). They included 2 females (29%) and 5 males (71%). The subjects were between 5 months and 2 years post-transplant and the mean serum creatinine was 0.9 mg/dL (range, 0.7-1.6 mg/dL). Cyclosporine dose per day ranged from 3.44 mg/kg/d to 9.62 mg/kg/d. Table 2 summarizes the results of the study.
| | | | Parameter | CsA Microemulsion Alone | CsA Microemulsion + Olestra | P-Value | |
|---|
| Mean CsA AUC(ng*hr/mL) | 5018 | 4086 | <.001 | |
| CsA Cmax (ng/mL) | 1202 | 876 | <.015 | |
| CsA half-life (hr) | 0.151 hr-1 | 0.150 hr-1 | N.S. | |
| Mean CsA trough level (ng/mL) | 143 +/− 64 | 124 +/− 41 | .05 | |
| | | | | |
Each patient enrolled in the study showed a consistent decrease in AUC when given olestra along with their usual dose of CsA (Figure 1).
The mean AUC after CsA alone was 5,018 ng-hr/mL, whereas the mean AUC after CsA plus olestra was 4,086 ng-hr/mL ( P < .001). The Cmax for CsA alone was 1,202 ng/mL, whereas the Cmax for CsA plus olestra was 876 ng/mL ( P < .015). The mean CsA elimination rate constant, represented by CsA half-life, was statistically similar for both medication regimens (0.151 hour-1 for CsA alone and 0.150 hour-1 for CsA plus olestra). Figs. 5 and 6 show that the CsA trough levels were statistically unchanged with both regimens (143 ± 64 ng/mL for CsA alone compared with 124 ± 41 ng/mL for CsA along with olestra ( P = .05). These results suggest olestra decreases CsA absorption and decreases the bioavailability of CsA, but does not affect the elimination rate constant or trough values. Discussion These results are particularly significant for the pediatric and adolescent renal transplant population for several reasons. First, the majority (75%-80%) of pediatric renal transplant recipients in the United States and Canada receive cyclosporine.10 Second, it is known that this population experiences great variability in cyclosporine absorption and pharmacokinetic parameters, even with the microemulsion formulation.11, 12 Third, pediatric and adolescent kidney transplant recipients are at higher risk for rejection than adult recipients.13 Fourth, children and adolescents are anticipated to consume the most olestra; it is estimated that 13- to 17-year-old males will consume 16.2 g of olestra per snack as compared with 10.2 g for all population subsets combined.14 Fifth, the consumption of olestra in this age group will only increase as olestra is substituted for fat in an increasing number of products. Finally, the impact of olestra on blood drug levels had never been investigated in the pediatric and adolescent population. Based on the results of this study, it appears that olestra significantly decreases the overall exposure to cyclosporine in pediatric renal transplant recipients. Although the sample size was small, the results did reached statistical significance. After evaluating the findings in these initial patients, it was felt that it could be detrimental to subsequent patients to continue the study because the CsA AUC was decreased and current rature indicates AUC monitoring is more important than CsA trough levels in this patient population.15, 16 The results of the study also indicate that olestra decreases the peak concentration and AUC for CsA, but does not affect the elimination rate constant for CsA. The cyclosporine trough values were not changed with or without olestra (Figure 2), which indicates that trough levels will not reliably predict changes in AUC when CsA is taken along with olestra.
This further supports that trough measurements are an inadequate method of monitoring CsA. In summary, these results suggest that pediatric and adolescent renal transplant recipients eating 0.35 mg/kg or up to 16 g of olestra (2 oz Lays WOW potato chips) in combination with their usual CsA dose will have alterations in CsA blood concentrations. Any decrease in AUC of CsA puts these patients at increased risk of allograft rejection. Because the cyclosporine trough levels were not statistically significant between regimens, trough values would not be predictive in determining whether olestra alters cyclosporine exposure. CsA noncompliance, which is not uncommon in the pediatric/adolescent population, will further exacerbate potential problems associated with decreased AUC. Although food items made with olestra are not typically recommended to pediatric kidney transplant patients, this population may choose these products on their own in an attempt to adhere to a low fat diet as recommended by their health care providers. Although it is somewhat unlikely that patients would consume foods made with olestra with their morning CsA dose, it is conceivable that these snacks foods could be consumed with their evening dose of CsA. Conclusion Based on the results of this study, transplant recipients taking CsA should be advised to avoid products containing olestra in combination with their usual CsA dose because of the decrease in total CsA exposure caused by this fat substitute. References 1.
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Transplant Int. 1998;11:46–52. * Pediatric Renal Dietition, Intermountain Pediatric-Adolescent Renal Disease Program, University of Utah Health Sciences Center, Salt Lake City, UT. † Assistant Professor, Pharmacy Practice, University of Utah, College of Pharmacy, Salt Lake City, UT. ‡ Director, Clinical Research in Kidney Transplant, Solid Organ Transplantation, University of Utah, Salt Lake City, UT. ** Medical Director, Pediatric Renal Transplant, Intermountain Pediatric-Adolescent Renal Disease Program, University of Utah Health Sciences Center, Salt Lake City, UT. ☆ Supported in part by the General Clinical Research Center, University of Utah Hospital. Funded by generous contributions from the National Kidney Foundation/Council on Renal Nutrition, Astra Clinical Pharmacy Research Award, and the University of Utah, College of Pharmacy Faculty Grants. ☆☆ Jennifer Lill is now with Department of Scientific Affairs, Berlex Laboratories. ★ Address reprint requests to Cynthia J. Terrill, RD, CS, CSR, Pediatric Renal Transplant Program, 85 North Medical Drive, East Room 201, Salt Lake City, UT 84112-5350. PII: S1051-2276(02)13407-8 doi:10.1053/jren.2003.50006 © 2003 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. | |
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