Bone Marrow Transplantation (2007) 40, 911–912 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00
www.nature.com/bmt
LETTER TO THE EDITOR
High-unbound mycophenolic acid concentrations in an infant on peritoneal dialysis following hematopoietic cell transplant Bone Marrow Transplantation (2007) 40, 911–912; doi:10.1038/sj.bmt.1705837; published online 27 August 2007 Mycophenolic acid (MPA) is a prodrug of the immune suppressant mycophenolate mofetil (MMF). MMF is hydrolyzed to MPA after oral and i.v. administration. It is metabolized further by glucuronosyltransferase enzymes to form the primary metabolite MPA 7-O-glucuronide (MPAG) and the minor metabolite acyl MPA glucuronide (AcMPAG). MPA and MPAG are extensively bound to albumin, 97–99 and 85%, respectively. Only unbound MPA is pharmacologically active. MPAG and AcMPAG are renally excreted and accumulate in renal dysfunction. Because clinical events may lead to the altered binding of MPA to albumin, assessment of systemic exposure based on total MPA concentrations alone may be misleading. A 7 month-old female infant with high risk, bilineage acute leukemia [t(11;19)] was admitted to the University of Minnesota for hematopoietic cell transplant (HCT). She received a myeloablative preparatory regimen of BU, melphalan and fludarabine. Immunosuppression was with MMF 110 mg (15.5 mg kg1) every 8 h i.v. and CY 15 mg every 8 h i.v. beginning on day 3. Her pretransplant labs were blood urea nitrogen 3 mg dl1, Cr 0.16 mg dl1, total bilirubin 0.2 mg dl1 and albumin 4.1 g dl1 and weight was 7.1 kg. By day 4 her weight had increased by 1.8 kg and Cr to 0.7 mg dl1. On day 0 she received an unrelated, partially matched double umbilical cord blood transplant. She was emergently intubated after the infusion secondary to acute hypoxia and pulmonary edema. She subsequently developed mild hepatic veno-occlusive disease although her bilirubin and liver enzymes increases only modestly. Because of weight gain, oliguria, rising Cr and worsening respiratory status, peritoneal dialysis (PD) was started on day þ 6 with 50 ml of dialysis solution containing 4.25% dextrose every 30 min with 15–20 min dwell times. Mycophenolate pharmacokinetic sampling was performed on day þ 9 during PD. No mycophenolate dose adjustments for renal dysfunction or dialysis were made. Total and unbound MPA concentrations were measured predose and 2, 4, 6 and 8 h after start of infusion and pharmacokinetic measures were calculated (Table 1). On the day of pharmacokinetic sampling the Cr was 0.46 mg/100 ml, blood urea nitrogen 31 mg/100 ml, WBC 0.5 109 cells ml1, albumin 3.1 g/100 ml, prealbumin 27 mg/100 ml and total bilirubin was o0.1 mg/100 ml. Medications on day of pharmacokinetics included CY, hydrocortisone, aminophylline, micafungin, ceftazidine, cefazolin, vancomycin (in the dialysis fluid), foscarnet, bumetanide, chlorothiazide, metolazone, amlodipine, prazosin, nifedipine, raniti-
dine, hydromorphone, midazolam, propofol, lorazepam, ursodiol and hydroxyzine. The total MPA and MPAG trough concentrations and area under curves (AUCs) for this patient were within the ranges that we have observed in other pediatric HCT recipients receiving the same dose with normal renal and hepatic function (Table 1). However, the unbound MPA AUC was nearly fourfold higher and unbound fraction was threefold higher (4.5%) than average. We previously reported a case of an adult patient with renal failure requiring continuous veno-venous dialysis, severe hepatic dysfunction and sepsis that had normal total MPA concentrations but extremely high-unbound fraction (29%).1 Clinical covariates associated with elevated unbound fraction have been proposed.2,3 In the current case, renal dysfunction, PD, respiratory failure or displacement of MPA from albumin by a concurrent medication (for example, bumetanide or propofol—also highly protein bound) may have contributed to altered protein binding. Interestingly, the MPAG AUC was not elevated to the extent expected in renal dysfunction,4,5 perhaps because MPAG may have been removed by PD or her residual renal function was adequate to eliminate the metabolite. It is not possible to determine the extent of removal of MPA by PD from this case although it has been previously shown in adults that MPA is not removed by hemodialysis or PD.4,5 There are limited data on dosing of MMF in patients with compromised organ function and its effect on protein binding. The manufacturer recommends dose reductions in adult patients with a GFRo25 ml/min/1.73 m2 with doses no greater than 1 g every 12 h.6 No dose adjustment data are available in children. The effect of high MPA concentrations in HCT patients is not known. Mycophenolate toxicity has been reported to occur in patients with normal total MPA concentrations Table 1
Pharmacokinetics
Total MPA trough (mg ml1) MPA AUC0–8 (mg h ml1) MPAG AUC0–8 (mg h ml1) Unbound MPA trough (mg ml1) MPA AUC0–8 (mg h ml1) Unbound fractionb
Patient
Mediana
0.144 15.98 348.9
0.36 11.8 260.6
0.011 0.726 4.5%
0.0056 0.189 1.6%
Abbreviations: AUC ¼ area under curve; MPA ¼ mycophenolic acid; MPAG ¼ MPA 7-O-glucuronide. a n ¼ 15 (Jacobson, personal communication). b Calculated from AUC.
Letter to the Editor
912
but elevated unbound concentrations.7,8 In pediatric kidney recipients, an unbound MPA AUC0–12 40.4 mg h ml1 is associated with a higher risk of infection and neutropenia.9 However, in the case of this child, hematologic toxicity was not apparent and neutrophil engraftment occurred despite elevated unbound concentrations. An albumin concentration o3.1 g/100 ml has been associated with a elevated unbound MPA concentration in kidney recipients,10 although this patient did not have a low albumin concentration. Given that only unbound MPA is pharmacologically active and that total concentrations do not always adequately represent exposure to the active component, there is a need for monitoring of unbound MPA concentrations in critically ill patients. MPA is glucuronidated in the liver and kidney; therefore, a compromise in either of these organ systems may result in altered drug disposition. Candidates for unbound concentration monitoring include those with renal or hepatic dysfunction, respiratory failure, sepsis or veno-occlusive disease. A thorough evaluation of the effects of organ dysfunction on MPA disposition is needed. 1,2
3
1
3
4
5
4,5
PA Jacobson , N Rydhom , J Huang , KS Baker and MR Verneris4,5 1 Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA; 2 University of Minnesota Cancer Center, Minneapolis, MN, USA; 3 Department of Pharmacy, Fairview University Medical Center, Minneapolis, MN, USA; 4 Department of Pediatrics, Division of Pediatric Hematology, Oncology and Transplantation, University of Minnesota, School of Medicine, Minneapolis, MN, USA and 5 Blood and Marrow Transplant Program, University of Minnesota, School of Medicine, Minneapolis, MN, USA E-mail:
[email protected]
References 1 Jacobson P, Long J, Rogosheske J, Brunstein C, Weisdorf D. High unbound mycophenolic acid concentrations in a
Bone Marrow Transplantation
2
6 7
8
9
10
hematopoietic cell transplantation patient with sepsis and renal and hepatic dysfunction. Biol Blood Marrow Transplant 2005; 11: 977–978. Weber LT, Shipkova M, Lamersdorf T, Niedmann PD, Wiesel M, Mandelbaum A et al. Pharmacokinetics of mycophenolic acid (MPA) and determinants of MPA free fraction in pediatric and adult renal transplant recipients. German study group on mycophenolate mofetil therapy in pediatric renal transplant recipients. J Am Soc Nephrol 1998; 9: 1511–1520. Weber LT, Lamersdorf T, Shipkova M, Niedmann PD, Wiesel M, Zimmerhackl LB et al. Area under the plasma concentration-time curve for total, but not for free, mycophenolic acid increases in the stable phase after renal transplantation: a longitudinal study in pediatric patients. German study group on mycophenolate mofetil therapy in pediatric renal transplant recipients. Ther Drug Monit 1999; 21: 498–506. Shaw LM, Mick R, Nowak I, Korecka M, Brayman KL. Pharmacokinetics of mycophenolic acid in renal transplant patients with delayed graft function. J Clin Pharmacol 1998; 38: 268–275. MacPhee IA, Spreafico S, Bewick M, Davis C, Eastwood JB, Johnston A et al. Pharmacokinetics of mycophenolate mofetil in patients with end-stage renal failure. Kidney Int 2000; 57: 1164–1168. Anonymous. CellCept, Package Insert. Roche Laboratories: Nutley, NJ, USA, 2004. Mudge DW, Atcheson BA, Taylor PJ, Pillans PI, Johnson DW. Severe toxicity associated with a markedly elevated mycophenolic acid free fraction in a renal transplant recipient. Ther Drug Monit 2004; 26: 453–455. Kaplan B, Gruber SA, Nallamathou R, Katz SM, Shaw LM. Decreased protein binding of mycophenolic acid associated with leukopenia in a pancreas transplant recipient with renal failure. Transplantation 1998; 65: 1127–1129. Weber LT, Shipkova M, Armstrong VW, Wagner N, Schutz E, Mehls O et al. The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic Acid in pediatric renal transplant recipients: a report of the German study group on mycophenolate mofetil therapy. J Am Soc Nephrol 2002; 13: 759–768. Atcheson BA, Taylor PJ, Kirkpatrick CM, Duffull SB, Mudge DW, Pillans PI et al. Free mycophenolic acid should be monitored in renal transplant recipients with hypoalbuminemia. Ther Drug Monit 2004; 26: 284–286.
