2013 - ISBTS 2013 Symposium

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Mini-Oral Communications 1

12.255 - Pharmacokinetics of mycophenolic acid and dose optimization in children after intestinal transplantation

Presenter: Florence , Lacaille, , France
Authors: Florence Lacaille1, Antonio Mellos1, Valerie Furlan2

Pharmacokinetics of mycophenolic acid and dose optimization in children after intestinal transplantation

Florence Lacaille1, Antonio Mellos1, Valerie Furlan2

1Pediatric Hepatogastroenterology-Nutrition, Hôpital Necker-Enfants malades, Paris, France; 2Pharmacy-Toxicology, Hôpital Bicêtre, Kremlin-Bicetre, France

Aim. Mycophenolate (MP) is an immunosuppressive drug commonly used after intestinal transplantation (ITx), despite its digestive side-effects, but without clear recommendations about the dose. The AUC0-12 of mycophenolic acid (MPA) is a reflection of exposure to the drug, and the standard criterion for monitoring. A therapeutic range of 30 to 60 mg/h/L is recommended in renal Tx. We report the MP dosage needed to achieve this range after ITx, and describe adverse effects, and effectiveness on the rejection risk. 
Patients and methods.Seven children after isolated small bowel Tx (SBTx, 3) or  combined liver-small bowel transplantation (L-SBTx, 4), for short bowel syndrome (3), Hirschsprung disease (1), chronic intestinal pseudoobstruction (1), congenital enteropathy (2). Indication for MP were renal failure (5) and increased immunosuppression for GVH (2). Mean age at pharmacokinetic study was 10.5 years. The first one was performed at a median of 50 months (3-126) post-Tx, at least 1 week after initiation of MP. The patients received also tacrolimus and prednisone. Blood  serum  level of MPA was measured before the dose, 30 mn, 1, 2, 4, 6 and 8 hours afterwards.
Results.Three patients underwent only 1 test, the others from 2 to 6. After the first  test,  the initial dose was increased in  5, decreased in 1. The treatment was stopped in 2 because of diarrhea. One patient with GVH developed a PTLD, well controlled with rituximab. None had myelosuppression, opportunistic infections or rejection. No secondary concentration peak was seen in most patients. The average initial dose of MP was 19 mg/kg or 505 mg/m² twice a day, while the average dose for achieving the target AUC was 25 mg/kg (9 – 44) or 692 mg/m² (228-1374) twice a day. Average percentage change of the dose was 37%.

Discussion.The average MP dose to achieve the target AUC is higher after ITx than after other organ Tx. Drug monitoring is recommended for the optimization of the MP dosage, early after introduction and regularly until the required exposure is achieved. Subsequently, MPA should be  monitored when the immunosuppression is changed, a potentially interacting drug is introduced or withdrawn, in cases of worsened graft function, changes in serum albumin concentration, renal or liver function. The adequate dose for an individual patient is unpredictable, and cannot be extrapolated from the other organ Tx . A  prospective trial should establish if the AUC0-12 therapeutic range of 30-60 mg/hour/L is associated with a reduced risk of rejection in ITx. Finally, larger studies are needed in order to determine if a limited sampling strategy, easier to perform, may be designed.

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