An Age-Dependent Pharmacokinetic Study of Intravenous and Oral Mycophenolate Mofetil in Combination with Tacrolimus for GVHD Prophylaxis in Pediatric Allogeneic Stem Cell Transplantation Recipients

Abstract

Acute graft-versus-host disease (aGVHD) still remains a major limiting factor following allogeneic stem cell transplantation (AlloSCT) in pediatric recipients. Mycophenolate mofetil (MMF), an uncompetitive selective inhibitor of inosine monophosphate dehydrogenase, is a new immunosuppressant agent without major mucosal, hepatic, or renal toxicity compared to other prophylactic aGVHD immunosuppressant drugs. Although there has been an extensive pharmacokinetic (PK) experience with MMF administration following solid organ transplantation in children, there is a paucity of PK data following its use in pediatric AlloSCT recipients. We investigated the safety and PK of MMF as GVHD prophylaxis following intravenous (i.v.) and oral (p.o.) administration (900 mg/m(2) every 6 hours) in conjunction with tacrolimus, after myeloablative (MA) and nonmyeloablative (NMA) conditioning and AlloSCT in 3 distinct age groups of pediatric AlloSCT recipients (0-6 years, 6-12 years, and 12-16 years). Mycophenolic acid (MPA) in plasma samples was measured either by high-performance liquid chromatography (HPLC) or liquid chromatography/mass spectrometry (LC/MS/MS) as we have previously described. Plasma samples were obtained at baseline and at 0.5, 1, 2, 3, 4, and 6 hours after i.v. dosing on days +1, +7, +14, and at 2 time points between day +45 and +100 after p.o. administration post AlloSCT. MPA PK analysis included AUC (0-6 hours), C(max), T(max), C(ss), V(ss), C trough (C(0)), CL, and T((1/2).) Thirty-eight patients, with a median age of 8 years (0.33-16 years), 20/18 M:F ratio, 21/17 malignant/nonmalignant disease, 17/21 MA: NMA conditioning, 16 of 22 related/unrelated allografts. Median time to myeloid and platelet engraftment was 18 and 31 days, respectively. Mean donor chimerism on day +60 and +100 was 83% and 90%, respectively. Probability of developing aGVHD grade II-IV and extensive chronic GVHD (cGVHD) was 54% and 34%, respectively. There was significant intra- and interpatient MMF PK variability. There was a significant increase in i.v. MPA area under the curve (AUC)(0-6 hour) and C(max) (P < .0003) and a significant decrease in CL(ss) (P < .002) and V(ss) (P < .001) on day +14 versus day +7. Children <12 years of age had a significant increase in i.v. MPA T(max) (P = .01), V(ss) (P = .028), and CL(ss) (P < .001) compared to the older age group. There was a trend in increased i.v. MPA CL(ss) following MA versus NMA conditioning (P < .054); i.v. and p.o. MMF administration (900 mg/m(2) every 6 hours) in combination with tacrolimus was well tolerated in pediatric AlloSCT recipients. There was a significant increase in MPA exposure on day +14 versus day +7, suggesting improved enterohepatic recirculation at day +14 post-AlloSCT. Children <12 years of age appear to have a significantly different MPA PK profile compared to older children and adolescents and may require more frequent dosing.

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

“…Age-dependent pharmacokinetics has been reported for several drugs, including cisplatin, busulfan, thioguanine, etoposide, lamivudine, and mycophenolate mofetil [161][162][163][164][165][166]. Our studies showed that roscovitine elimination half-life was 14-fold higher in young rats compared to adults.…”

A pilot study of reduced toxicity conditioning with BU, fludarabine and alemtuzumab before the allogeneic hematopoietic SCT in children and adolescents

“…9 We have previously shown that the use of FK506/MMF has been associated with good tolerability and low overlapping toxicities, and it may be equivalent or superior to standard regimens in preventing aGVHD with the appropriate monitoring. 17,25 Thirdly, faster implementation of growth factors, which were started at day 0 in our study, whereas day þ 21 in the Horn et al study. 9 As sequential administration of GM-CSF/G-CSF post-myeloablative AlloHSCT was safe, and resulted in prompt myeloid engraftment, 19 this can possibly contribute to more sustained engraftment.…”

Reduced toxicity, myeloablative conditioning with BU, fludarabine, alemtuzumab and SCT from sibling donors in children with sickle cell disease

“…19,20 MMF was tapered if patients had ⩽ grade II aGVHD on day +180 and tacrolimus was tapered upon conclusion of the MMF taper. 19,20 aGVHD and chronic GVHD (cGVHD) were graded according to Seattle consensus criteria. 21 Supportive care and infection prophylaxis Sargramostim (250 μg/m 2 /day) was started i.v.…”