Pharmacokinetics of mycophenolic acid in liver transplant patients after intravenous and oral administration of mycophenolate mofetil

Jain, Ashokkumar; Venkataramanan, Raman; Kwong, Tai C.; Mohanka, Ravi; Orloff, Mark S.; Abt, Peter L.; Kashyap, Randeep; Tsoulfas, Georgios; Mack, C.; Williamson, Mary A.; Batzold, Pam; Bozorgzadeh, Adel

doi:10.1002/lt.21146

Cited by 32 publications

(26 citation statements)

References 44 publications

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“…In healthy patients, bioavailability after single-dose oral administration of 1.5 g of MMF was 85.7% for the MPA AUC 0 -24 and 93.3% for the MPA AUC 0 -ϱ in comparison with the intravenous formulation (25). However, MMF bioavailability seems to be decreased to 48.5% in liver transplant patients treated with 1 g of oral MMF two times daily (26). Also, in hematopoietic stem cell transplant recipients treated with 1 g of MMF in combination with cyclosporine, a decreased and highly variable bioavailability was seen (F ϭ 72.3%, range 20.5% to 172%) (27).…”

Section: Discussionmentioning

confidence: 90%

Nonlinear Relationship between Mycophenolate Mofetil Dose and Mycophenolic Acid Exposure

Winter

Mathôt

Sombogaard

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Mycophenolate mofetil (MMF) is an immunosuppressive drug used in renal transplant patients. Upon oral administration it is hydrolyzed to the active agent mycophenolic acid (MPA). In renal transplant recipients, MMF therapy is optimal when the area under the curve of MPA is 30 to 60 mg⅐h/L. When MMF doses are adjusted, a linear relationship between dose and MPA exposure is assumed. In this study, the linearity of MMF pharmacokinetics was investigated.Design, setting, participants, & measurements MPA concentration-time profiles from renal transplant recipients cotreated with cyclosporine (n ϭ 140) or tacrolimus (n ϭ 101) were analyzed retrospectively using nonlinear mixed-effects modeling. The correlation between the MMF dose and the pharmacokinetics parameters was evaluated. ResultsIn the developed population pharmacokinetics model MPA clearance and the central volume of distribution were correlated with cyclosporine coadministration and time posttransplantation. The pharmacokinetics of MPA were not linear. Bioavailability decreased with increasing MMF doses. Compared with an MMF dose of 1000 mg (ϭ100%), relative bioavailability was 123%, 111%, 94%, and 90% in patients receiving MMF doses of 250, 500, 1500, and 2000 mg in combination with cyclosporine (P Ͻ 0.001); respective values in tacrolimus-cotreated patients were 176%, 133%, 85%, and 76% (P Ͻ 0.001). Because of the decreasing relative bioavailability, MPA exposure will increase less than proportionally with increasing MMF doses.Conclusions MMF exhibits nonlinear pharmacokinetics. This should be taken into account when performing therapeutic drug monitoring.

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Section: Discussionmentioning

confidence: 90%

Nonlinear Relationship between Mycophenolate Mofetil Dose and Mycophenolic Acid Exposure

Winter

Mathôt

Sombogaard

et al. 2011

Clinical Journal of the American Society of Nephrology

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“…Clinical practice suggests that a target Ն1 mg/L is important in the first year after transplantation to minimize rejection, whereas levels should be kept below approximately 3.5 mg/L subsequently to reduce the incidence of adverse effects. Initial intravenous MMF dosing can be considered in liver (and possibly bowel) transplantation to compensate for decreased drug bioavailability early after grafting (12).…”

Section: Liver Bowel and Pancreas Transplantationmentioning

confidence: 99%

Consensus Report on Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplantation

Kuypers¹,

Meur²,

Cantarovich³

et al. 2010

Clinical Journal of the American Society of Nephrology

285

252

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“…Large interindividual variation in MPA pharmacokinetics after oral administration has been well‐recognized in liver transplant recipients 9, 11, 17. In this study, such a phenomenon still remained not only in DDLT patients but also in LDLT patients.…”

Section: Discussionmentioning

confidence: 64%

Comparison of pharmacokinetics of mycophenolic acid and its metabolites between living donor liver transplant recipients and deceased donor liver transplant recipients

et al. 2009

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Living-donor liver transplantation (LDLT) has been considered an alternative method for treatment of patients with end-stage liver disease. However, the characteristics of pharmacokinetics of mycophenolic acid (MPA) in patients who underwent LDLT were not clear. This study was designed to compare the pharmacokinetics of MPA and its metabolites between LDLT patients and deceased donor liver transplant (DDLT) patients after oral administration of mycophenolate mofetil (MMF). Thirteen patients who underwent LDLT and 14 patients who underwent DDLT were enrolled prospectively. All patients received oral MMF administration (1.0 g, twice daily) in combination with tacrolimus (TAC). The plasma concentrations of MPA, free MPA, glucuronide (MPAG), and acyl glucuronide (AcMPAG) was determined by high-performance liquid chromatography method. There was a wide variation in various pharmacokinetic parameters of MPA and its metabolites in patients who underwent LDLT and DDLT after oral MMF administration. Although mean MPA area under the plasma concentration time curve for 0-12 hours (AUC 0-12h ) of MPA and MPAG in DDLT patients were higher than those in LDLT patients, there was no significant difference between the two groups. MPA concentration at 6 hours (C 6h ), C 10h , C 12h , and MPA AUC 6-12h were significantly higher in DDLT group than those in LDLT group (P Ͻ 0.05). Inversely, higher free MPA AUC 0-12h and significant free MPA fraction (P Ͻ 0.05) in LDLT patients were observed in DDLT patients when compared with DDLT group. AcMPAG concentrations at 4, 8, and 10 hours and AcMPAG AUC 0-12h were significantly higher in the DDLT group (P Ͻ 0.05). In conclusion, after a fixed oral dose of MMF, DDLT patients had higher enterohepatic recycling contributing to total MPA exposure compared with LDLT patients. The function of glucuronide conjugation in LDLT patients was decreased compared with that in DDLT patients. Higher free MPA AUC 0-12h and a significantly higher fraction of free MPA in LDLT patients suggested that a lower oral dose of MMF may be administered for patients who underwent LDLT.

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Pharmacokinetics of mycophenolic acid in liver transplant patients after intravenous and oral administration of mycophenolate mofetil

Cited by 32 publications

References 44 publications

Nonlinear Relationship between Mycophenolate Mofetil Dose and Mycophenolic Acid Exposure

Nonlinear Relationship between Mycophenolate Mofetil Dose and Mycophenolic Acid Exposure

Consensus Report on Therapeutic Drug Monitoring of Mycophenolic Acid in Solid Organ Transplantation

Comparison of pharmacokinetics of mycophenolic acid and its metabolites between living donor liver transplant recipients and deceased donor liver transplant recipients

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