Population Pharmacokinetics of Mycophenolic Acid in Renal Transplant Recipients

Hest, Reinier M. van; Gelder, Teun van; Vulto, Arnold G.; Mathôt, Ron A. A.

doi:10.2165/00003088-200544100-00006

Cited by 93 publications

(82 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5,[14][15][16] In contrast, the average plasma half-life in liver and renal transplant patients is about 6 and 11 h, respectively. 17,18 For healthy adults half-lives of about 16-18 h were determined. 19,20 In consequence, similar MMF doses as used in SOT achieved lower AUC values in the range of 10-30 mg/ml h and C min levels o1 mg/ml.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

Lange

Mueller

Altmann

et al. 2007

Bone Marrow Transplant

View full text Add to dashboard Cite

Mycophenolate mofetil (MMF) has been used successfully in solid organ transplantation (SOT) and more recently in nonmyeloablative hematopoietic stem cell transplantation (HSCT) for prophylaxis of graft rejection and acute graft-versus-host disease. However, the pharmacokinetics of MMF seem to differ when applied in HSCT compared to SOT. Here, we analyzed pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF, in a nonmyeloablative canine HSCT model. Dogs received nonmyeloablative TBI for conditioning followed by leukocyte antigen-identical littermate HSCT and immunosuppression containing cyclosporin A (CsA) and different doses of MMF. Pharmacokinetics were performed on days 2, 14 and 27. Dose escalation of MMF from 10 to 30 mg/kg tended to increase area under the curve (AUC) and the apparent oral clearance by 45 and 110%, respectively. Doses applied had no linear association with MPA concentration or blood trough level. No significant drug accumulation occurred over time. Using a twice daily MMF regimen, we conclude that an AUC of 30-60 lg/ml h as recommended for SOT cannot be reached in HSCT. Toxicities did not permit single doses higher than 30 mg/kg. Thus, if larger AUCs are desired in order to assure sufficient immunosuppression in HSCT, MMF might have to be administered at least three times daily.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation

Lange

Mueller

Altmann

et al. 2007

Bone Marrow Transplant

View full text Add to dashboard Cite

show abstract

“…A more detailed description of the technical aspects of the methods that are used for pharmacokinetic modeling are reported elsewhere (unpublished observations, Van Hest et al, 2005). Briefly, during the first step of the analysis, a compartmental population pharmacokinetic model was developed describing the pharmacokinetics of MPA and quantifying between-and within-patient variability in MPA pharmacokinetics.…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

“…For example, some studies found that impaired renal function and low albumin levels result in high total MPA clearance and thus low total MPA exposure (5,9,11,13,14), although this could not be confirmed in all stud-ies (15)(16)(17)(18)(19)(20). Also with regard to the effect of the use of comedication (3,10,18,21,22), diabetes (23,24), body weight (11,13,17,20), age (5,11,18 -20), gender (11,20,23), and race (9,23,25), contrasting results have been obtained. Most of these studies were underpowered, based on MPA predose levels only, and some studies did not control adequately for confounding factors.…”

mentioning

confidence: 99%

Explaining Variability in Mycophenolic Acid Exposure to Optimize Mycophenolate Mofetil Dosing

Hest¹,

Mathôt²,

Pescovitz

et al. 2006

Journal of the American Society of Nephrology

Self Cite

177

View full text Add to dashboard Cite

Large between-and within-patient variability has been observed in the pharmacokinetics of mycophenolic acid (MPA). However, conflicting results exist about the influence of patient characteristics that explain the variability in MPA exposure. This population pharmacokinetic meta-analysis of MPA in renal transplant recipients was performed to explore whether race, renal function, albumin level, delayed graft function, diabetes, and co-medication are determinants of total MPA exposure. A total of 13,346 MPA concentration-time data points from 468 renal transplant patients who participated in six clinical studies were combined and analyzed retrospectively. Sampling occasions ranged from day 1 after transplantation to 10 yr after transplantation. Concentration-time data were analyzed with nonlinear mixed-effect modeling. Exposure to total MPA, as determined by MPA clearance, significantly increased with increasing renal function, albumin level, and hemoglobin as well as decreasing cyclosporine predose level (P < 0.001). These variables could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure. Differences in MPA exposure between patients with or without delayed graft function or between patients of different races are likely to be caused by the effect of renal function on MPA exposure. Diabetes did not have an effect on MPA exposure. The clinical implication is that a change in renal function or albumin level provides an indication for therapeutic drug monitoring as MPA exposure may be altered. Patients in whom cyclosporine and mycophenolate mofetil are combined may need higher mycophenolate mofetil doses, especially during the early phase after transplantation than currently recommended for optimal MPA exposure.

show abstract

“…With the use of population PK modeling and including the early posttransplantation period (days 3 to 140), major factors identified thus far that correlate significantly with MPA clearance include creatinine clearance, plasma albumin concentration, and CsA daily dosage (32). In a meta-analysis of longitudinal data in which MPA PK values were available from day 1 after transplantation out to 10 yr, it was estimated that kidney function, plasma albumin concentration, hemoglobin concentration, and CsA predose concentration could explain 18% of the between-patient and 38% of the within-patient variability in MPA exposure (29).…”

Section: Population Pk Modelsmentioning

confidence: 99%