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Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

ABSTRACT: We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2?L/hour and 36.4?L, respectively, for a 70?kg patient receiving tacrolimus with a serum albumin of 3.4?g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25?hours, 1.25?hours, 2?hours, and 4?hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.

SUBMITTER: Li H

PROVIDER: S-EPMC3612130 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

Li H H Mager D E DE Sandmaier B M BM Maloney D G DG Bemer M J MJ McCune J S JS

Journal of clinical pharmacology 20130204 4

We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from ...[more]

PMID: 23382105

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Project description:ImportanceFirst-line systemic therapy for morphea includes methotrexate with or without systemic corticosteroids. When this regimen is ineffective, not tolerated, or contraindicated, a trial of mycophenolate mofetil (MMF) or mycophenolic acid (MPA)-referred to herein as mycophenolate-is recommended; however, evidence to support this recommendation remains weak.ObjectiveTo evaluate the effectiveness and tolerability of mycophenolate for the treatment of morphea.Design, setting, and participantsA retrospective cohort study was conducted from January 1, 1999, to December 31, 2018, among 77 patients with morphea from 8 institutions who were treated with mycophenolate.Main outcomes and measuresThe primary outcome was morphea disease activity, severity, and response at 0, 3 to 6, and 9 to 12 months of mycophenolate treatment. A secondary outcome was whether mycophenolate was a well-tolerated treatment of morphea.ResultsThere were 61 female patients (79%) and 16 male patients (21%) in the study, with a median age at disease onset of 36 years (interquartile range, 16-53 years) and median diagnostic delay of 8 months (interquartile range, 4-14 months). Generalized morphea (37 [48%]), pansclerotic morphea (12 [16%]), and linear morphea of the trunk and/or extremities (9 [12%]) were the most common subtypes of morphea identified. Forty-one patients (53%) had an associated functional impairment, and 49 patients (64%) had severe disease. Twelve patients received initial treatment with mycophenolate as monotherapy or combination therapy and 65 patients received mycophenolate after prior treatment was ineffective (50 of 65 [77%]) or poorly tolerated (21 of 65 [32%]). Treatments prior to mycophenolate included methotrexate (48 of 65 [74%]), systemic corticosteroids (42 of 65 [65%]), hydroxychloroquine (20 of 65 [31%]), and/or phototherapy (14 of 65 [22%]). After 3 to 6 months of mycophenolate treatment, 66 of 73 patients had stable (n = 22) or improved (n = 44) disease. After 9 to 12 months of treatment, 47 of 54 patients had stable (n = 14) or improved (n = 33) disease. Twenty-seven patients (35%) achieved disease remission at completion of the study. Treatments received in conjunction with mycophenolate were frequent. Mycophenolate was well tolerated. Gastrointestinal adverse effects were the most common (24 [31%]); cytopenia (3 [4%]) and infection (2 [3%]) occurred less frequently.Conclusions and relevanceThis study suggests that mycophenolate is a well-tolerated and beneficial treatment of recalcitrant, severe morphea.

Project description:BackgroundWe compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression.Methods and findingsATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design.ConclusionsIn this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.Trial registrationClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.

Dataset Information

Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

Publications

Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

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