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PHARMACOKINETICS |
From Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis (P. A. Jacobson, K. G. Green) and Diabetes Institute for Immunology and Transplantation, Department of Surgery, University of Minnesota, Minneapolis (B. J. Hering).
Address for reprints: Pamala A. Jacobson, PharmD, Experimental and Clinical Pharmacology, WDH 7-189, 308 Harvard St. SE, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Mycophenolic acid • mycophenolate mofetil • mycophenolic acid glucuronide • pharmacokinetics
Mycophenolate mofetil is an ester prodrug of the active form, mycophenolic acid (MPA). It is hydrolyzed (95%) to MPA by esterases in the blood, gut wall, liver, and tissues. Mycophenolic acid undergoes glucuronidation by UDP glucuronosyltransferases in the intestine, liver, and kidney to form the inactive metabolite, mycophenolic acid glucuronide (MPAG).8-10 Mycophenolic acid glucuronide is transported to the gut via the bile or excreted into the urine and eliminated. Mycophenolic acid glucuronide present in the bile is subject to deglucuronidation, where it is converted back to MPA through enterohepatic recycling. Mycophenolic acid and MPAG are highly protein bound to plasma albumin at clinically relevant concentrations.11 Only unbound MPA is pharmacologically active, and unbound concentrations in the plasma are typically 1% to 2% of total MPA but may be higher in some disease states.12-15
Mycophenolate mofetil is approved at a fixed dose of 1 or 1.5 g twice daily (bid) for the prevention of acute rejection in renal, hepatic, and cardiac transplantation. Subsequent to Food and Drug Administration (FDA) approval, large inter- and intrapatient variability in pharmacokinetic measures were identified, and exposure-response relationships were established in kidney and cardiac transplantation.16,17 These trials demonstrated that fixed doses are not optimal in all transplant types and that therapeutic drug monitoring improves outcomes. However, the pharmacokinetics and degree of kinetic variability change with transplant type, therefore making pharmacokinetic assessment and the establishment of the exposure-response relationship necessary in each transplant type.
Islet cell immunosuppressive regimens typically employ steroid-free prophylaxis. In kidney transplantation, MPA exposure using standard doses of MMF is significantly increased during steroid tapering or in the absence of steroids compared to exposure during steroid treatment (P < .05), suggesting that lower doses of MMF may be necessary in the steroid-free regimens.18 However, there are no data in islet cell regimens regarding the effect of a steroid-free regimen on MPA exposure. There is also a potential for MMF-induced aggravation of diabetic gastroparesis, diminished bowel mobility, and altered absorption in this diabetic population. In addition, there are no unbound MPA pharmacokinetic data in the islet cell transplant setting and whether unbound concentrations are highly correlated with total MPA concentrations. A poor correlation would suggest that unbound MPA concentrations might be more closely linked to an immunosuppressive response than total concentrations. Optimal immunosuppression is a critical factor in graft function and survival, and because there is a potential for altered MPA exposure in these patients, we performed an intensive and thorough pharmacokinetic evaluation in subjects enrolled in a pilot single-donor islet cell transplant study.19 The primary objectives were to characterize MPA pharmacokinetics in a steroid-free, calcineurin-sparing regimen; determine interand intrapatient variability over time; and ascertain the relationship between unbound and total MPA exposure.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Immunosuppressive Regimen
Patients received rabbit antithymocyte globulin intravenously (IV) on days –2 to +2, methylprednisolone on day –2, daclizumab IV Q 2 weeks x 5 doses starting on day 0, and entanercept IV pretransplant and repeated on days +3, +7 and +10. Maintenance immunosuppression consisted of sirolimus PO beginning on day –2 with doses adjusted to target trough concentrations of 5 to 15 ng/mL, as well as low-dose tacrolimus PO beginning on day +1 with doses adjusted to whole-blood concentrations of 3 to 6 ng/mL. Median (range) tacrolimus and sirolimus concentrations over the 1-year study period were 4.0 ng/mL (3.0-10.2) and 8.8 ng/mL (2.7-16.8), respectively. Beginning at 1 month posttransplant, mycophenolate mofetil (750-1000 g bid PO) was initiated, and tacrolimus was tapered off or dosed to achieve low trough concentrations (<3 ng/mL) if sirolimus target concentrations were not achievable. The goal was to discontinue or minimize tacrolimus once the MMF was initiated. Mycophenolate mofetil doses were modified according to drug tolerance and side effects.
Study Design
This was a longitudinal study in the first year posttransplantation of steady-state oral pharmacokinetics of total and unbound MPA and MPAG in 8 Caucasian women. A full pharmacokinetic profile (times 0, 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose) was obtained on days 28 and 42. Thereafter, abbreviated pharmacokinetic profiles (times 0, 1, 3, and 6 hours postdose) were obtained in months 2, 3, 6, 9, and 12. Venous blood samples (5 mL) from a temporary peripheral venous catheter were collected in EDTA tubes. Blood was centrifuged at 2000 rpm for 10 minutes, and plasma was removed and stored at –80°C until time of analysis. Serum albumin, serum creatinine (SCr), total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase were measured on each pharmacokinetic sampling day. A list of concomitant medications, as well as tacrolimus and sirolimus concentrations obtained within 48 hours of the time of pharmacokinetic sampling, was recorded.
Data Analysis
Total and unbound MPA and total MPAG plasma steady-state concentration-time data were analyzed with noncompartmental methods using WinNonlin Professional 4.0 (Pharsight Corp, Mountain View, Calif), and the area under the concentration curve (AUC) was calculated with the linear trapezoidal method. Total and unbound MPA and total MPAG AUC0-6 and AUC0-12 were calculated for days 28 and 42. In months 2, 3, 6, 9, and 12, the total and unbound MPA and total MPAG AUC0-6 were determined using the trapezoidal method, and total MPA AUC0-12 were estimated using a limited sampling model.20 The limited sampling model estimated total AUC0-12 using 4 plasma concentrations over 6 hours, where total MPA AUC0-12 = 9.02 + (3.77 · conc. at 0 hour) + (1.33 · conc. at 1 hour) + (1.68 · conc. at 3 hours) + (2.96 · conc. at 6 hours) [conc. is total MPA in mcg/mL].
To determine if there would be substantial bias in using the limited sampling model, we compared the total AUC0-12 on days 28 and 42 obtained from the model to those obtained from the trapezoidal method. The AUCs were well correlated (r2 = 0.84). The residuals were randomly distributed above and below the line of best fit, and therefore there was no trend toward over- or underestimation of the true AUC. We concluded that the limited sampling model would also be unbiased for months 2 to 12.
A limited sampling model was not available for unbound AUC estimation; therefore, the unbound AUC0-12 was derived by multiplying total AUC0-12 by each subject's average percent unbound from all samples obtained on that day. Because of the high concordance between total and unbound MPA (r2 = 0.94), this estimate should be an accurate approximation. The 24-hour MPA exposure was the product of AUC0-12 ·2 if receiving a bid regimen or AUC0-6 · 4 if receiving a daily (qd) regimen. The 24-hour exposure was not calculated for three times a day (tid) dosing. Average steady-state concentration (Css) was the ratio of AUC0-12 and the dosing interval (12 hours) and was calculated for the bid regimens. Trough concentrations were taken as the time 0 measurement. Apparent total body clearance (CL/F) at steady state was the ratio of MPA equivalents of the MMF dose to the corresponding AUC0-12. The percent unbound MPA was determined by calculating the average ratio of unbound and total MPA concentration over the dosing interval x 100. The MPAG/MPA ratio was calculated by dividing the MPAG concentration (mcg/mL) by its corresponding total MPA concentration (mcg/mL). Creatinine clearance (CrCL) was estimated using the Cockcroft and Gault equation.21
Statistical Analysis
Distribution of continuous data was plotted and inspected. Normally distributed data were expressed as a median (range) or mean ± SD. Intra- and interpatient variability in pharmacokinetic measures was expressed as coefficient of variation (CV). Analysis of variance (ANOVA) for repeated measures was determined for pharmacokinetic exposure measures, as appropriate. Associations between pharmacokinetic measures and renal and hepatic function, albumin, tacrolimus and sirolimus trough concentrations, weight, and body surface area were evaluated using univariate regression analysis. Statistical analyses were performed using the SAS system Version 8.2 for Windows (SAS Institute, Cary, NC).
Bioanalysis
Plasma concentrations of total and unbound MPA and total MPAG were measured on each sample with validated assays. The total MPA and MPAG assay and the unbound MPA assay were developed using modifications of previously published assays.22-24 Analysis was conducted on an Agilent 1100 series (Agilent Technologies, Wilmington, Del) high-performance liquid chromatographic system equipped with a variable wavelength UV detector and a Synergi Polar-RP, 4.6 x 250-mm, reversed-phase C-18 column (Phenomenex, Torrance, Calif). Total MPA and MPAG were measured at a wavelength of 300 nm with a switch to 224 nm for the internal standard (naphthylacetic acid). Unbound MPA concentrations were measured after membrane ultrafiltration. Plasma (1 mL) was centrifuged through a Centrifree 30 000 MW microfiltration device (Amicon, Millipore, Milford, Mass) at 37°C for 1 hour at 2000g in a fixed-angle centrifuge (Jouan, Winchester, Va). Then, 500 µL of the filtered sample, 500 µLof sodium acetate (50 mM, pH 7.0), and internal standard (as used in total analyses) were combined and extracted with an Oasis MAX SPE cartridge. For the unbound MPA assay, the wavelength was held constant at 216 nm. The MPA and MPAG standards were obtained from Sigma-Aldrich (St Louis, Mo) and F. Hoffmann–La Roche (Basel, Switzerland), respectively. The total MPA standard curve was prepared over the concentrations of 0.025 to 10 mcg/mL and MPAG over 1 to 100 mcg/mL. The unbound MPA standard curve was prepared over the concentrations of 0.001 to 0.5 mcg/mL. Samples above the range were diluted and reanalyzed. Assay accuracy, intrabatch precision, and total assay precision were 96.3% to 117.5%, 1.0% to 8.1%, and 1.5% to 9.7%, respectively.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacokinetics of Total Mycophenolic Acid
Pharmacokinetic data are reported in Table I. Median AUC0-6 and AUC0-12 tended to be higher early posttransplant (days 28 and 42) than later, although not significantly (P = .41 and .61, respectively). Mean dose was higher in the early period (821-958 mg per dose). Intra- and interpatient variability of pharmacokinetic measures was highest for Cmax and trough concentrations (Figure 1). Interpatient total MPA AUC0-12 CV on days 28, 42, 60, 90, 180, 270, and 360 was 38.5%, 55.5%, 41.0%, 27.2%, 48.9%, 41.7%, and 30.3%, respectively. The correlation between MPA trough and AUC0-6 or AUC0-12 was r2 = 0.48 and 0.65, respectively (Figure 2). The median MPA Css over a 12-hour dosing interval over the 1-year study period was 4.0 mcg/mL (range, 0.96-8.24). Apparent MPA clearance ranged from 10.4 to 14.2 L/h and did not change over time (P = .93). Dose-normalized AUCs were stable over time (P = .12, data not shown).
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Pharmacokinetics of Unbound Mycophenolic Acid
Pharmacokinetic data are reported in Table I. The median unbound MPA AUC0-6 was higher early posttransplant (days 28 and 42) than later, although it did not change significantly over the study period (P = .16). Mean inter- and intrapatient variability in unbound pharmacokinetic measures (AUC0-12, Cmax, and trough) was high, with CVs ranging from 38.4% to 88.0%. Median percent unbound MPA was 0.95% (range, 0.74%-3.04%) and did not change over time (P = .96). In those patients whose dose was reduced for toxicity, the unbound AUC0-12 after dose reduction did not drop uniformly as expected and rarely fell below 400 ng·h/mL.
Individual unbound and total MPA concentrations (n = 255) were highly correlated (r2 = 0.94; Figure 3). Unbound and total MPA AUC0-6 (r2 = 0.84) and AUC0-12 (r2 = 0.81) were also highly correlated (plots not shown). Unbound and total MPA Cmax concentrations were less well correlated (r2 = 0.67).
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Relationships Between Clinical Outcomes, Mycophenolic Acid Exposure, Laboratory Parameters, and Tacrolimus and Sirolimus Levels
All 8 subjects initially achieved insulin independence. Graft function was lost in 3 subjects on days >177, 207, and 330. The mean 24-hour total MPA exposure (a cumulative AUC) was 98.78, 97.66, and 137 mcg·h/mL in the study periods preceding graft loss (n = 3 subjects) and 195, 85.8, 71.5, 93.1, and 85.6 mcg·h/mL in subjects who successfully maintained insulin independence (n = 5 subjects; Figure 4). The mean 24-hour unbound MPA exposure was 1208, 1040, and 1236 ng·h/mL in the study periods preceding graft loss and 1662, 908, 696, 976, and 772 ng·h/mL in subjects who remained insulin independent. The mean tacrolimus trough concentrations prior to graft failure in the patients with loss of graft function were 0 (discontinued per protocol), 3, and 4.43 ng/mL, respectively. In those patients with continuous graft function, the mean tacrolimus trough concentrations over the year posttransplant were 0 (discontinued per protocol), 3.8, 3.7, 4.5, and 5.8 ng/mL, respectively. The mean sirolimus trough concentrations in the patients with loss of graft function were 8, 8.9, and 7.9 ng/mL, respectively, and were not different from those with a continuous graft function of 9.1, 4.1, 5.5, 4.3, and 10.8 ng/mL, respectively.
Six of the 8 patients required 1 or more MMF dose reductions due to presumed MMF intolerance or exacerbation of preexisting toxicity. Most dose reductions occurred after day 42. Adverse effects leading to dose reduction were diarrhea, nausea, vomiting, neutropenia, and mild thrombocytopenia. Neutropenia and thrombocytopenia were not exclusively attributable to the MMF due to the use of sirolimus and thymoglobulin.
Dose-adjusted total and unbound MPA and MPAG AUC0-6 and AUC0-12 were poorly correlated with SCr, CrCl, ALT, AST, and albumin (all r2 < 0.15). Total bilirubin was modestly correlated with MPAG AUC0-12 (r2 = 0.62). There was a poor correlation between MPA AUC0-12 and actual body weight (kg), dose corrected for body weight (mg/kg), or body surface area in m2 (all r2 < 0.22). Total and unbound MPA AUC0-6 and AUC0-12 and trough concentrations were weakly correlated with tacrolimus (r2 < 0.42) or sirolimus (r2 < 0.04) trough concentrations.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Mycophenolic acid pharmacokinetics are well described in kidney and liver transplantation. In these populations, exposure measures are highly variable and differ with concomitant therapy and transplant type.12,26 However, the effect of diabetes and steroid therapy (or lack of) on MPA exposure is not well elucidated. In a previous study, nondiabetic patients had higher total MPA trough concentrations (2.94 mcg/mL) compared to diabetics (1.24 mcg/mL) (P < .001).27 In kidney recipients, MPA exposure is significantly greater (P < .05) in the absence of steroids or during steroid tapering compared to standard steroid doses due to induction of UDP-glucuronosyltransferase by glucocorticoids, suggesting that lower doses of MMF may be necessary in a steroid-free regimen.18 In addition, disease states associated with altered protein binding, kidney impairment, altered oral absorption, or drug interactions may result in greater variability of MPA exposure. Considering the lack of published data in islet cell transplantation, the pharmacokinetic uncertainty, absence of steroids, and the calcineurin-sparing regimen, it was unclear if standard doses of MMF were optimal. Therefore, a thorough examination of the pharmacokinetic behavior of MPA was undertaken.
Our observed total MPA AUC values are consistent with published data in organ transplantation.20,28-31 However, our AUC0-12 was higher (median > 60 mcg·h/mL) on days 28 and 42 than later posttransplant. Other studies report an increase in total MPA exposure over time.11,32 All but 1 patient were initiated on 1000 mg bid on day 24, and then due to presumed MMF-related or exacerbation of preexisting toxicity, 6 of the 8 subjects required dose reductions, mostly after day 42, and AUCs fell concordantly although not uniformly in proportion to the dose change. The decline in AUC is most likely due to MMF dose reductions because clearance was stable over time (P = .93). We did not perform formal toxicity grading and therefore are unable to directly assess whether higher MPA exposure in the early period contributed directly to toxicity. Toxicity assessment is complicated by the use of sirolimus and thymoglobulin because both have overlapping toxicities with MMF. Kidney recipients who receive MMF, prednisolone, and sirolimus prophylaxis have significantly higher rates of thrombocytopenia, leukopenia, and diarrhea compared to those receiving MMF, prednisolone, and cyclosporine.33 Hence, it is possible that lower doses of MMF and lower AUC targets will be necessary in MMF regimens using sirolimus to reduce hematologic toxicity.
Mean intrapatient and interpatient variability of pharmacokinetic measures was high (37.3%-66.6%). Cmax and trough concentrations had the greatest variability. To explore potential reasons for variability, we evaluated the associations between pharmacokinetic measures and renal status, hepatic function, albumin, body surface area, and weight. All associations were weak (r2 < 0.15). Because MPA apparent clearance estimates were stable over time, this suggests that variability in exposure was not due to changes in drug metabolism but possibly reductions or alterations in dose, enterohepatic recycling, or poor compliance. The predose trough concentrations were modestly correlated with total MPA AUC0-6 (r2 = 0.48) and AUC0-12 (r2 = 0.65) and are consistent with other studies.20,34 Hence, trough concentrations are a poor marker of total drug exposure over a dosing interval and possibly clinical pharmacodynamic effect. Exposure-response studies in islet cell transplant will be necessary to define which pharmacokinetic measure (trough or AUC) is associated with graft survival and toxicity.
Mycophenolic acid is >95% protein bound to albumin, and only the unbound fraction is associated with in vitro inosine-5'-monophosphate dehydrogenase (IMPDH) inhibition.13 Medical conditions resulting in a decline in protein binding may increase the amount of unbound MPA while resulting in minor changes in total MPA exposure.35-37 Should reduced or variable protein binding be present, MPA immunosuppressive activity would be difficult to predict from total concentrations alone. In our study, the unbound fraction of MPA was similar to other reports (0.95%; range, 0.74%-3.04%) and was stable over time. We also found an excellent correlation between total and unbound MPA plasma concentrations (r2 = 0.94), and therefore it is unlikely that routine measurement of unbound concentrations would be necessary in the typical uncomplicated, toxicity-free patient. However, unbound MPA may be important in certain individuals because elevated unbound exposure (unbound AUC0-12 > 400-600 ng·h/mL) has been proposed to be associated with greater toxicity.14,38,39 Interestingly, the median unbound MPA AUC0-12 on days 28 and 42 were 666 and 555 ng·h/mL, respectively, and 6 of the 8 patients went on to require dose reduction for toxicity.
Low MPA exposure is related to increased rejection rates in kidney transplantation.16,40 In our population, the MPA exposure immediately prior to rejection did not appear to be different from those who maintained graft function (Figure 4). However, because rejection in islet cell transplantation is multifactorial and the number of patients is small, larger studies will be necessary to establish the optimal MPA exposure target.
In conclusion, these data demonstrate high variability in MPA exposure and high total and unbound MPA AUC0-12 (>60 mcg·h/mL and >550 ng·h/mL, respectively) prior to day 60 posttransplant. Our initial dose of 1 g bid may be associated with gastrointestinal and hematologic toxicity, and dose reductions were common. Therapeutic MPA targets in islet cell transplantation need to be established.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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  P. J. Martin, B. E. Storer, S. D. Rowley, M. E. D. Flowers, S. J. Lee, P. A. Carpenter, J. R. Wingard, P. J. Shaughnessy, M. P. DeVetten, M. Jagasia, et al. Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease Blood, May 21, 2009; 113(21): 5074 - 5082. [Abstract] [Full Text] [PDF]
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 P. Jacobson, J. Huang, N. Rydholm, M. Tran, T. DeFor, J. Tolar, and P. J. Orchard Higher Mycophenolate Dose Requirements in Children Undergoing Hematopoietic Cell Transplant (HCT) J. Clin. Pharmacol., April 1, 2008; 48(4): 485 - 494. [Abstract] [Full Text] [PDF]
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P. Jacobson, K. Green, J. Rogosheske, C. Brunstein, B. Ebeling, T. DeFor, P. McGlave, and D. Weisdorf Highly Variable Mycophenolate Mofetil Bioavailability Following Nonmyeloablative Hematopoietic Cell Transplantation J. Clin. Pharmacol., January 1, 2007; 47(1): 6 - 12. [Abstract] [Full Text] [PDF]
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 O. Bernard, J. Tojcic, K. Journault, L. Perusse, and C. Guillemette Influence of Nonsynonymous Polymorphisms of UGT1A8 and UGT2B7 Metabolizing Enzymes on the Formation of Phenolic and Acyl Glucuronides of Mycophenolic Acid Drug Metab. Dispos., September 1, 2006; 34(9): 1539 - 1545. [Abstract] [Full Text] [PDF]
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