Development of an Abbreviated Mycophenolic Acid Area Under the Time-Concentration Curve for Renal Transplant Patients Under Enteric-Coated Mycophenolate Sodium: A Comparison With Critical Analysis of Available Equations.

BACKGROUND: Enteric-coated mycophenolate sodium is frequently used in renal transplantation. The pharmacokinetic profile of mycophenolic acid (MPA) shows a broad range of time-to-maximum concentration (Tmax) that limits the use of a single MPA concentration to calculate the area under the time-concentration curve (AUC). For both research and clinical MPA monitoring, measuring a complete AUC is troublesome to the center and patients. METHODS: We obtained 171 complete MPA-AUC12h (0, 20, 40, 60, 90, 120, 180, 240, 360, 480, 600, and 720 minutes) from 59 adult (54 ± 16 years) patients (29 men and 43 whites) who have been receiving stable doses of tacrolimus/enteric-coated mycophenolate sodium and steroids. We used the 59 curves drawn at 31 ± 4 days after transplantation to develop the abbreviated equations, and the remaining 112 curves drawn at 109 ± 59 days were used to validate them. We used 5 other proposed equations to estimate MPA-AUC (eAUC) (4 with enzyme-multiplied immunoassay technique assay and one with high-performance liquid chromatography [HPLC]) and then used these results to compare with our measured AUC, the bias, and the 10% and 30% accuracy. MPA was measured by ultraperformance liquid chromatography coupled to a tandem mass spectrometry, and AUC was calculated by the trapezoidal rule. RESULTS: For both MPA-measuring methods, enzyme-multiplied immunoassay technique and ultraperformance liquid chromatography coupled to a tandem mass spectrometry, the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) equations, and others that measure MPA up to 6 hours after the dose had an acceptable low bias with more results in the 10%-30% range than those using data collected until 4 hours. A highly adequate eAUC is obtained using blood collected at 8 hours. CONCLUSIONS: This analysis offers blood-sampling alternatives for MPA monitoring depending on the precision needed.

Evaluation of MDRD4, CKD-EPI, BIS-1, and modified Cockcroft-Gault equations to estimate glomerular filtration rate in the elderly renal-transplanted recipients.

Equations to estimate glomerular filtration rate (eGFR) were developed in patients using the variables age, body weight, and serum creatinine, which may be different in the elderly. Elderly renal transplant patients (EG; n=70; mean age 65 ± 4 y) who measured plasma 51 Cr-EDTA-Clearance (mGFR) had mGFR compared to eGFR obtained by the Cockcroft-Gault corrected by body surface area (CG-BSA), the modification of diet in renal disease (MDRD-4), the Berlin Initiative Study (BIS-1), and the chronic kidney disease epidemiology collaboration (CKD-EPI). Results were validated using a cohort of 43, of the 70 elderly recipients, who performed a second 51 Cr-EDTA-Clearance. Mean mGFR was 47 ± 16 mL/min/1.73 m2 and statistically lower than eGFR by MDRD (52 ± 19, P=.001) and BIS-1 (51 ± 13, P=.007) but not different from the CG-BSA (47 ± 15) and CKD-EPI (49 ± 18). The CKD-EPI and CG-BSA presented the lowest bias but only CKD-EPI also showed the highest 30% and 10% accuracy. The same findings were repeated in the validation set. For a cohort of elderly recipients ≥65 years (n=35, 68 ± 3y), the CKD-EPI performed better with the lowest bias (0 ± 12 mL/min/1.73 m2 ) and best 30% and 10% accuracy. The CKD-EPI equation is a valuable tool to monitor GFR in the elderly RTx recipients.

Longitudinal Pharmacokinetics of Mycophenolic Acid in Elderly Renal Transplant Recipients Compared to a Younger Control Group: Data from the nEverOld Trial.

BACKGROUND AND OBJECTIVES: Elderly patients are increasingly likely to be recipients of transplants. However, the pharmacokinetics of mycophenolic acid (MPA) in this population are yet to be studied in detail. The objective of this study was to assess whether there were differences in MPA pharmacokinetic parameter values between elderly recipients and younger-adult recipients during the 6 months immediately following renal transplantation. METHODS: In this analysis, the longitudinal 12-h pharmacokinetics of MPA, administered as enteric-coated mycophenolate sodium (EC-MPS), were evaluated in 44 elderly renal transplant recipients and compared with the corresponding pharmacokinetics of MPA in 31 younger adult recipients. Measurements were performed at 7, 30, 60, 90, and 180 days post-transplantation. All patients received tacrolimus and prednisone. RESULTS: The elderly patients were 30 years older than the younger controls, with a predominance of males and Caucasians. Elderly patients had lower serum albumin than the younger controls during the first 6 months after transplantation. The mean estimated total body MPA clearance of the elderly recipients was not significantly different from that of the controls at any analyzed time point (the mean clearance across all time points was 0.31 ± 0.17 vs 0.30 ± 0.25 L/h/kg). MPA exposure, as evaluated from the area under the 12-h time versus measured MPA concentration (adjusted for dose/body weight) curve, did not differ between the groups at any time point (mean exposure across all time points was 4.68 ± 3.61 vs 5.95 ± 4.29 µg·h/mL per mg/kg for the elderly recipients and the controls). CONCLUSIONS: These data show that the pharmacokinetics of MPA in elderly renal transplant recipients were no different to those of younger-adult recipients in this study population. CLINICALTRIALS.GOV: NCT 01631058.

Longitudinal Pharmacokinetics of Tacrolimus in Elderly Compared With Younger Recipients in the First 6 Months After Renal Transplantation.

BACKGROUND: Elderly (Eld) (≥60 years) recipients are receiving renal transplants more frequently. The pharmacokinetics (PK) studies of immunosuppressive drugs in healthy volunteers, rarely, include old patients. METHODS: We studied 208 12-hour tacrolimus (TAC) PK (0, 20, 40, 60, 90, 120, 180, 240, 360, 480, 600, 720 min) in 44 Eld (65 ± 3 years) and compared the results with 31 younger controls (Ctrl) (35 ± 6 years) recipients, taking oral TAC/mycophenolate sodium (MPS)/prednisone, at 4 different timepoints: PK1 (8 ± 2 days; n = 72), PK2 (31 ± 4 days; n = 61), PK3 (63 ± 6 days; n = 44), and PK4 (185 ± 10 days; n = 31). Tacrolimus PK was measured by ultraperformance liquid chromatography coupled to a mass spectrometer repetition and noncompartmental PKs were analyzed using Phoenix WinNonlin. RESULTS: Mean TAC dose was lower in the Eld group than in Ctrl ones throughout timepoints either by total daily dose or adjusted (Adj) per body weight. Mean TAC trough level (Cmin), used to adjust daily dose, was not different between the 2 groups in all timepoints. AdjCmax and AdjTAC-area under the curve at dosing interval were both higher in the Eld compared to the Ctrl group in PKs1, 3, and 4. Estimated total body clearance normalized by dose and weight was lower in the Eld group compared with the Ctrl in all PKs and statistically lower at PKs 1 and 3. Similar to younger recipients TAC trough level has also a high correlation (R = 0.76) with area under the curve at dosing interval. CONCLUSIONS: These data indicate that Eld recipients have a lower TAC clearance and therefore need a lower TAC dose than younger recipients.

Longitudinal Pharmacokinetics of Everolimus When Combined With Low-level of Tacrolimus in Elderly Renal Transplant Recipients.

BACKGROUND: Although the proportion of elderly patients among renal transplant recipients has increased, pharmacokinetic (PK) studies of immunosuppressants rarely include older patients. METHODS: We studied 12-hour everolimus (EVL) PK in 16 elderly renal transplant recipients (all whites; 10 men; mean age, 64 ± 2 years (61-71 years), in 4 separate timepoints (at 7, 30, 60, and 150 days) after EVL introduction, corresponding to a mean postrenal transplantation day: PK1 (43 ± 4 days), PK2 (65 ± 7 days), PK3 (106 ± 17 days), and PK4 (206 ± 40 days). Patients received EVL (target trough level (Ctrough, 3-8 ng/mL), prednisone, and tacrolimus (TCL) (target Ctrough, 2-5 ng/mL). RESULTS: Mean TCL-Ctrough was 7.2 ± 3.8, 4.9 ± 2.2, 4.9 ± 2.2, and 4.5 ± 1.2 ng/mL at PK1, PK2, PK3, and PK4, respectively. There were no differences among timepoints for mean EVL daily dose (data shown as PK3) (3.5 ± 1.3 mg/d), Ctrough (4.7 ± 2.5 ng/mL), AUC0-12h (106 ± 51 ng/h per mL), Caverage (8.8 ± 4.2 ng/mL), Cmax (19.2 ± 9.7 ng/mL), apparent Half-life (11.7 ± 4.2 hours), estimated total body clearance (0.39 ± 0.27 L/h), or fluctuation (166 ± 65%). Also, none of those PK parameters differed statistically when adjusted for body weight. EVL-Ctrough showed a very high correlation (r = 0.849) with AUC0-12h. CONCLUSIONS: Our data indicate that elderly renal transplant recipients starting EVL 1 month after transplantation along with a steady-state TCL level, present stable EVL-PK parameters without significant changes in dose or exposure during the first 6 months after renal transplantation.