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Dirk R J Kuypers

Publications and source records attributed to Dirk R J Kuypers.

At least 19 recordsLinked to original sources
PubMed2006

Multidrug resistance protein 2 genetic polymorphisms influence mycophenolic acid exposure in renal allograft recipients.

BACKGROUND: Mycophenolic acid (MPA) is glucuronidated by uridine diphosphate-glucuronosyltransferases (UGTs) to its pharmacologically inactive 7-O-glucuronide metabolite (MPAG). MPAG is excreted into the bile via the multidrug resistance-associated protein 2 (MRP2/ABCC2), which is essential for enterohepatic (re)circulation (EHC) of MPA(G). METHODS: The objective of this study was to determine the relationship between single nucleotide polymorphisms (SNPs) in the MRP2 (G-1549A, G-1023A, A-1019G, C-24, G1249A, C3972T and G4544A) and UGT1A9 (C-2152T, T-275AandT98C) genes and MPA pharmacokinetics in 95 renal allograft recipients at days 7, 42, 90, and 360 after transplantation. In addition to mycophenolate mofetil, all patients received tacrolimus and corticosteroids as immunosuppression. RESULTS: At day seven after transplantation, in the absence of the MRP2 C-24T SNP, mild liver dysfunction was associated with significantly lower MPA dose-interval exposure and higher MPA oral clearance, while liver dysfunction did not affect MPA pharmacokinetics in patients with the MRP2 C-24T variant. A similar effect is noted for the C-3972T variant, which is in linkage disequilibrium with C-24T. At later time points after transplantation the MRP2 C-24T SNP was associated with significantly higher dose-corrected MPA trough levels. Patients with the MRP2 C-24T variant had significantly more diarrhea in the first year after transplantation. CONCLUSIONS: The MRP2 C-24T and C-3972T polymorphisms protect renal transplant recipients from a decrease in MPA exposure associated with mild liver dysfunction. Furthermore, this study suggests that the C-24T SNP is associated with a lower oral clearance of MPA in steady-state conditions.

Adrenal Cortex Hormones↗
PubMed2006

Rifampin induces alterations in mycophenolic acid glucuronidation and elimination: implications for drug exposure in renal allograft recipients.

BACKGROUND: Exposure to mycophenolic acid (MPA) and its main metabolites (MPA 7-O-glucuronide [MPAG] and MPA acyl-glucuronide [AcMPAG]) is characterized by a large interindividual and intraindividual variability, resulting in part from variability in glucuronidation (via uridine diphosphate-glucuronosyltransferase isoforms) and excretion via multidrug resistance-associated protein 2 (MRP2). It can be hypothesized that drugs interfering with glucuronidation and excretion will alter (Ac)MPA(G) exposure. METHODS: This prospective, open-label, nonrandomized, controlled pharmacokinetic interaction study included 8 stable renal allograft recipients, all treated with mycophenolate mofetil. Rifampin (INN, rifampicin), administered once daily (600 mg/d) for 8 days, was used as the probe drug because of its known effects on both uridine diphosphate-glucuronosyltransferase activity and MRP2 transport capacity. A 12-hour pharmacokinetic time-concentration profile was assessed before rifampin administration was started, and this was repeated on the last day of rifampin administration. Total and free MPA, MPAG, and AcMPAG concentrations in plasma and urine were measured by use of HPLC with tandem mass spectrometry detection. RESULTS: Total MPA area under the plasma concentration-time curve (AUC) from 0 to 12 hours decreased significantly after rifampin coadministration (17.5% decrease [95% confidence interval (CI), 5.18%-29.9%]; P=.0234). This was mainly a result of a decrease in total MPA AUC from 6 to 12 hours (32.9% decrease [95% CI, 15.4%-50.4%]; P=.0078), representing decreased enterohepatic recirculation. Free MPA AUC from 6 to 12 hours decreased significantly, by 22.4% (95% CI, 4.71%-49.5%; P=.0391). Total MPAG and AcMPAG AUC from 0 to 12 hours increased by 34.4% (95% CI, 13.5%-55.4%; P=.0156) and 193% (95% CI, 30.3%-355%; P=.0078) respectively. Urinary recovery of MPAG and AcMPAG increased significantly (P=.0078), but renal clearance of these glucuronides did not change after rifampin coadministration. CONCLUSION: This study demonstrates an interaction between mycophenolate mofetil and rifampin, which is a result of induction of MPA glucuronidation and possibly also rifampin-associated alterations in MRP2-mediated transport of MPAG and AcMPAG. This interaction should be taken into account when rifampin or other drugs influencing pregnane X receptor activity are coadministered with mycophenolate mofetil.

Adult↗
PubMed2005

A simplified strategy for clinical management of late cytomegalovirus infection after oral ganciclovir prophylaxis in renal recipients.

OBJECTIVES: Late cytomegalovirus disease after completion of prophylactic therapy occurs in 5-21% of renal allograft recipients within the first year post-transplantation. Identifying patients at risk for late infection is clinically difficult; prolonged cytomegalovirus (CMV) monitoring is costly and cumbersome as follow-up intervals lengthen. PATIENTS AND METHODS: We performed a prospective 1 year study in 54 de novo renal recipients to assess the minimum CMV monitoring frequency for identifying patients at risk. RESULTS AND CONCLUSIONS: CMV DNA PCR monitoring on the last day, and again 2 weeks after conclusion of oral ganciclovir prophylaxis, seemed sufficient for identifying recipients at risk for developing clinically relevant late CMV disease and for whom closer clinical follow-up is warranted.

Administration, Oral↗
PubMed2005

A prospective, randomized, double-blind crossover study on the use of 5% citrate lock versus 10% citrate lock in permanent hemodialysis catheters.

Central venous catheters are used as permanent vascular access for chronic hemodialysis when construction of an arteriovenous fistula is not possible or contraindicated. We prospectively evaluated the efficacy and safety of a 5% citrate versus 10% citrate catheter lock for permanent single-lumen dialysis catheters in a double-blind, crossover study of 28 patients during 1,876 dialysis sessions. There was a slightly higher number of dialysis sessions with clot formation in the 5% citrate group; entirely attributable to the formation of small clots. There was no statistically significant difference in the formation of large clots, complete obstruction of the catheter or the need for urokinase between the 2 study groups. In view of the ongoing debate on the safety of high-concentration citrate catheter locks, we conclude that a 5% citrate lock is equally efficient in preventing catheter dysfunction compared with a 10% citrate lock and is therefore the preferred citrate catheter-locking solution.

Aged↗
PubMed2005

Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase.

The tuberculostatic compound rifampin (INN, rifampicin) induces the expression of a number of drug metabolism-related genes involved in multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), cytochromes (cytochrome P450 [CYP] 3A4), uridine diphosphate-glucuronosyltransferases, monoamine oxidases, and glutathione S -transferases. Drugs that depend on these enzymes for their metabolism are prone to drug interactions when coadministered with rifampin. A novel, clinically relevant drug interaction is described between rifampin and mycophenolate mofetil (MMF), a cornerstone immunosuppressive molecule used in solid organ transplantation. Long-term rifampin therapy caused a more than twofold reduction in dose-corrected mycophenolic acid (MPA) exposure (dose-interval area under the concentration curve from 0 to 12 hours [AUC 0-12]) when administered simultaneously in a heart-lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout (dose-corrected AUC 0-12 after rifampin withdrawal, 19.7 mg.h.L-1.g -1 versus 6.13 mg.h.L-1.g-1 before rifampin withdrawal [221% change]; dose-uncorrected AUC 0-12 after rifampin withdrawal, 29.6 mg.h/L [daily MMF dose, 3 g] versus 18.4 mg.h/L [daily MMF dose, 6 g] during rifampin administration [60.8% change]). Failure to recognize this drug interaction could potentially lead to MPA underexposure and loss of clinical efficacy. The effect of rifampin on MPA metabolism can, at least in part, be explained by simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA.

Area Under Curve↗
PubMed2005

The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients.

BACKGROUND: Mycophenolic acid (MPA), an effective immunosuppressive drug used in renal transplantation, is extensively glucuronidated by several uridine diphosphate-glucuronosyltransferases (UGTs) into an inactive 7-O-glucuronide and, to a lesser extent, into a pharmacologically active acyl-glucuronide. Experiments using human liver microsomes have shown that T--275A and C--2152T single-nucleotide polymorphisms (SNPs) of the UGT1A9 promoter region are associated with higher hepatic expression of UGT1A9 and increased in vitro glucuronidation activity for MPA. METHODS: The distribution of UGT1A9 promoter region T-275A and C-2152T SNPs and the less frequent UGT1A9*3 coding region mutation, which results in decreased in vitro activity, was determined in 95 de novo renal recipients. The impact of these UGT1A9 SNPs on early clinical MPA pharmacokinetics was evaluated. RESULTS: Only in patients taking 2 g mycophenolate mofetil daily was a decreased MPA exposure observed in those who carried either the T-275 A or the C-2152 T polymorphism (or both) compared with those who did not (area under concentration-time curve [AUC] from 0 to 12 hours, 31.7+/--17.6 mg.h/L versus 63.6+/--30.9 mg.h/L [P=.009]; predose trough plasma concentration, 1.23 +/--.25 mg/L versus 2.84+/--1.64 mg/L [P=.04]). The partial MPA AUC from 6 to 12 hours (AUC6--12)-an estimate of MPA enterohepatic recirculation-and the ratio between partial MPA AUC6--12 and dose-interval AUC from 0 to 12 hours decreased when either or both UGT1A9 promoter region SNPs were present (AUC6--12, 6.2+/-5.4 mg.h/L versus 21.5+/-14.9 mg.h/L [P=.002]; ratio, 18.4%+/- 7.8% versus 31.7%+/- 8.8% [P=.002]). CONCLUSION: The T-275A and C-2152T SNPs of the UGT1A9 gene promoter are associated with significantly lower MPA exposure in renal recipients treated with 2 g mycophenolate mofetil daily, and part of this effect is caused by interruption of enterohepatic recirculation of MPA.

Area Under Curve↗
PubMed2005

Secondary renal amyloidosis due to long-standing tubulointerstitial nephritis in a patient with Sjögren syndrome.

A 53-year-old patient with long-standing primary Sjögren syndrome presented with acute renal failure and nephrotic syndrome caused by secondary (AA) renal amyloidosis. Ten years before, he had been admitted because of exacerbation of the systemic disease. At that time, a pseudolymphoma of the kidney was diagnosed. To our knowledge, this is the first report of a patient with primary Sjögren syndrome and secondary (AA) amyloidosis with amyloid deposition in the kidneys causing nephrotic syndrome.

Acute Kidney Injury↗
PubMed2005

Secondary effects of immunosuppressive drugs after simultaneous pancreas-kidney transplantation.

BACKGROUND: This report examines the early and late secondary effects of tacrolimus, cyclosporin microemulsion (ME), mycophenolate mofetil (MMF) and rabbit anti-thymocyte globulin (rATG) in simultaneous pancreas-kidney (SPK) recipients. METHODS: Of the 205 patients participating in the Euro-SPK 001 study, 103 were randomized to tacrolimus (0.2 mg/kg) and 102 to cyclosporin-ME (7 mg/kg). All patients received rATG for 4 days [ATG-Fresenius (ATG-F) 4 mg/kg/day or Thymoglobulin (Thymo-S) 1.25 mg/kg/day] plus MMF and short-term corticosteroids. RESULTS: Thymo-S induction therapy was associated with a lower white cell count in the first 3 months than was seen with ATG-F, while ATG-F caused a lower initial nadir in platelet count. Both polyclonal preparations were well tolerated and no clinically relevant differences were observed with respect to side effects such as infections and malignancies. High cyclosporin-ME trough levels were associated with pancreas graft thrombosis, and concentrations >150 ng/ml were associated with poor renal allograft function. Treatment discontinuation was higher with cyclosporin-ME (57.8%) than with tacrolimus-based therapy (36.9%) due to more frequent toxicity, graft loss and lack of efficacy requiring a switch to tacrolimus. The main reason for withdrawal in the tacrolimus group was MMF discontinuation; MMF-related side effects resulted in more frequent dose reductions to <2 g/day and discontinuations in the tacrolimus group, and indirectly indicate a higher dose-corrected exposure to mycophenolic acid, as previously observed in kidney transplant patients. CONCLUSIONS: Short-term induction therapy is effective and well tolerated in patients undergoing SPK transplantation. Tacrolimus was the preferred immunosuppressive agent, resulting in fewer cases of pancreas graft loss and drug discontinuation compared with cyclosporin-ME.

Antilymphocyte Serum↗
PubMed2005

Immunosuppressive drug monitoring - what to use in clinical practice today to improve renal graft outcome.

Therapeutic drug monitoring (TDM) of immunosuppressive therapy is becoming an increasingly complex matter as the number of compounds and their respective combinations are continuously expanding. Unfortunately, in clinical practice, monitoring predose trough blood concentrations is often not sufficient for guiding optimal long-term dosing of these drugs. The excellent short-term results obtained nowadays in renal transplantation confer a misleading feeling of safety despite the fact that long-term results have not substantially improved, definitely not to a point where longer graft survival could counteract the increasing need for transplant organs and less toxicity and side-effects could ameliorate patient survival. It is therefore a challenging task to try to tailor immunosuppressive drug therapy to the individual patient profile and this in a time-dependent manner. For the majority of currently used immunosuppressive drugs, measurement of total drug exposure by determination of the dose-interval area under the concentration curve (AUC) seems to provide more useful information for clinicians in terms of concentration-exposure and exposure-response as well as reproducibility. To simplify this laborious way of measuring drug exposure, several validated abbreviated AUC profiles, accurately predicting the dose-interval AUC, have been put forward. Together with an increasing knowledge of the time-related pharmacokinetic behaviour of immunosuppressive drug and their metabolites, studies are focusing on how to apply abbreviated AUC sampling methods in clinical transplantation, taking into account the numerous factors affecting drug pharmacokinetics. Eventually, TDM using abbreviated AUC profiles has to be prospectively tested against classic methods of drug monitoring in terms of cost-effectiveness, feasibility and clinical relevance with the ultimate goal of improving patient and graft survival.

Calcineurin Inhibitors↗
PubMed2005

Polyomavirus interstitial nephritis and concurrent post-transplant lymphoma in a renal allograft: coincidence or more?

We describe a case of an Epstein-Barr virus (EBV)-negative post-transplant large B-cell non-Hodgkin lymphoma located in the renal allograft, spleen, liver and left inguinal lymph node of a renal recipient and accompanied by a simultaneous polyomavirus-associated nephropathy. To our knowledge, this is the first report of a simultaneous polyomavirus infection and post-transplant lymphoproliferative disorder.

Adult↗
PubMed2005

Adjuvant low-dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients.

BK virus interstitial nephritis (BKVIN) is a serious complication after kidney grafting, necessitating drastic reduction of immunosuppressive therapy in order to enable viral clearance. Despite these measures, progressive graft dysfunction and graft loss occur in the majority of recipients. We diagnosed BKVIN in 21 recipients grafted between 1998 and 2004. Eight of 21 patients were treated with weekly, adjuvant low-dose cidofovir in addition to reduction of immunosuppressive therapy. BKVIN caused irreversible deterioration of graft function in all patients but renal function stabilized after antiviral treatment (creatinine clearance: 51.8-32 mL/min; p=0.001) and no graft loss occurred in cidofovir-treated recipients during 24.8 (8-41) months follow-up. Peak serum cidofovir concentrations were dose-dependent and attained approximately one-tenth of thein vitroEC50 for cidofovir against BK-virus, while pre-treatment with probenecid did not alter peak serum concentrations nor affected the incidence of nephrotoxicity. In fact, no cidofovir-related renal toxicity occurred; few patients had minor transient side effects (nausea, skin rash). In contrast, 9 of 13 patient who received no adjuvant cidofovir therapy lost their graft after median 8 (4-40) months. In this selected group of recipients with BKVIN, the use of adjuvant low-dose cidofovir therapy resulted in prolonged graft survival and stabilized graft function.

Adult↗
PubMed2005

Benefit-risk assessment of sirolimus in renal transplantation.

Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.

Animals↗
PubMed2004

The rate of gastric emptying determines the timing but not the extent of oral tacrolimus absorption: simultaneous measurement of drug exposure and gastric emptying by carbon-14-octanoic acid breath test in stable renal allograft recipients.

Tacrolimus is characterized by a highly variable oral bioavailability and narrow therapeutic window. Tacrolimus absorption from the gastrointestinal tract is to a large extent determined by the genotypic, phenotypic, and functional expression of P-glycoprotein and CYP3A in the gut wall and liver. It is disputed whether the gastric emptying rate per se is important for determining oral bioavailability of tacrolimus and whether delayed gastric emptying is clinically relevant for therapeutic drug dosing. We conducted a pharmacokinetic study in 50 renal recipients, measuring simultaneously the rate of gastric emptying using a carbon-14-octanoic acid breath test and quantifying drug exposure by area under the concentration-time curve sampling. Gastric half emptying time (t1/2) significantly correlated with time to reach maximum blood tacrolimus (tmax) concentration (r2 = 0.30; p < 0.0001), whereas the gastric emptying coefficient, reflecting the overall gastric emptying rate, showed a weak inverse correlation with tmax (r2 = 0.14; p = 0.007). The time-dependent rate of gastric emptying strongly correlated with the simultaneously measured blood tacrolimus concentration over the first 4 h after oral drug administration (r2 = 0.96; p < 0.0001). Comparison between patients with and without delayed gastric emptying confirmed that maximum blood tacrolimus concentration was reached significantly more slowly in the former group (tmax, 2 +/- 1 h versus 1.48 +/- 0.68 h; p = 0.04), whereas the extent of tacrolimus absorption was not different. Despite a strong association between gastric emptying rate and the timing of tacrolimus absorption from the gut in stable recipients, gastric emptying rate does not affect the total extent of drug absorption and is not responsible for significant alterations in drug exposure, even in situations of delayed gastric emptying.

Administration, Oral↗
PubMed2004

Time to reach tacrolimus maximum blood concentration,mean residence time, and acute renal allograft rejection: an open-label, prospective, pharmacokinetic study in adult recipients.

OBJECTIVES: The aims of this study were to determine whether disposition-related pharmacokinetic parameters such as T(max) and mean residence time (MRT) could be used as predictors of clinical efficacy of tacrolimus in renal transplant recipients, and to what extent these parameters would be influenced by clinical variables. METHODS: We previously demonstrated, in a prospective pharmacokinetic study in de novo renal allograft recipients, that patients who experienced early acute rejection did not differ from patients free from rejection in terms of tacrolimus pharmacokinetic exposure parameters (dose interval AUC, preadministration trough blood concentration, C(max), dose). However, recipients with acute rejection reached mean (SD) tacrolimus T(max) significantly faster than those who were free from rejection (0.96 [0.56] hour vs 1.77 [1.06] hours; P < 0.001). Taking into account that neither differences in tacrolimus steady-state clearance nor T(1/2) could explain this unusual finding, we used data from the previous study to calculate MRT from the concentration-time curves. RESULTS: As part of the previous study, 100 patients (59 male, 41 female; mean [SD] age, 51.4 [13.8] years;age range, 20-75 years) were enrolled in the study The calculated MRT was significantly shorter in recipients with acute allograft rejection (11.32 [031] hours vs 11.52 [028] hours; P = 0.02), just like T(max) was an independent risk factor for acute rejection in a multivariate logistic regression model (odds ratio, 0.092 [95% CI, 0.014-0.629]; P = 0.01). Analyzing the impact of demographic, transplantation-related, and biochemical variables on MRT, we found that increasing serum albumin and hematocrit concentrations were associated with a prolonged MRT (P < 0.05). Conversely, serum albumin and hematocrit concentrations were significantly lower in recipients with acute rejection (P < (101). CONCLUSIONS: In this selected population of de novo renal allograft recipients, a shorter tacrolimus T(max) and calculated MRT were associated with a higher incidence of early acute graft rejection. These findings suggest that a shorter transit time of tacrolimus in certain tissue compartments, rather than failure to obtain a maximum absolute tacrolimus blood concentration, might lead to inadequate immunosuppression early after transplantation.

Acute Disease↗
PubMed2004

Clinical efficacy and toxicity profile of tacrolimus and mycophenolic acid in relation to combined long-term pharmacokinetics in de novo renal allograft recipients.

INTRODUCTION: Tacrolimus and mycophenolate mofetil are effective drugs characterized by specific toxicity profiles that may compromise their long-term use in renal transplant recipients. Clinicians, therefore, need reliable drug monitoring tools for relating efficacy and toxicity to drug exposure. Study design We conducted a prospective 12-month pharmacokinetic study of tacrolimus and mycophenolic acid in 100 de novo recipients. The aim was to examine whether tacrolimus and mycophenolic acid exposure parameters (predose trough blood concentration [C(0)], area under the concentration curve from 0 to 12 hours [AUC(0-12)], maximum blood or plasma concentration [C(max)], and dose) would reflect clinical efficacy and toxicity at different time points after transplantation (7 days, 6 weeks, and 3, 6, and 12 months). RESULTS: Initially, after grafting, the tacrolimus AUC(0-12) was higher in recipients with infection (P =.01 on day 7, P =.02 at week 6), whereas the mycophenolic acid AUC(0-12) was not different. There was no difference in tacrolimus exposure between patients who had arterial hypertension or hyperlipidemia and those who did not. Patients with tacrolimus nephrotoxicity received a higher drug dose (P =.03) and had higher drug clearance (P =.02). From 3 months, recipients with anemia or leukopenia had higher mycophenolic acid AUC(0-12) (anemia, P =.03 at month 3 and P =.01 at month 12; leukopenia, P =.01 at month 3 and P =.04 at 1 year) and C(0) (anemia, P =.001 at month 3 and P =.001 at month 12; leukopenia, P =.01 at month 3 and P =.04 at 1 year). Finally, for recipients who did not simultaneously have a target tacrolimus AUC(0-12) of 150 ng x h/mL and a mycophenolic acid AUC(0-12) of 45 mg x h/L by day 7, the incidence of acute rejection tended to be higher (26.3%) compared with patients who reached both target values (7.7%) (P =.07). CONCLUSIONS: Pharmacokinetic exposure parameters of tacrolimus and mycophenolic acid are related to specific drug-induced side effects in a time-dependent fashion. In addition, this study has provided a conceptual basis for defining a combined target therapeutic window for tacrolimus and mycophenolic acid based on sparse AUC(0-12) measurements.

Area Under Curve↗