Relationship between In Vivo CYP3A4 Activity, CYP3A5 Genotype, and Systemic Tacrolimus Metabolite/Parent Drug Ratio in Renal Transplant Recipients and Healthy Volunteers.

CYP3A5 genotype is a major determinant of tacrolimus clearance, and has been shown to affect systemic tacrolimus metabolite/parent ratios in healthy volunteers, which may have implications for efficacy and toxicity. In a cohort of 50 renal transplant recipients who underwent quantification of CYP3A4 activity using the oral midazolam drug probe, we confirmed that CYP3A5 genotype is the single most important determinant of tacrolimus metabolite/parent ratio [CYP3A5 expressors displayed 2.7- and 2-fold higher relative exposure to 13-desmethyltacrolimus (DMT) and 31-DMT, respectively; < 0.

Comparative performance of oral midazolam clearance and plasma 4β-hydroxycholesterol to explain interindividual variability in tacrolimus clearance.

Aims: We compared the CYP3A4 metrics weight-corrected midazolam apparent oral clearance (MDZ Cl/F/W) and plasma 4β-hydroxycholesterol/cholesterol (4β-OHC/C) as they relate to tacrolimus (TAC) Cl/F/W in renal transplant recipients.

Methods: For a cohort of 147 patients, 8 h area under the curve (AUC) values for TAC and oral MDZ were calculated besides measurement of 4β-OHC/C. A subgroup of 70 patients additionally underwent intravenous erythromycin breath test (EBT) and were administered the intravenous MDZ probe.

Progressive decline in tacrolimus clearance after renal transplantation is partially explained by decreasing CYP3A4 activity and increasing haematocrit.

Aims: The long-term disposition of tacrolimus following kidney transplantation is characterized by a gradual decrease in dose requirements and increase in dose-corrected exposure. This phenomenon has been attributed to a progressive decline in cytochrome P450 3A4 (CYP3A4) activity, although this has never been demonstrated in vivo.

Methods: Sixty-five tacrolimus- and 10 cyclosporine-treated renal transplant recipients underwent pharmacokinetic testing at day 7 and months 1, 3, 6 and 12 after transplantation, including 8-h area under the concentration-time curve (AUC) for tacrolimus or cyclosporine and assessment of CYP3A4 activity using oral and intravenous midazolam (MDZ) drug probes.

Rhodococcus equi Sepsis in a Renal Transplant Recipient: A Case Study.

Rhodococcus equi is an unusual cause of infection in humans, but has emerged as an opportunistic pathogen among immunocompromised patients. Primary pulmonary involvement is the most common clinical presentation, although the spectrum of disease is broad. Diagnosing R.

Combined effects of CYP3A5*1, POR*28, and CYP3A4*22 single nucleotide polymorphisms on early concentration-controlled tacrolimus exposure in de-novo renal recipients.

Aim: In a cohort of 298 de-novo renal recipients treated with a standard tacrolimus loading dose of 0.2 mg/kg, the combined effects of the CYP3A5*1, POR*28, and CYP3A4*22 genotypes on early tacrolimus exposure (C0), dose requirements, and achievement of the therapeutic target, C0, were examined. The incidence of clinical events (e.

Intrarenal resistive index after renal transplantation.

Background: The intrarenal resistive index is routinely measured in many renal-transplantation centers for assessment of renal-allograft status, although the value of the resistive index remains unclear.

Methods: In a single-center, prospective study involving 321 renal-allograft recipients, we measured the resistive index at baseline, at the time of protocol-specified renal-allograft biopsies (3, 12, and 24 months after transplantation), and at the time of biopsies performed because of graft dysfunction. A total of 1124 renal-allograft resistive-index measurements were included in the analysis.

Impact of CYP3A5 genotype on tacrolimus versus midazolam clearance in renal transplant recipients: new insights in CYP3A5-mediated drug metabolism.

Background & Aim: In vitro studies have identified both midazolam and tacrolimus as dual CYP3A4 and CYP3A5 substrates. In vivo; however, the CYP3A5 genotype has a marked impact on tacrolimus pharmacokinetics, whereas it seems not to affect midazolam pharmacokinetics. The aim of the current study was to explore this paradigm in a relevant clinical setting.

The once-daily formulation of tacrolimus: a step forward in kidney transplantation?

Nonadherence is a critical issue in transplantation. Recently, Astellas designed a once-daily-extended release formulation of tacrolimus (Tac). Despite initial reports showing bioequivalence of Tac once-daily (Advagraf) with the original formulation requiring twice-daily intake (Tac twice-daily, Prograf), several groups have now shown a sustained decrease in Tac exposure upon conversion from Prograf to Advagraf.

The P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients.

Aim: Recently a SNP of the gene encoding P450 oxidoreductase (POR*28; rs1057868C>T) has been associated with increased in vivo CYP3A activity using midazolam as a drug probe. Because tacrolimus is metabolized by CYP3A isoenzymes, this SNP might affect tacrolimus pharmacokinetics.

Materials & Methods: To test this hypothesis we performed a study in a cohort of 298 de novo renal allograft recipients stratified according to CYP3A5 genotype, which has a known impact on tacrolimus pharmacokinetics.

A highly sensitive liquid chromatography tandem mass spectrometry method for simultaneous quantification of midazolam, 1'-hydroxymidazolam and 4-hydroxymidazolam in human plasma.

A highly sensitive liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of midazolam and its major metabolites 1'-hydroxymidazolam and 4-hydroxymidazolam in human plasma was developed and validated. Stable isotope-labeled midazolam-D(4) and 1'-hydroxymidazolam-D(4) were used as internal standards. Compounds were extracted from 0.

A prospective, open-label, observational clinical cohort study of the association between delayed renal allograft function, tacrolimus exposure, and CYP3A5 genotype in adult recipients.

Background: Tacrolimus, a calcineurin inhibitor with a macrolide lactone structure, is currently used as a cornerstone immunosuppressive drug in solid organ transplantation. It is metabolized by hepatic and intestinal cytochrome P450 (CYP) 3A4/3A5 enzymes and is a substrate for P-glycoprotein (ABCB1). The disposition of tacrolimus might be influenced by severe renal allograft dysfunction (eg, in cases of delayed graft function [DGF]).

Cutaneous phaeohyphomycosis in renal allograft recipients: report of 2 cases and review of the literature.

Dematiaceous molds are increasingly recognized as important human pathogens. We report 2 cases of cutaneous phaeohyphomycosis in renal allograft recipients, caused by Alternaria alternata and Curvularia spp., respectively, which demonstrate the diversity in clinical presentation, the different therapeutic strategies, and the clinical importance of azole antifungal-induced drug-drug interactions with immunosuppressive therapy.

Apparent elevation of cyclosporine whole blood concentrations in a renal allograft recipient.

We describe a 77-year-old cyclosporine-treated renal allograft recipient in whom falsely elevated whole blood cyclosporine concentrations were encountered using the antibody conjugated magnetic immunoassay (ACMIA) for therapeutic drug monitoring.

Reduced C0 concentrations and increased dose requirements in renal allograft recipients converted to the novel once-daily tacrolimus formulation.

Background: Recently, a once-daily prolonged release formulation of tacrolimus (TacOD) has been approved for the prevention of renal allograft rejection. Studies reported equivalent area under the concentration-time curve0-24 and predose trough (C0) concentrations when compared with the standard twice-daily tacrolimus (Tac) formulation. Hence, the package insert advices a 1:1 mg conversion.

Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients.

Objectives: Prolonged calcineurin inhibitor maintenance therapy in kidney allograft recipients is complicated by the development of chronic irreversible drug-induced nephrotoxicity (CNIT).

Methods: In 304 de novo renal graft recipients, the association among tacrolimus exposure indices (dose, C(0), AUC(0-12h)), CYP3A5, CYP3A4 and ABCB1 polymorphisms, clinical covariables and de novo arteriolar hyalinization as a histologic sign of CNIT was examined.

Results: Tacrolimus C(0) and AUC(0-12h) at 3 and 12 months posttransplantation did not differ between patients with and without CNIT.

Donor age and renal P-glycoprotein expression associate with chronic histological damage in renal allografts.

The contributions of donor kidney quality (partially determined by donor age), allograft rejection, and calcineurin inhibitor nephrotoxicity on the progression of histologic damage of renal allografts are not completely defined. Moreover, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity are not known but may include variability in drug transport and metabolism. In a prospective cohort of 252 adult renal allograft recipients treated with a combination of tacrolimus, mycophenolate mofetil, and corticosteroids, we studied 744 renal allograft biopsies obtained regularly from time of transplantation for 3 yr.

New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation.

Although therapeutic drug monitoring (TDM) of immunosuppressive drugs has been an integral part of routine clinical practice in solid organ transplantation for many years, ongoing research in the field of immunosuppressive drug metabolism, pharmacokinetics, pharmacogenetics, pharmacodynamics, and clinical TDM keeps yielding new insights that might have future clinical implications. In this review, the authors will highlight some of these new insights for the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus and the antimetabolite mycophenolic acid (MPA) and will discuss the possible consequences. For CNIs, important relevant lessons for TDM can be learned from the results of 2 recently published large CNI minimization trials.

Calcium metabolism in the early posttransplantation period.

Background And Objectives: Information on the time course of serum calcium levels after renal transplantation is scanty, especially in the early posttransplantation period. Both the abrupt cessation of calcium-containing phosphorus binders and vitamin D (analogs) at the time of surgery and the recovery of renal function may be hypothesized to affect serum calcium levels in this period.

Design, Setting, Participants, & Measurements: In this prospective observational study, biointact parathyroid hormone, calcidiol, calcitriol, calcium, and phosphorus levels were monitored in 201 renal transplant recipients at the time of transplantation and 3 mo thereafter.

Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation.

Background And Objectives: In the first months after successful kidney transplantation, hypophosphatemia and renal phosphorus wasting are common and related to inappropriately high parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) levels. Little is known about the long-term natural history of renal phosphorus homeostasis in renal transplant recipients.

Design, Setting, Participants: We prospectively followed parameters of mineral metabolism (including full-length PTH and FGF-23) in 50 renal transplant recipients at the time of transplantation (Tx), at month 3 (M3) and at month 12 (M12).

Effects of CYP3A5 and MDR1 single nucleotide polymorphisms on drug interactions between tacrolimus and fluconazole in renal allograft recipients.

Objective: Drug interactions between tacrolimus and azole antifungals are characterized by a large clinical variability. The aim of this study was to examine the influence of the CYP3A4, CYP3A5, and MDR1 single nucleotide polymorphisms on changes in tacrolimus exposure and dosing in renal allograft recipients treated with fluconazole.

Methods: Twenty-nine patients who had received documented fluconazole treatment were identified out of a total of 753 renal recipients on maintenance tacrolimus therapy.

Pharmacogenetics in solid organ transplantation: current status and future directions.

Tailoring of immunosuppressive drug therapy to the specific requirements of the individual patient to optimize efficacy and minimize toxicity remains one of the biggest challenges in solid organ transplantation. Pharmacogenetic and pharmacogenomic research, studying the effects of genetic polymorphisms on drug disposition and action, holds promise to produce useful clinical tools for individualizing immunosuppressive therapy. In the past years, many interesting studies have been reported, assessing the impact of single nucleotide polymorphisms of genes encoding drug metabolizing enzymes, drug transporters and-to lesser extent-pharmacological target molecules, on pharmacokinetics and pharmacodynamics of immunosuppressive drugs like tacrolimus, cyclosporine, sirolimus, mycophenolic acid, and corticosteroids.

Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients.

Background: Two recent randomized clinical trials--Fixed Dose Versus Concentration Controlled and the Apomygre--evaluating the benefit of therapeutic drug monitoring of mycophenolate mofetil (MMF) in renal allograft recipients reported conflicting results. In both studies, target mycophenolic acid (MPA) AUC(0-12 h) ranges (ie, values used to guide MMF dosing) were derived from a previous study establishing target MPA AUC(0-12 h) ranges in cyclosporine-treated patients between 30 and 60 mg/L x h(-1). Both studies found an association between MPA exposure and acute rejection.

Comparison of peritoneal dialysis and haemodialysis after renal transplant failure.

Background: A growing number of patients are returning to dialysis after renal transplant failure. The aim of this study is to determine whether peritoneal dialysis (PD) is a safe and good treatment option for these patients.

Methods: All patients returning to PD or haemodialysis (HD) after renal transplant failure before 1 October 2002 at the University Hospital Gasthuisberg, Leuven, Belgium, were evaluated.