Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients.

Administration of azole antifungals to tacrolimus-treated solid organ recipients results in a major drug-drug interaction characterized by increased exposure to tacrolimus. The magnitude of this interaction is highly variable but cannot currently be predicted. We performed a retrospective analysis of 126 solid organ recipients (95 lung, 31 kidney) co-treated with tacrolimus and voriconazole (n = 100) or posaconazole (n = 26). Predictors of the change in tacrolimus dose-corrected trough concentrations (C/D) between baseline and tacrolimus-azole co-therapy were assessed using linear mixed modeling. Patients were genotyped for relevant polymorphisms in CYP3A4, CYP3A5, MDR1, CYP2C19, POR, and UGT1A4. Tacrolimus C/D increased by a factor 5.0 ± 2.7 (range 1.0-20.2) for voriconazole and 4.4 ± 2.6 (range 0.9-18.0) for posaconazole, suggesting that a 66% dose reduction is insufficient for the majority of patients. Change in C/D was blunted in CYP3A5 expressors (estimated effect: -43%, p = 0.017) and affected by hematocrit (+8% per %, p = 0.004), baseline C/D (-14% per 100% increase, p < 0.001), and age (+1%, p = 0.008). However, the final model explained only 22% of interindividual variability in C/D change. In conclusion, CYP3A5 genotype and several clinical variables were identified as modulators of the tacrolimus-azole interaction, but these did not permit accurate predictions in individual patients.

Effect of ABCB1 diplotype on tacrolimus disposition in renal recipients depends on CYP3A5 and CYP3A4 genotype.

The relevance of most genetic polymorphisms beyond CYP3A5*1 on tacrolimus disposition remains unclear. We constructed a predictive mixed model for tacrolimus dose-corrected trough concentration (C0/dose) at months 3, 12 and 24 after transplantation in a retrospective cohort of 766 predominantly Causasian adult renal recipients (n=2042 trough concentrations). All patients were genotyped for 32 single-nucleotide polymorphisms with a proven or possible relevance to tacrolimus disposition based on the previous studies. Of these, ABCB1, ABCC2, OATP1B1, COMT, FMO, PPARA and APOA5 were analyzed as (functional) diplotype groups. Predictors of C0/dose were CYP3A5*1, hematocrit, age, CYP3A4*22, use of concomitant CYP3A4 inhibitor or inducer, ALT, estimated glomerular filtration rate, tacrolimus formulation (once vs twice daily), ABCB1 diplotype and time after transplantation. The effect of ABCB1 diplotype was small but strongly accentuated in CYP3A4*22 carriers and non-existent in CYP3A5 expressors. ABCC2 diplotype had a limited effect on C0/dose that was only statistically significant in CYP3A5 non-expressors.

High Intrapatient Variability of Tacrolimus Concentrations Predicts Accelerated Progression of Chronic Histologic Lesions in Renal Recipients.

High intrapatient variability (IPV) of tacrolimus concentrations is increasingly recognized as a predictor of poor outcome in solid organ recipients. How it relates to evolution of histology has not been explored. We analyzed tacrolimus IPV using the coefficient of variability (CV) from months 6-12 after transplantation in a cohort of 220 renal recipients for whom paired protocol biopsies at 3 mo and 2 years were available. Recipients in the highest CV tertile had an increased risk of moderate to severe fibrosis and tubular atrophy by 2 years compared with the low-IPV tertile (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.09-5.60, p = 0.031; and OR 2.40, 95% CI 1.03-5.60, p = 0.043, respectively). Other predictors were donor age, severity of chronic lesions at 3 mo, and presence of borderline or subclinical rejection at 3 mo. Chronicity score increased significantly more in the high CV tertile group than in the middle and low tertiles (mean increase 1.97 ± 2.03 vs. 1.18 ± 2.44 and 1.12 ± 1.80, respectively; p < 0.05). CV did not predict evolution of renal function, which did not deteriorate within the 2-year follow-up period. These results indicate that high IPV is related to accelerated progression of chronic histologic lesions before any evidence of renal dysfunction.

The CYP3A4*22 C>T single nucleotide polymorphism is associated with reduced midazolam and tacrolimus clearance in stable renal allograft recipients.

Tacrolimus, a dual substrate of CYP3A4 and CYP3A5 has a narrow therapeutic index and is characterized by high between-subject variability in oral bioavailability. This study investigated the effects of the recently described CYP3A4*22 intron 6 C>T single nucleotide polymorphism on in vivo CYP3A4 activity as measured by midazolam (MDZ) clearance and tacrolimus pharmacokinetics in two cohorts of renal allograft recipients, taking into account the CYP3A5*1/*3 genotype and other determinants of drug disposition. In CYP3A5 non-expressers, the presence of one CYP3A4*22T-allele was associated with a 31.7-33.6% reduction in MDZ apparent oral clearance, reflecting reduced in vivo CYP3A4 activity. In addition, at ⩾12 months after transplantation, steady-state clearance of tacrolimus was 36.8% decreased compared with homozygous CYP3A4*22CC-wild type patients, leading to 50% lower dose requirements. Both concurrent observations in stable renal allograft recipients are consistent with a reduced in vivo CYP3A4 activity for the CYP3A4*22T-allele.

Chronic histological damage in early indication biopsies is an independent risk factor for late renal allograft failure.

The impact of early histological lesions of renal allografts on long-term graft survival remains unclear. We included all renal allograft recipients transplanted at a single center from 1991 to 2001 (N = 1197). All indication biopsies performed within the first year after transplantation were rescored according to the current Banff classification. Mean follow-up time was 14.8 ± 2.80 years. In multivariate Cox proportional hazards analysis, arteriolar hyalinosis and transplant glomerulopathy were independently associated with death-censored graft survival, adjusted for baseline demographic covariates. Arteriolar hyalinosis correlated with interstitial fibrosis, tubular atrophy, mesangial matrix increase, vascular intimal thickening and glomerulosclerosis. Clustering of the patients according to these chronic lesions, reflecting the global burden of chronic injury, associated better with long-term graft survival than each of the chronic lesions separately. Early chronic histological damage was an independent risk factor for late graft loss, irrespective whether a specific, progressive disease was diagnosed or not, while T cell-mediated rejection did not. We conclude that individual chronic lesions like arteriolar hyalinosis, tubular atrophy, interstitial fibrosis, glomerulosclerosis, mesangial matrix increase and vascular intimal thickening cannot be seen as individual entities. The global burden of early chronic histological damage within the first year after transplantation importantly affects the fate of the allografts.

Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results.

Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection ≥ grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.

Disseminated histoplasmosis in a kidney liver transplant patient from a non-endemic area: A diagnostic challenge.

Disseminated histoplasmosis is a rare opportunistic infection in non-endemic areas, where the disease is often diagnosed late. The spectrum of clinical manifestations is broad and life-threatening complications occur. We present a detailed case of a kidney liver transplant patient with disseminated histoplasmosis in a non-endemic area. Our case highlights the wide range of pathogens to consider in the immunocompromised patient, the delayed diagnosis of Histoplasmosis Capsulatum in non-endemic areas and the possibility of severe gastrointestinal disease. We also briefly review diagnostic tests and treatment options.

Posttransplant Epstein-Barr virus-associated myogenic tumors: case report and review of the literature.

Epstein-Barr virus (EBV) has been implicated in the pathogenesis of different types of malignancies. While nonmelanoma skin cancers, lymphomas and Kaposi sarcomas are the most frequently reported malignancies after solid organ transplantation, EBV-associated smooth muscle tumors (EBV-SMT) after transplantation are rare and thus far only 18 cases in kidney recipients have been reported. A case of a 51-year-old kidney transplant recipient diagnosed with EBV-SMT is reported together with a review of the literature.

Pseudoaneurysm complicating protocol renal transplant biopsies: case reports.

Pseudoaneurysm is a rare complication of a renal biopsy procedure. We describe two cases of kidney transplant recipients who were diagnosed with a pseudoaneurysm more than 48 hours after protocol renal allograft biopsy and were successfully treated by selective embolization of the afferent artery.

Immunosuppressive drugs after simultaneous pancreas-kidney transplantation.

INTRODUCTION: We report the early and late secondary effects of tacrolimus or cyclosporine-microemulsion (ME), in combination with mycophenolate mofetil (MMF), and rATG. PATIENTS AND METHODS: One hundred three patients were randomly assigned to tacrolimus (initial oral dose 0.2 mg/kg) and 102 to cyclosporine-ME (initial daily oral dose 7 mg/kg). All patients received 4 days of concomitant rATG induction therapy [ATG-Fresenius Biotech GmbH (ATG-F) daily dose of 4 mg/kg or Thymoglobulin-Genzyme/Sangstat (Thymo-S) 1.25 mg/kg], MMF (2 to 3 g per day), and short-term corticosteroids. RESULTS: Thymo-S was associated with a transiently lower white cell count in the first 3 months compared with ATG-F, while ATG-F caused a lower albeit transient early nadir in platelet count. Both polyclonal preparations were well tolerated; they did not differ with respect to clinically relevant side effects such as infections and malignancies. Higher cyclosporine-ME trough levels were associated with pancreas graft thrombosis. Study withdrawal was more frequent among patients on cyclosporine-ME therapy, because of toxicities, graft loss, and lack of efficacy, the last being the cause of subsequent switch to tacrolimus. Tacrolimus-treated patients were mainly withdrawn from the study due to MMF discontinuation. CONCLUSION: Short-term induction therapy in combined kidney-pancreas transplantation is effective and well tolerated. Tacrolimus causes fewer pancreas graft losses and fewer drug discontinuations due to side effects. When MMF is combined with tacrolimus, dose reductions and discontinuations are common.

Calcium channel blockade and preservation of renal graft function in cyclosporine-treated recipients: a prospective randomized placebo-controlled 2-year study.

BACKGROUND: Studies have provided conflicting results as to the protective role of calcium channel blockers (CCB) in cyclosporine-treated patients with regard to blood pressure control and preservation of renal graft function. Lacidipine is a dihydropyridine CCB that possesses antioxidative, anti-atherosclerotic, and anti-adhesion properties and was shown to prevent cyclosporine-induced nephrotoxicity in a rat model. METHODS: We conducted a multicenter prospective, randomized, placebo-controlled study in 131 de novo recipients of a cadaveric renal allograft on cyclosporine therapy. The aim of this 2-year study was to assess the effects of lacidipine on graft function (plasma iohexol clearance), renal plasma flow, anastomotic arterial blood flow, deterioration of renal function, blood pressure, acute rejection, and hospitalization rate. RESULTS: A total of 118 recipients were available for intention-to-treat analysis on efficacy (lacidipine: n=59; placebo: n=59). Graft function assessed by serum creatinine concentration and glomerular filtration rate measured as plasma iohexol clearance, was persistently better in lacidipine-treated patients from 1 year onwards (respectively, P<0.01 and P<0.05). Renal plasma flow and anastomotic blood flow were not significantly higher in lacidipine-treated patients. Three patients on lacidipine therapy and four on placebo experienced treatment failure defined as an increase in serum creatinine from baseline of more than 60% (log-rank test: P=0.57). Study groups did not differ in acute rejection rate, trough blood cyclosporine concentrations, blood pressure, number of antihypertensive drugs, hospitalization rate, and adverse event rate. CONCLUSIONS: The use of calcium channel blockers in cyclosporine-treated renal recipients results in a significantly better allograft function at 2 years and this effect is independent of blood pressure lowering.

Predictors of renal transplant histology at three months.

BACKGROUND: The quality of a damaged kidney, the complexity of the surgery, and the events in the first weeks after transplantation, such as delayed graft function (DGF) and acute rejection, may influence its histological appearance and long-term survival. The aim of this study was to evaluate the importance of these factors in predicting renal allograft histology at 3 months. METHODS: Prospective, protocol kidney biopsy specimens (n=112), obtained 3 months after transplantation, were scored for chronic damage by the Banff schema and evaluated by multivariate analysis against donor factors, implantation histology, prior recipient sensitization, ischemia, perioperative factors, and subsequent clinical events, such as DGF and acute rejection. RESULTS: Adequate samples were obtained in 102 of 112 biopsies and classified as chronic Banff grade 0 (n=22), grade I (n=56), grade II (n=23), or grade III (n=1). Acute Banff scores were minimal. DGF occurred in 49% and was the strongest predictor of tubulointerstitial damage at 3 months. DGF correlated with acute tubular necrosis on the implantation biopsy specimen and with the number of acute rejection episodes; DGF also correlated with the Banff grades of chronic glomerulitis, chronic interstitial fibrosis, and tubular atrophy scores (P<0.05-0.001) in the 3-month biopsy specimen. By multivariate analysis, chronic tubular atrophy was independently predicted by the presence of vascular disease in the donor biopsy specimen, DGF, and vascular rejection occurring within the first 3 months (P<0.05-0.001). Chronic interstitial fibrosis was unrelated to fibrosis in the donor biopsy specimen but was independently predicted by DGF, donor age, and vascular rejection (P<0.05-0.001). Vascular disease in the donor biopsy specimen correlated with chronic intimal thickening (r=0.36, P<0.01) and arteriolar hyalinosis score (r=0.54, P<0.001) on the 3-month biopsy specimen. Banff chronic intimal vascular thickening was independently predicted by donor biopsy specimen vascular grade, prior vascular rejection episodes, and renal cold ischemia time (P<0.05-0.01). There were no correlates with the mean cyclosporine (CsA) dose, blood levels, diagnosis of CsA toxicity, or cellular rejection within the first 3 months. CONCLUSIONS: This study has demonstrated that the quality of the donor organ at implantation was strongly predictive of subsequent renal histology in grafts functioning at 3 months. Vascular rejection and DGF had a significant long-term effect on graft damage, but cellular rejection and simple measures of CsA exposure did not.

Effect of histological damage on long-term kidney transplant outcome.

BACKGROUND: Chronic renal allograft failure remains a major challenge to overcome. Factors such as donor quality, delayed graft function (DGF), acute rejection, and immunosuppression are known to affect long-term outcome, but their relationship to histological damage to graft outcome is unclear. METHODS: Protocol kidney biopsies (n=112) obtained at 3 months after transplantation yielded 102 with adequate tissue. Histology was scored by the Banff schema, and compared with implantation biopsies (n=91), repeat 12-month histology (n=39), decline in serum creatinine and serial isotopic glomerular filtration rate, onset of chronic allograft nephropathy (CAN), and actuarial graft survival censored for death with a functioning graft. RESULTS: At a median follow-up of 9.3 years, 20 patients had graft failure and 26 died with a functioning graft. Banff chronic nephropathy was present in 24% of 3-month biopsies, and was predicted by microvascular disease in the donor, cold ischemia, DGF, and acute vascular rejection (P<0.001). Acute glomerulitis at 3 months correlated with segmental glomerulosclerosis at 12 months, subsequent recurrent glomerulonephritis, and graft failure (P<0.01). Subclinical rejection at 3 months occurred in 29% of biopsies, correlated with prior acute rejection and HLA mismatch, and led to chronic histological damage by 12 months (r=0.25-0.67, P<0.05-0.001). Subclinical rejection, arteriolar hyalinosis, and tubulitis present at 3 months had resolved by 12 months. The 10-year survival rates for Banff chronic nephropathy were 90.4% for grade 0, 81.0% grade 1, and 57.9% for grades 2 or greater (P<0.01). Early tubulointerstitial damage at 3 months profoundly influenced graft survival beyond 10 years. CAN was predicted by kidney ischemia, 3-month chronic intimal vascular thickening, tubular injury, proteinuria, and late rejection. Chronic fibrointimal thickening of the small arteries and chronic interstitial fibrosis at 3 months independently predicted graft loss and decline in renal function (P<0.05-0.001). CONCLUSIONS: Early transplant damage occurs in the tubulointerstitial compartment from preexisting donor kidney injury and discrete events such as vascular rejection and DGF. Subsequent chronic damage and graft failure reflect accumulated previous injury and chronic interstitial fibrosis, vascular impairment, subclinical rejection, and injury from late rejection. CAN may be conceptualized as the sequelae of incremental and cumulative damage to the transplanted kidney. The duration of graft survival is dependent and predicted by the quality of the transplanted donor kidney combined with the intensity, frequency, and irreversibility of these damaging insults.

Long-term changes in mycophenolic acid exposure in combination with tacrolimus and corticosteroids are dose dependent and not reflected by trough plasma concentration: a prospective study in 100 de novo renal allograft recipients.

Tacrolimus and cyclosporine A have different effects on exposure to concomitantly administered mycophenolate mofetil (MMF), measured as the mycophenolic acid (MPA) dose interval area under the plasma concentration versus time curve (AUC0-12 h) or the plasma MPA predose concentration (C0). This has led to recommendations in using a 50% lower dose of MMF in combination with tacrolimus compared to cyclosporin A. At present, no long-term data are available regarding the pharmacokinetics (PK) of different dosages of MMF in combination with tacrolimus and the clinical variables that influence the dose-exposure relationship of MPA. A prospective 12-month pharmacokinetic study was performed in 100 de novo renal transplant recipients treated with two different MMF dosages (1 g/day vs. 2 g/day) in combination with tacrolimus and corticosteroids. MPA AUC data were collected 7 days, 6 weeks, and 3 and 12 months posttransplantation, and model-independent PK parameters were calculated. Clinical variables that could possibly influence MPA PK were evaluated. The MPA AUC0-12 h significantly increased toward 6 weeks (p < 0.05) but only in the 2-g MMF dosing group. The MPA AUC0-12 h in the 1-g MMF group reached its nadir at 3 months, while in the 2-g MMF group, it remained elevated until 3 months, returning to baseline values by 12 months. This differential evolution in exposure was not only inadequately reflected by the corresponding MPA C0 concentrations, but the MPA C0 concentrations also were not significantly different between the two dosing groups at early postgrafting (day 7) and at 12 months. Using multiple stepwise regression analysis, C0 (r = 0.51, p < 0.0001) and end-of-dose interval MPA plasma concentration (C12: r2 = 0.61, p < 0.0001) were found to poorly predict MPA AUC0-12 h, while MPA plasma concentrations at 4 hours (C4: r2 = 0.85, p < 0.0001) and 6 hours postdosing (C6: r2 = 0.83, p < 0.0001) were superior but hampered by a large prediction bias and imprecision. An abbreviated 2-hour AUC measurement (r2 = 0.78), using three sampling points (C0, C40 [MPA plasma concentration 40 min postdosing], C2), provided the best compromise between a monitoring tool that is theoretically ideal and practically feasible. MPA pharmacokinetics were not influenced by recipient age, gender, and body weight or by serum albumin concentrations, allograft function, or corticosteroid or tacrolimus dose. Mild hepatic dysfunction early after grafting did result in significantly reduced MPA exposure (MPA AUC0-12 h, p = 0.01 and C0, p = 0.03). In this study, it was demonstrated for the first time that the dynamics of long-term MPA pharmacokinetics in combination with tacrolimus differ according to the daily MMF dose and that this effect is not adequately reflected by MPA trough concentrations. Using the latter as a routine measure for therapeutic drug monitoring might mislead clinicians into drawing wrong conclusions in terms of relating questions of efficacy or toxicity to MPA exposure.

Clinical use of rapamycin in renal allograft recipients identifies its relevant toxicity profile and raises unsolved questions: a single-center experience.

Rapamycin is an immunosuppressive drug with a distinct and unique mode of action and a specific side effect profile. We report here briefly on our personal clinical experience using this immunosuppressive drug in different combinations and settings. Rapamycin is without any doubt an efficient drug capable of preventing acute allograft rejection in a variety of immunosuppressive combinations. It is also a very potent drug that is not devoid of serious side effects. Infectious complications as a result of strong inhibition of the immune system are a frequent cause of hospitalization with severe morbidity and even mortality. Fungal infections and pneumonia are among the most devastating complications. As clinical experience with rapamycin grows and the therapeutic window of the drug can be further narrowed, these infectious complications will improve. Wound healing problems and lymphocoeles form another frequent surgical dilemma and are related to the antiproliferative properties of rapamycin. Last, hyperlipidemia warrants the use of statins in the majority of rapamycin-treated patients and whether this unfavorable side effect will offset the theoretically beneficial cardiovascular effects of the drug remains to be determined in controlled trials with long-term follow-up. Finally, the specific antiproliferative properties of rapamycin and the fact that it exerts no nephrotoxicity make this drug an alternative for calcineurin inhibitors and could make it an ideal candidate for treating chronic allograft dysfunction.

Chronic wounds in a kidney transplant recipient with moderate renal impairment.

Calcific uremic arteriolopathy (CUA) or calciphylaxis is a condition predominantly observed in patients with end-stage kidney disease characterized by small vessel calcification, intimal proliferation, endovascular fibrosis and intravascular thrombosis causing down-stream infarction predominantly of skin resulting in extremely painful necrotic ulceration. Several interventions have been proposed in an attempt to attenuate the high mortality associated with CUA. One of the most promising therapeutic approaches is the administration of sodium thiosulfate which is able to chelate cations such as calcium and in this way possibly dissolving tissue calcium deposits into more hydrophilic calcium thiosulfate. Due to the scarcity of reports of CUA patients treated with sodium thiosulfate the safety profile of this drug is not (well) established at this moment especially in patients not receiving kidney replacement therapy. Here, we describe a case of a kidney transplant recipient with CUA and moderately declined kidney function who was treated with sodium thiosulfate and developed important hypernatremia and high anion gap acidosis necessitating significant reduction in dosing.

In vivo CYP3A4 activity, CYP3A5 genotype, and hematocrit predict tacrolimus dose requirements and clearance in renal transplant patients.

Tacrolimus is metabolized by CYP3A4 and CYP3A5 and is characterized by a narrow therapeutic index and highly variable pharmacokinetics. This cross-sectional study in 59 renal transplant patients investigated the relationship among in vivo CYP3A4 activity (assessed using midazolam as a drug probe), CYP3A5 genotype on the one hand, and tacrolimus pharmacokinetics on the other hand, taking into account other potential determinants of tacrolimus disposition. In vivo CYP3A4 activity and CYP3A5 genotype explain 56-59% of variability in tacrolimus dose requirements and clearance, contributing ~25 and 30%, respectively. Hematocrit explains an additional 4-14%. These data indicate that CYP3A4- and CYP3A5-mediated tacrolimus metabolisms are major determinants of tacrolimus disposition in vivo and explain a substantial part of the clinically observed high interindividual variability in tacrolimus pharmacokinetics. Furthermore, these data provide a potential basis for a comprehensive approach to predicting tacrolimus dose requirement in individual patients and hence provide a strategy to tailor immunosuppressive therapy in transplant recipients.

In vivo CYP3A activity is significantly lower in cyclosporine-treated as compared with tacrolimus-treated renal allograft recipients.

In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 ± 73 vs. 354 ± 102 ml/min, P = 0.022) and 31% (479 ± 190 vs. 688 ± 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients.