Oral Dose Of Tacrolimus Research Articles

A retrospective cohort study exploring diltiazem as a pharmaco‐enhancer for tacrolimus, in a post–heart transplant setting

A significant proportion of heart transplant-associated expenditure are attributable to immunosuppressants. Post-transplant hypertension adds to the pill burden and subsequent costs. In this study, we describe the effect of diltiazem-the antihypertensive and pharmaco-enhancer-on reducing the required oral dose of tacrolimus. We included 17 recipients who had successfully undergone heart transplants but later developed post-transplant hypertension and were treated with diltiazem. Serum trough levels of the immunosuppressant tacrolimus were measured every 2weeks. Required doses before and after the introduction of diltiazem were compared. Patients were assessed at each follow-up visit for any evidence of toxicity. Medication-related expenditure was estimated based on government-mandated standardized retail price. The power of the study was 98.92% at α=0.05. The mean tacrolimus dose required prior to initiation of diltiazem was 5.85±1.55mg. After initiating diltiazem, the mean required doses reduced to 2.88±1.24mg (p<.0001). Relatively, the required doses reduced by 52.4±10.9%-independently of age, sex, and dose of diltiazem. Medication-related monthly expenditure reduced by 50.3±10.4%. No patient demonstrated evidence of toxicity. Concomitant use of diltiazem and tacrolimus can safely, effectively, and predictably reduce the required dose of tacrolimus and significantly reduce corresponding costs.

Clinical Factors Affecting the Dose Conversion Ratio from Intravenous to Oral Tacrolimus Formulation among Pediatric Hematopoietic Stem Cell Transplantation Recipients.

Tacrolimus is converted from intravenous to oral formulation for the prophylaxis of graft-versus-host disease when patients can tolerate oral intake and graft-versus-host disease is under control. Oral tacrolimus formulation presents poor bioavailability with intraindividual and interindividual variations; however, some factors affecting its blood concentration among pediatric hematopoietic stem cell transplantation (HCT) recipients are still unclear. This study aimed to identify the clinical factors affecting tacrolimus blood concentrations after switching its formulation. Changes in the blood concentration/dose ratio (C/D) of tacrolimus in pediatric HCT recipients were analyzed after the switching of tacrolimus from intravenous to oral formulation. Clinical records of 57 pediatric patients who underwent allogenic HCT from January 2006 to April 2019 in our institute were retrospectively reviewed. The C/D of tacrolimus before discontinuation of intravenous infusion (C/Div) was compared with the tacrolimus trough level within 10 days after the initiation of oral administration (C/Dpo). Multiple linear regression analysis was performed to identify factors affecting (C/Dpo)/(C/Div). The constant coefficient of (C/Dpo)/(C/Div) was 0.1692 [95% confidence interval (CI), 0.137-0.2011]. The concomitant use of voriconazole or itraconazole and female sex were significant variables with a beta coefficient of 0.0974 (95% CI, 0.062-0.133) and -0.0373 (95% CI, -0.072 to -0.002), respectively. After switching of tacrolimus formulation, pediatric HCT recipients might need oral tacrolimus dose that is 5-6 and 3.5-4.5 times the intravenous dose to maintain tacrolimus blood concentrations and area under the concentration-time curve, respectively. With the concomitant use of voriconazole or itraconazole, an oral tacrolimus dose of 4-5 times the intravenous dose seemed appropriate to maintain blood tacrolimus concentration.

Tacrolimus for ulcerative colitis in children: a multicenter survey in Japan.

Background/AimsTacrolimus is effective for refractory ulcerative colitis in adults, while data for children is sparse. We aimed to evaluate the effectiveness and safety of tacrolimus for induction and maintenance therapy in Japanese children with ulcerative colitis. MethodsWe retrospectively reviewed the multicenter survey data of 67 patients with ulcerative colitis aged < 17 years treated with tacrolimus between 2000 and 2012. Patients’ characteristics, disease activity, Pediatric Ulcerative Colitis Activity Index (PUCAI) score, initial oral tacrolimus dose, short-term (2-week) and long-term (1-year) outcomes, steroid-sparing effects, and adverse events were evaluated. Clinical remission was defined as a PUCAI score < 10; treatment response was defined as a PUCAI score reduction of ≥ 20 points compared with baseline. ResultsPatients included 35 boys and 32 girls (median [interquartile range] at admission: 13 [11–15] years). Thirty-nine patients were steroid-dependent and 26 were steroidrefractory; 20 had severe colitis and 43 had moderate colitis. The initial tacrolimus dose was 0.09 mg/kg/day (range, 0.05–0.12 mg/kg/day). The short-term clinical remission rate was 47.8%, and the clinical response rate was 37.3%. The mean prednisolone dose was reduced from 19.2 mg/day at tacrolimus initiation to 5.7 mg/day at week 8 (P< 0.001). The adverse event rate was 53.7%; 6 patients required discontinuation of tacrolimus therapy. ConclusionsTacrolimus was a safe and effective second-line induction therapy for steroid-dependent and steroid-refractory ulcerative colitis in Japanese children.

Commensal Gut Bacteria Convert the Immunosuppressant Tacrolimus to Less Potent Metabolites

Tacrolimus exhibits low and variable drug exposure after oral dosing, but the contributing factors remain unclear. Based on our recent report showing a positive correlation between fecal abundance of Faecalibacterium prausnitzii and oral tacrolimus dose in kidney transplant patients, we tested whether F. prausnitzii and other gut abundant bacteria are capable of metabolizing tacrolimus. Incubation of F. prausnitzii with tacrolimus led to production of two compounds (the major one named M1), which was not observed upon tacrolimus incubation with hepatic microsomes. Isolation, purification, and structure elucidation using mass spectrometry and nuclear magnetic resonance spectroscopy indicated that M1 is a C-9 keto-reduction product of tacrolimus. Pharmacological activity testing using human peripheral blood mononuclear cells demonstrated that M1 is 15-fold less potent than tacrolimus as an immunosuppressant. Screening of 22 gut bacteria species revealed that most Clostridiales bacteria are extensive tacrolimus metabolizers. Tacrolimus conversion to M1 was verified in fresh stool samples from two healthy adults. M1 was also detected in the stool samples from kidney transplant recipients who had been taking tacrolimus orally. Together, this study presents gut bacteria metabolism as a previously unrecognized elimination route of tacrolimus, potentially contributing to the low and variable tacrolimus exposure after oral dosing.

Clinical Pharmacokinetics and Drug‐Drug Interaction Potential for Coadministered SCY‐078, an Oral Fungicidal Glucan Synthase Inhibitor, and Tacrolimus

SCY-078 is an orally bioavailable triterpenoid glucan synthase inhibitor in clinical development as an intravenous and oral treatment of fungal infections caused by Candida and Aspergillus species. This was a sequential, single-center, open-label phase 1 study to assess the drug-drug interaction potential between SCY-078 and tacrolimus during concomitant administration in healthy subjects. In cohort 1, period 1, subjects received a single oral dose of tacrolimus 2mg in the fasted state. In period 2 after a ≥15 day washout, subjects received a single loading dose of SCY-078 1250mg on day 1 followed by maintenance doses of SCY-780 750mg on days 2 through 8. On day 3 of period 2, subjects also received a single dose of tacrolimus 2mg concurrent with SCY-078. In cohort 2, subjects received a loading dose of SCY-078 1250mg on day 1 followed by maintenance doses of SCY-780 750mg on days 2 and 3. Pharmacokinetic (PK) parameters were compared to assess both the impact of steady-state SCY-078 on tacrolimus and the impact of tacrolimus on the PK of steady-state SCY-078. The concurrent coadministration of tacrolimus and SCY-078 had no effect on the maximum blood levels of tacrolimus, as evidenced by no change in maximum concentration of drug in blood plasma and a 1.4-fold increase in total area under the plasma drug concentration-time curve. The concurrent coadministration of tacrolimus and SCY-078 resulted in a weaker interaction than typically observed with the azole class of antifungals. The current data indicate that an initial dose adjustment for tacrolimus may not be warranted when combined with SCY-078, as the modest increase in exposure is less than the therapeutic window, although tacrolimus monitoring, as with addition of any new medication, is recommended. These results support the coadministration of SCY-078 and tacrolimus.

CYP3A pharmacogenetic association with tacrolimus pharmacokinetics differs based on route of drug administration.

Tacrolimus is prescribed to the majority of transplant recipients to prevent graft rejection, and although patients are maintained on oral administration, nonoral routes of administration are frequently used in the initial post-transplant period. CYP3A5 genotype is an established predictor of oral tacrolimus dose requirements, and clinical guideline recommendations exist for CYP3A5-guided dose selection. However, the association between CYP3A5 and nonoral tacrolimus administration is currently poorly understood, and differs from the oral tacrolimus relationship. In addition to CYP3A5, other pharmacogenes associated with CYP3A activity, including CYP3A4, CYP3A7 and POR have also been identified as predictors of tacrolimus exposure. This review will describe the current understanding of the relationship between these pharmacogenes and tacrolimus pharmacokinetics after oral and nonoral administration.

Effectiveness of Measuring Genetic Polymorphisms in Metabolizing Enzymes of Tacrolimus within One Medical Facility.

Because genetic polymorphisms cause diverse activity in drug metabolizing enzymes, drug concentrations in the blood may be variable among patients. We analyzed the genotypes of CYP3A5 and MDR1, and investigated their relationship with whole blood drug concentrations. Eight patients were administered an oral dose of tacrolimus for one week or longer prior to enrollment in this study. Whole blood concentrations for tacrolimus were measured 12 hours post oral administration, on the same day as genotyping, within our hospital using a fully automated gene analyzer. The procedures became so rapid that collection of blood samples could be completed within the same day (approximately one hour). The genotype frequency of CYP3A5 was *3/*3 in five patients, *1/*3 in two patients, and *1/*1 in one patient. All five patients with *3/*3 showed favorable increases in tacrolimus blood concentrations. In the two patients with *1/*3, an increase in tacrolimus blood concentration was not readily achieved in one patient, but increased favorably in the other patient. In the patient with *1/*1, tacrolimus was not detectable in the patient's blood. A favorable treatment effect was obtained by changing tacrolimus to cyclosporine. It is notable that genotypes in patients where tacrolimus was not detected in the blood were wild types: 2677G/G and 3435C/C in MDR1. The measurement of genetic polymorphisms in metabolizing enzymes of tacrolimus, within one medical facility, is applicable for the selection of immunosuppressants and individual dosing for the treatment of autoimmune disease.

An Open-Label Investigation into Drug–Drug Interactions Between Multiple Doses of Daclatasvir and Single-Dose Cyclosporine or Tacrolimus in Healthy Subjects

Background and ObjectiveChronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug–drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir—a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)—and cyclosporine or tacrolimus in healthy subjects.MethodsHealthy fasted subjects (aged 18–49 years; body mass index 18–32 kg/m2) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4–11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8–19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC–MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC–MS/MS methods.ResultsDaclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration–time curve of daclatasvir but did not affect its maximum observed concentration.ConclusionOn the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required.

Comparison of Once-Daily and Twice-Daily Low-Dose Tacrolimus in Living Related Kidney Transplantation -Prospective Trial of Once-Daily vs. Twice-Daily Tac -3 Years Second Report.

Background; A prolonged-release formulation of Tacrolimus (Tac-QD) has been developed to allow once-daily dosing with a similar safety and efficacy profile to that of twice-daily tacrolimus (Tac-BD). Previously, we reported a comparison of the safety and pharmacokinetics between Tac-QD and BD in the early phase after kidney transplantation. In this study, we report longer-term results in the same recipient population 3 years after the aforementioned prospective study. Materials and methods; Between November 2009 and January 2011, 130 consecutive adult patients were randomized to receive either low-dose Tac-QD or Tac-BD. The transplant operation was cancelled due to other reasons after enrollment in this study in 9 cases. During the 3- to 5-years' observation period, the treatment was switched from Tac-BD to Tac-QD in 5 cases, and from Tac-QD to Tac-BD in 2 cases. The drug itself was switched from tacrolimus to cyclosporine in 2 cases. One patient died and 5 cases lost their grafts. In the remaining 106 cases included as the subjects of this study, we examined the patient and graft survival rates, the incidence rates of graft rejection, the serum tacrolimus trough level, and the total oral dose of tacrolimus. Results; The patient survival rates are 100% and 98% in the QD and BD groups. The graft survival rate is 98% in both groups. The current tacrolimus dose is 2.9±1.7 mg/day in the QD group and 2.4±1.2 mg/day in the BD group (P=0.32). The mean tacrolimus trough level is 5.1±0.9 ng/ml in the QD group and 5.0±1.1 ng/ml in the BD group (P=0.81). There is no statistically significant difference in the graft function between the QD and BD groups (serum creatinine level; 1.2±0.4 mg/dl in the QD group vs. 1.1±0.2 mg/dl in the BD group; P=0.55). The incidence rate of acute/chronic T cell-mediated rejection until 3 years after Tx was 10% (2/19) in the QD group and 12 % (3/25) in the BD group (P=0.95). The incidence rate of acute/chronic antibody-mediated rejection until 3 years after Tx was 5% (1/19) in the QD group and 8% (2/25) in the BD group (P=0.87). There has been no significant difference in the graft rejection rate, CNI toxicity, incidence of BK nephropathy and recurrence of IgA nephropathy between the two groups. Conclusion; The clinical efficacy and safety profile of Tac-QD and Tac-BD are almost the same, even 3 to 5 years after kidney transplantation.

Determination of the Most Influential Sources of Variability in Tacrolimus Trough Blood Concentrations in Adult Liver Transplant Recipients: A Bottom-Up Approach

Tacrolimus, an immunosuppressant drug, presents a narrow therapeutic window and a large pharmacokinetic variability with poor correlation between drug dosing regimen and blood concentration. The objective was to identify predictive factors influencing tacrolimus trough concentrations (C0) using a bottom-up approach. A physiologically based pharmacokinetic (PBPK) model of tacrolimus was proposed, taking into account the body weight, the proportion of fat (P(fat)), hematocrit, lipid fraction of organs, typical intrinsic clearance (CLi(typ)), CYP3A5 genotype of liver donor, plasma unbound fraction of tacrolimus (fu(p)), and concomitant drugs (CYP3A4 inhibitors). For the evaluation of the PBPK model, mean C0 and concentrations 2 h after oral dose of tacrolimus were compared with those from 66 liver transplant recipients included in a multicentric pharmacokinetic study and were found very close. Tacrolimus concentration profiles were simulated in a virtual population defined by a set of covariate values similar to those from the real population. The sensitivity of tacrolimus C0 with respect to each covariate has been tested to identify the most influential ones. With the range of covariate values tested, the impact of each covariate on tacrolimus C0 may be ranked as follows: fu(p), CLi(typ), bioavailability, body weight, hematocrit, CYP3A5 polymorphism, P(fat), and CYP3A4 inhibitory drug-drug interactions. Values for initial dosing regimen of tacrolimus in order to reach a C0 of 10 ng/ml at day 5 (assuming a constant dosing schedule) as a function of CYP3A5 donor genotype and patient's hematocrit and body weight are proposed.

Excess fluid distribution affects tacrolimus absorption in peritoneal dialysis patients

Excess fluid distribution is a common disorder in peritoneal dialysis (PD) patients. Tacrolimus malabsorption may also occur in PD patients, and may lead to acute allograft rejection after transplantation. The purpose of this study was to evaluate the relationship between tacrolimus pharmacokinetics and excess fluid distribution according to pre-transplant dialysis modality. We retrospectively analyzed 41 adult living-donor kidney transplantations, including nine PD patients and 32 hemodialysis (HD) patients. We examined tacrolimus pharmacokinetics in the peri-operative period and determined the association between the tacrolimus absorption rate and body weight reduction. The absorption efficacy of tacrolimus was evaluated as the dose-normalized tacrolimus absorption rate. Tacrolimus concentrations in PD effluent were measured by high-performance liquid chromatography. The tacrolimus absorption rate on the day before kidney transplantation tended to be lower in PD patients than in HD patients; however, the rate improved after kidney transplantation and was similar in both groups of patients. The peak tacrolimus concentration time was later in PD patients than in HD patients. The body weight reduction after kidney transplantation was greater in PD patients than in HD patients, and was significantly associated with the change in tacrolimus absorption rate (p=0.04, r=0.32). Only 0.002% of the oral tacrolimus dose was removed by PD itself. Excess fluid distribution in PD patients appears to contribute to tacrolimus malabsorption rather than PD itself. We should consider the risk of tacrolimus malabsorption in patients with possible excess fluid distribution, particularly in PD patients.

The evaluation of potential pharmacokinetic interaction between sirolimus and tacrolimus in healthy volunteers

Sirolimus and tacrolimus are immunosuppressive compounds that have been used concomitantly in renal transplant patients. Both drugs are dosed orally and have common intestinal and hepatic metabolism and intestinal transport mechanisms. As such, there is a potential for pharmacokinetic drug interaction. A single-dose, open-label, four-period, four-treatment, randomized crossover study was conducted in 27 healthy fasting volunteers. Each subject received a 15-mg oral dose of sirolimus alone, a 10-mg oral dose of tacrolimus alone, sirolimus and tacrolimus administered simultaneously, and tacrolimus administered 4 h before sirolimus. Whole blood and plasma samples for sirolimus and tacrolimus testing were analyzed by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters were assessed using noncompartmental methods and were compared using analysis of variance (ANOVA). The geometric mean ratio and 90 % confidence interval (CI) area under the concentration-time curve from time 0 to infinity (AUCinf) for sirolimus administered simultaneously with tacrolimus versus sirolimus alone were 97 and 89-106, respectively, and, when administered in a staggered approach versus sirolimus alone, 107 and 98-117, respectively. The geometric mean ratio (%) and 90 % CI AUCinf for tacrolimus administered simultaneously with sirolimus versus tacrolimus alone were 92 and 82-102, respectively, and, when administered in a staggered approach versus tacrolimus alone, 94 and 84-105, respectively. The results of this study demonstrate a lack of any clinically important drug interaction between sirolimus and tacrolimus in healthy subjects after single-dose administration. However, due to the complexity of anti-rejection immunosuppressive therapy dosing, we suggest that sirolimus and tacrolimus concentration monitoring be performed when changes in dosing are made for either drug regimen.

2262 PERSONALIZED INITIAL DOSE OF TACROLIMUS BASED ON THE CYP3A5 POLYMORPHISM AND ITS IMPACT ON THE 1-MONTH GRAFT FUNCTION: A PRELIMINARY EXPERIENCE

INTRODUCTION AND OBJECTIVES: Patients with CYP3A5*1 allele (CYP3A5 expressers) require a higher daily tacrolimus dose than those with CYP3A5*3/*3 genotype (non-expressers) in order to maintain target trough levels (C0) (Tsuchiya, Transplantation, 2004). Recently, we reported that renal cortical interstitial fibrosis (IF) from 0-hour to 1-year post-transplantation increased in non-expressers than CYP3A5 expressers. Unexpected highly tacrolimus levels in non-expressers might influence the development of IF, despite therapeutic drug monitoring (Miura, Transplantation 2011). Therefore, since January 2011, we have started to a personalized initial dosing regimen of controlled-release tacrolimus based on the CYP3A5 polymorphism. The present study investigated the impact of personalized regimen of tacrolimus on the pharmacokinetics and 1-month graft function comparing to the non-personalized regimen. METHODS: Initial oral doses of tacrolimus were 0.20mg/kg for CYP3A5 expressers and 0.10mg/kg for non-expressers. In the nonpersonalized regimen, all patients received 0.20mg/kg of tacrolimus. The target trough levels of tacrolimus were same between the two regimes. RESULTS: Twenty patients were involved in the personalized regimen; CYP3A5 expressers in 6 and non-expressers in 14 cases. Twenty-five patients were in involved in the non-personalized regimen; CYP3A5 expressers in 10 and non-expressers in 15 cases. In the non-personalized regimen, C0 and area under the blood concentrationtime curve (AUC) of tacrolimus and estimated glomerular filtration rate (eGFR) in CYP3A5 expressers and non-expressers were: C0 (4.8 vs. 8.5 ng/ml, p 0.001) and AUC (218 vs. 373 nghr/ml, p 0.001) at day 1 after first administration of tacrolimus, C0 (5.4 vs 7.8 ng/ml, p 0.004) and AUC (218 vs 287 nghr/ml, p 0.013) and eGFR (59.2 vs 42.4 ml/min/1.73m2, p 0.028) at day 28 post-transplantation. In the personalized regimen, C0 and AUC of tacrolimus and eGFR in CYP3A5 expressers and non-expressers were; C0 (6.9 vs 2.7 ng/ml, p 0.279) and AUC (377 vs 136 nghr/ml, p 0.268) at day 1, C0 (8.9 vs 5.2 ng/mL, p 0.0270) and AUC (332 vs 226 nghr/mL, p 0.073) and eGFR (47.7 vs 64.6 ml/min/1.73m2, p 0.202) at day 28. CONCLUSIONS: The personalized medicine of tacrolimus based on the CYP3A5 polymorphism may decrease the pharmacokinetic difference between CYP3A5 expressers and non-expressers, and it may contribute better graft function in non-expressers in the early post-transplantation.

Pharmacokinetic Differences Corroborate Observed Low Tacrolimus Dosage in Native American Renal Transplant Patients

We have observed in clinical practice that Native Americans require lower dosages of tacrolimus to attain similar target blood trough levels compared to whites after renal transplant. Because there are no pharmacokinetic studies of tacrolimus in this ethnic group, we investigated whether this clinical observation could be corroborated by pharmacokinetic differences between Native Americans and other ethnic and racial groups. We recruited 24 adult Native American kidney transplant recipients on stable oral doses of tacrolimus for at least 1 month posttransplant. We conducted a 12-h steady-state pharmacokinetic profile for all of the patients and estimated pharmacokinetic parameters using NONMEM. The concentration-time data were fit to a linear two compartment model with first-order absorption and lag time using an empirical Bayesian approach. The mean estimate of oral clearance (CL/F) was 11.1 l/h. Compared with previously reported data in other ethnic and racial groups, the Native American cohort has approximately one third the clearance of other groups. Our pharmacokinetic study reveals the clinically observed low dose of tacrolimus in Native American renal transplant patients is associated with a decreased oral tacrolimus clearance. There is scant information available on the genetic or environmental characteristics unique to this ethnic group that affect pharmacokinetics compared to other, better-studied groups, and elucidation of these factors will provide information to further facilitate individualized drug treatment for tacrolimus and a wide range of other drugs with similar clearance processes.

Clinical Pharmacokinetics of Tacrolimus after the First Oral Administration in Renal Transplant Recipients on Triple Immunosuppressive Therapy

Monitoring of tacrolimus blood concentration is of utmost importance in the management of renal transplant recipients because of Narrow Therapeutic Index and highly variable pharmacokinetics. The aim of this study was to detect inter-patient pharmacokinetic variability of tacrolimus and to assess the predictability of individual tacrolimus concentrations at various times of the area under the curve (AUC) seeking to find the best sampling time to predict the exposure of tacrolimus in renal transplant recipients with triple therapy. This oral dose tacrolimus pharmacokinetics study was conducted in 18 Serbian renal transplant recipients on triple immunosuppressive therapy, including basiliximab. The first oral dose of tacrolimus (0.05 mg/kg) was given on day 5 post-transplant; blood concentration was measured by microparticle enzyme immunoassay method. Associations between each sampling time-point of concentrations and AUC(12) were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple, stepwise regression analyses. The variance in the strength of association between predicted AUC (AUC(p)) and AUC(12) was reflected by linear regression coefficients. AUC(12) showed remarkable inter-individual variations after the first oral dose of tacrolimus. The area of the maximum AUC was four times higher than that of the minimum AUC. C(4) seems to be an indicator of total body exposure to tacrolimus. Alternatively, the concentrations at 1.5, 4 and 8 hr as an abbreviated AUC were as good a predictor as a full pharmacokinetic study. Our results show a significant difference between men and women. A three-point sampling method seemed to be the best abbreviated AUC for a cost-effective tacrolimus monitoring strategy.

Interindividual Variation of Maximal Blood Levels of Tacrolimus After Its Oral Administration in Hematopoietic Cell Transplant Recipients

We investigated the pharmacokinetics of oral tacrolimus in 31 hematopoietic cell transplant recipients, identifying 2 subgroups based on the differences between C 0 (trough) and C max (maximal) levels: group A (n = 21; 68%) with a C max-C 0 value of <10 ng/mL, and group B (n = 10; 32%) with a C max-C 0 value of ≥10 ng/mL. Although the C 0 and C 12 values were not significantly different between the 2 groups, the mean area under the concentration curve for 12 hours (AUC 0–12) was significantly greater in group B than group A (200.9 ± 36.3 vs 155.1 ± 43.1 ng · h/mL; P < .05), and the mean half-life was significantly shorter in group B than group A (13.55 ± 6.70 vs 18.17 ± 6.30 hours; P < .05). Thus after the oral administration of tacrolimus, we observed a notably high AUC due to high peak level, which we were unable to predict simply by measuring the trough level. A pharmacokinetic analysis of each patient was essential to optimize the oral tacrolimus dose.

Combination therapy with oral tacrolimus (FK506) and azathioprine or 6-mercaptopurine for treatment-refractory Crohn's disease perianal fistulae

Our aim was to report the clinical experience with combination treatment using tacrolimus and either azathioprine (AZA) or 6-mercaptopurine (6MP) in patients with Crohn's disease (CD) perianal fistulae. The medical records of all patients with Crohn's disease perianal fistulae seen at the Mayo Clinic from 1996-1998 who were treated with tacrolimus were reviewed. Clinical response was classified as: complete response, partial response, and nonresponse. Eleven patients were treated with oral tacrolimus for a mean duration of 22 weeks. The initial oral dose of tacrolimus ranged from 0.15 to 0.31 mg/kg/day. Azathioprine or 6MP was continued in combination with tacrolimus in seven patients and initiated simultaneously with tacrolimus in four patients. All patients improved clinically, seven had a complete response, and four had a partial response. The mean time to initial improvement was 2.4 weeks, and the mean time to complete response was 12.2 weeks. The most frequent adverse events were nausea, paresthesias, nephrotoxicity, and tremor. Patients with nephrotoxicity had a significantly higher mean initial tacrolimus dose (0.31 mg/kg/day) compared with patients who did not have nephrotoxicity (0.25 mg/kg/day) (p = 0.035); however, there was not a statistically significant association between the starting dose or mean blood level and clinical response. Combination therapy with oral tacrolimus and AZA or 6MP may be effective treatment for CD perianal fistulae. Higher initial tacrolimus doses increase the risk of nephrotoxicity without improving clinical response.

A nomogram for predicting the optimal oral dosage of tacrolimus in liver transplant recipients with small‐for‐size grafts

No optimal tacrolimus dosage regimen suitable for clinical use in liver transplant recipients has yet been established. The purpose of this study was to determine the factors affecting the optimal dosage and pharmacokinetics of tacrolimus in living donor liver transplantation, and a nomogram for optimal tacrolimus dosage in the immediate postoperative period for recipients with small-for-size grafts was constructed. Twenty-four liver transplant patients (nine males and 15 females) and 24 donors (10 males and 14 females) were enrolled in this study. Two studies were performed. In study 1, the effect of the actual ratio of graft volume to standard liver volume (GV/SV ratio) on the elimination half-life (T1/2) of tacrolimus in the immediate postoperative period was analysed, and a nomogram for estimating the optimal oral dose of tacrolimus required to reach a target concentration was established. In study 2, the effect of donor age on the recovery of hepatic function with ability of the graft to eliminate tacrolimus was analysed. In the immediate postoperative period, T1/2 of tacrolimus showed great variability between patients, with values ranging from 16.3 to 110.9 h. Graft size (GV/SV ratio) is important and could influence intraindividual variations in the optimal dosage and T1/2 of tacrolimus. The recovered T1/2 ratio (T1/2 ratio=T1/2 1-10 d/T1/2 30-40 d), this ratio being related to the recovery of hepatic function with ability of the graft to eliminate tacrolimus, showed great variability between patients, with values ranging from 1.08 to 4.21 (mean+/-SD, 1.95+/-0.81). Age of the donor is a major factor affecting the recovered ratio of the graft to metabolize tacrolimus. The nomogram that we have constructed, based on graft size (GV/SV ratio), will easily provide optimal dose for each patient with small-for-size graft in the early postoperative period.

Effect of hepatitis C infection on tacrolimus doses and blood levels in liver transplantation recipients

In our cohort of patients with hepatitis-C virus, which is the most common indication for liver transplantation, we have noted higher relative blood levels of tacrolimus compared to patients without hepatitis-C virus. To verify this observation and determine its clinical significance, we performed a comparison of doses and blood levels of tacrolimus in hepatitis-C virus and non- hepatitis-C virus liver transplantation recipients. Tacrolimus dose and trough level, as well as mean alanine aminotransferase, for all patients transplanted at our center with a deceased donor between 1/1995 and 12/1999 with hepatitis-C virus were recorded at monthly intervals during the first 24 months following transplantation and compared to patients without hepatitis-C virus. The tacrolimus levels for hepatitis-C virus and non-hepatitis-C virus patients were not significantly different at any of the monthly intervals, except month 9. In addition, the overall mean tacrolimus levels for hepatitis-C virus and non-hepatitis-C virus patients were not significantly different (P = ns). However, the mean tacrolimus dose (mg/kg) was significantly higher for hepatitis-C virus patients at 12, 15, 18, 21 and 24 months, P < 0.01. The total mean tacrolimus dose in hepatitis-C virus patients was lower during year one by 39% (P = 0.018) and by 73% (P = 0.001) during year two. The total difference in cost of tacrolimus (for year one and two) administered to hepatitis-C virus patients was $4920, P = 0.03. The serum alanine aminotransferase was significantly higher in hepatitis-C virus patients at each monthly interval except month 1, P < or = 0.01. Liver transplant recipients with hepatitis-C virus require significantly lower oral doses of tacrolimus to achieve the same blood levels compared to non-hepatitis-C virus patients. This difference may result in a significant reduction in the cost of tacrolimus in hepatitis-C virus patients. The most likely explanation for these findings is decreased hepatic clearance of tacrolimus caused by mild hepatic injury from recurrent hepatitis-C virus.

Initial Dosage Adjustment for Oral Administration of Tacrolimus Using the Intestinal MDR1 Level in Living-Donor Liver Transplant Recipients

The role of intestinal P-glycoprotein (encoded by the MDR1/ ABCB1 gene) and/or metabolic enzyme CYP3A4 for tacrolimus therapy was examined in recipients of living-donor liver transplantation (LDLT), under the hypothesis that these proteins are factors for pharmacokinetic variability. The intestinal mRNA expression level of MDR1 and CYP3A4 was evaluated by real-time polymerase chain reaction (PCR), using the upper jejunum from a part of the Roux-en-Y limb for biliary reconstruction at LDLT. For 7 days postoperatively, good inverse correlation was found between the tacrolimus concentration/dose (C/D) ratio and the intestinal mRNA level of MDR1 ( r = −0.776), but not of CYP3A4 ( r = −0.096), in the 46 cases. After classifying the patients according to median of the intestinal MDR1 mRNA expression, the oral dose of tacrolimus in the high-MDR1 group was approximately twofold higher than in the low-MDR1 group ( P < .001), whereas its trough level was similar between the two groups. In addition, the correlation between the intestinal MDR1 mRNA level and the tacrolimus C/D ratio was confirmed with a larger population ( r = −0.645, n = 104). Using the regression line between the intestinal MDR1 mRNA level and tacrolimus C/D ratio, we could prospectively predict the individual C/D ratio of tacrolimus immediately after LDLT. Known genetic variations of the MDR1 gene had no effect on intestinal MDR1 mRNA level and tacrolimus C/D ratio in LDLT patients. This suggests that the intestinal mRNA level of MDR1 is a useful molecular marker for determination of the personalized oral dose of tacrolimus in recipients of LDLT immediately after surgery.