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Tacrolimus is the most commonly used immunosuppression drug after solid organ transplantation; however, its dosing is challenging due to substantial inter-individual variability, often resulting in blood levels that deviate from the target therapeutic range. We explored whether a dynamically customized, phenotypic-outcome-guided drug dosing method could improve maintenance of drug trough levels within pre-determined target ranges, focusing on tacrolimus immediately after liver transplantation. This single-center, partially blinded, completed clinical trial involved 62 adults undergoing liver transplantation, block randomized into parallel groups: standard-of-care (SOC) clinician-determined or Phenotypic Personalized Medicine (PPM)-guided tacrolimus dosing. The primary outcome was percentage of post-transplant days with large (>2 ng/mL) deviations from the target range. At trial completion, analysis found statistically significant improvement in the PPM group ( n  = 27): 24.2% of days showing large deviations compared to 38.4% in the SOC group ( n  = 29) (difference −14.2%, 95% CI: −26.7 to −1.5 %, P  = 0.029) with no increase in adverse events. These results demonstrate that PPM-guided tacrolimus dosing more effectively maintains drug levels within the target range compared to SOC, suggesting a promising approach to improving drug dosing. The trial was registered at ClinicalTrials.gov with the identifier NCT03527238. Tacrolimus is a critical immunosuppressant for liver transplant recipients, but its dosing is challenging due to individual variability. Here, the authors show that a phenotypic personalized medicine approach improves tacrolimus dosing precision, reducing large deviations from target levels and shortening hospital stays in a Phase 2 randomized trial.

Tacrolimus is metabolized in the liver with the participation of cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5). Omeprazole, unlike famotidine, is a substrate and inhibitor of CYP2C19, CYP3A4, CYP3A5 enzymes. The aim of the study is to compare the effect of omeprazole and famotidine on the tacrolimus concentration and the kidney transplant function. A randomized study was conducted in 24 adult patients with stable kidney transplant function who received a standard triple immunosuppression regimen. Patients were assigned to the group I (n = 12) additionally receiving omeprazole (20 mg) or the group II (n = 12) receiving famotidine (20 mg). At the time of qualification and during follow-up visits, tacrolimus blood concentration and selected laboratory tests were performed. Statistical analysis was performed using the MedCalc system. The value of tacrolimus concentration in the blood increased after a year in the group I (7.27 ± 2.33 vs 9.20 ± 2.46 ng/mL, p = 0.0478). A reduction in tacrolimus dosage was observed after three years in the group I (3.56 ± 1.75 vs 2.78 ± 1.00 mg, p = 0.0440) and in the group II (2.72 ± 0.84 vs 2.10 ± 0.48 mg, p = 0.0051). There was significant difference in the percentage changes of glomerular filtration rate between the groups after 3 years of the study (− 5.56% vs 9.13%, p = 0.0343). Omeprazole significantly change the concentration of tacrolimus in the blood when administered together with tacrolimus after one year of observation. There was no effect of famotidine or omeprazole on the function of the kidney transplant. ClinicalTrials.gov identifier: NCT05061303.

Background and aims: Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis (UC), while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies. Methods: Patients with refractory active UC were randomly assigned to a high trough concentration (10–15 ng/ml) group (HT group) (n = 21), low trough concentration (5–10 ng/ml) group (LT group) (n = 22), or placebo group (n = 20). Patients received an initial oral dose of 0.05 mg/kg tacrolimus or placebo twice daily. Efficacy was evaluated in 60 patients based on a disease activity index (DAI) score. Fifty eight patients had additional treatment with tacrolimus and were evaluated for efficacy in a 10 week open label extension. Results: An improvement in DAI score (⩾4 points, all categories improved) was observed for 68.4% of cases in the HT group compared with 10.0% in the placebo group (p<0.001). In the HT group, 20.0% of patients had clinical remission and 78.9% had mucosal healing. In the open label extension, 55.2% of all patients had an improved DAI score at week 10. Mean dose of prednisolone was reduced from 19.7 mg/day at study entry to 7.8 mg/day at week 10. The incidence of side effects in the HT group was significantly higher than that of the placebo group (p = 0.043). The most common event was mild finger tremor. Conclusions: Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC. The optimal target range appears to be 10–15 ng/ml in terms of efficacy with two week therapy.

Background and Objectives Tacrolimus PR is a new prolonged-release once-daily formulation of the calcineurin inhibitor tacrolimus, currently used in adult transplant patients. As there are no pharmacokinetic data available in pediatric kidney transplant recipients, the aims of this study were to develop a population pharmacokinetic model of tacrolimus PR in pediatric and adolescent kidney transplant recipients and to identify covariates that have a significant impacts on tacrolimus PR pharmacokinetics, including CYP3A5 polymorphism. Methods Pharmacokinetic samples were collected from 22 pediatric kidney transplant patients. Population pharmacokinetic analysis was performed using NONMEM. Pharmacogenetic analysis was performed on the CYP3A5 gene. Results The pharmacokinetic data were best described by a one-compartment model with first order absorption and lag-time. The weight normalized oral clearance CL/F [CL/F/ (weight/70) 0.75 ] was lower in patients with CYP3A5*3/*3 as compared to patients with the CYP3A5*1/*3 (32.2 ± 10.1 vs. 53.5 ± 20.2 L/h, p = 0.01). Conclusions The population pharmacokinetic model of tacrolimus PR was developed and validated in pediatric and adolescent kidney transplant patients. Body weight and CYP3A5 polymorphism were identified as significant factors influencing pharmacokinetics. The developed model could be useful to optimize individual pediatric tacrolimus PR dosing regimen in routine clinical practice.

PurposeTacrolimus is distributed mainly in red blood cells (RBCs) after transfer into blood. This study aimed to evaluate the effect of FK506-binding proteins (FKBPs) on RBC distribution of tacrolimus in a physiological environment.MethodsHuman RBCs were isolated from fresh blood samples from healthy volunteers. The effect of FKBPs on each process of the RBC distribution of tacrolimus was evaluated in vitro. Effect of intracellular FKBPs was assessed by inhibition experiment with rapamycin, which competitively inhibits the binding of tacrolimus to FKBPs. Effect of extracellular FKBPs was examined by pre-exposure of RBCs to FKBP and preincubation of tacrolimus with FKBP.ResultsPretreatment with rapamycin significantly reduced the rate of tacrolimus distribution in RBCs in a concentration-dependent manner. Pre-exposure of RBCs to FKBP12 followed by exposure to tacrolimus significantly decreased tacrolimus distribution in RBCs in a concentration-dependent manner. In addition, preincubation of tacrolimus with FKBP12 significantly reduced the rate of tacrolimus distribution in RBCs.ConclusionsFKBP played an important role in the distribution of tacrolimus in RBCs. The effect of intracellular and extracellular FKBPs on RBC distribution of tacrolimus in circulating blood was substantial. FKBP was shown as a potential biomarker for predicting the pharmacokinetics and pharmacodynamics of tacrolimus.

We evaluated the efficacy and safety of tacrolimus in patients receiving glucocorticoid therapy for lupus nephritis. Patients with persistent nephritis were randomized to receive 28 weeks of double-blind treatment with tacrolimus (3 mg/day) or placebo. The primary endpoint was the change in the lupus nephritis disease activity index (LNDAI) calculated from scores for daily urinary protein excretion, urinary red cells, serum creatinine, anti-double-stranded DNA antibody, and serum complement. Statistical analysis was performed using the full analysis set. The LNDAI was decreased by 32.9 ± 31.0% (mean ± SD) in the tacrolimus group ( n  = 28) and was increased by 2.3 ± 38.2% in the placebo group ( n  = 35) at final evaluation. There was significant improvement in the tacrolimus group. Daily urinary protein excretion showed a significant decrease in the tacrolimus group ( p  < 0.001). The complement (C3) level showed a significant increase in the tacrolimus group ( p  = 0.001). Treatment-related adverse events occurred in 92.9% of the tacrolimus group and 80.0% of the placebo group, but the difference was not significant. In patients on glucocorticoid therapy for lupus nephritis, addition of tacrolimus to basal therapy achieved significant improvement compared with placebo. Tacrolimus may therefore be a useful alternative treatment for lupus nephritis.

Purpose Solid-organ transplant recipients present a high rate of non-adherence to drug treatment. Few interventional studies have included approaches aimed at increasing adherence. The objective of this study was to evaluate the impact of an educational and behavioral strategy on treatment adherence of kidney transplant recipients. Methods In a randomized prospective study, incident renal transplant patients ( n  = 111) were divided into two groups: control group (received usual transplant patient education) and treatment group (usual transplant patient education plus ten additional weekly 30-min education/counseling sessions about immunosuppressive drugs and behavioral changes). Treatment adherence was assessed using ITAS adherence questionnaire after 3 months. Renal function at 3, 6, and 12 months, and the incidence of transplant rejection were evaluated. Results The non-adherence rates were 46.4 and 14.5 % in the control and treatment groups ( p  = 0.001), respectively. The relative risk for non-adherence was 2.59 times (CI 1.38–4.88) higher in the control group. Multivariate analysis demonstrated a 5.84 times (CI 1.8–18.8, p  = 0.003) higher risk of non-adherence in the control group. There were no differences in renal function and rejection rates between groups. Conclusions A behavioral and educational strategy addressing the patient’s perceptions and knowledge about the anti-rejection drugs significantly improved the short-term adherence to immunosuppressive therapy.

Purpose The interactions between grapefruit juice (GFJ) and tacrolimus (FK506) metabolism remain obscure. The aim of this prospective study was to explore the effect of GFJ on the blood concentration of FK506 in liver transplant patients. Methods Thirty liver transplant patients were enrolled in the study 1 month post-transplant and randomly divided into three equal-sized groups. Group A patients were treated with the standard FK506-based immunosuppressant regimen only and therefore served as the control; group B and C patients were treated with the standard FK506-based immunosuppressant regimen as well as one of two different kinds of GFJ, respectively. The blood concentrations of FK506 on the seventh day after GFJ intake were compared within each group and among groups. The dose of FK506 was adjusted depending on the valley concentration measured to a treatment window. Results The blood concentration of FK506 in both group B and group C patients was significantly enhanced, by 1.56 ± 0.95 and 10.33 ± 5.59 ng/ml, respectively, following the administration of GFJ for 1 week (compared with the concentration at the start of the experiment in each group; p  < 0.05). However, at the end time point, the blood concentration of FK506 in group C patients was significantly increased ( p  < 0.05) relative to that of the control patients, while this was not the case in group B patients ( p  > 0.05). Group C patients could be treated with a smaller dose of FK506 (decreased by 2.3 ± 1.3 mg/day for all patients; p  = 0.011), amounting to a decrease in drug costs of approximately $8.70 ± 5.60/day ( p  = 0.011). Conclusion In the setting of a controlled clinical study, the co-administration of GFJ with FK506 increased the bioavailability of FK506. However, the concentration of tacrolimus should be closely monitored and the dose adjusted to the treatment window.

Background: The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) were prospectively examined in steroid-dependent or steroid-resistant primary focal segmental glomerulosclerosis (FSGS). Methods: Patients with biopsy-proven FSGS were enrolled and randomly divided into two groups: CTX and TAC. Patients treated with CTX (0.5–0.75 g/m 2 ·month, i.v.) received prednisone at 0.8 mg/kg·day, while patients treated with TAC (0.1 mg/kg·day) received prednisone at 0.5 mg/kg·day. The plasma concentration of TAC was monitored and maintained at 5–10 ng/ml. After a 6-month treatment the patients were evaluated. Patients with complete remission (CR) and partial remission (PR) continued the treatment for 12 months with the dose tapered, whereas the patients with no response were excluded from the study and underwent an alternative treatment. Results: A total of 33 patients were recruited and 27 completed the 12-month follow-up. The TAC-treated patients (n = 15) showed a quick remission. The initial remission time averaged 1.23 ± 0.21 versus 2.21 ± 0.77 months in the CTX group (n = 18), but no significant difference was achieved (p > 0.05). At 6 months, the two groups showed a similar outcome. Ten patients from each group showed remission (7 CR and 3 PR). At 12 months, the CTX group had 9 CR and 3 PR while the TAC group had 6 CR and 5 PR. Remission rates in TAC tended to be higher than that in CTX, but there was no difference. CTX patients had a high prevalence of infections (50.0 vs. 13.3% in TAC, p < 0.05). In contrast, TAC-treated patients showed a high incidence of hyperglycemia (26.7 vs. 0.0% in CTX, p < 0.05). Conclusion: These results suggest that CTX and TAC had a similar efficacy in steroid-dependent and steroid-resistant FSGS as manifested by reduced proteinuria, improved serum albumin level and renal function.