Evaluating the evidence for genotype-informed Bayesian dosing of tacrolimus in children undergoing solid organ transplantation: A systematic literature review.

Tacrolimus, a calcineurin inhibitor, is a highly effective immunosuppressant used in solid organ transplantation (SOT). However, it is characterized by a narrow therapeutic range and high inter-patient variability in pharmacokinetics. Standard weight-based dosing followed by empiric dose titration is suboptimal in controlling drug concentrations, increasing risk of rejection or toxicity, particularly in the initial months post transplantation. This review explores the potential of combined pre-transplant genotyping and pharmacokinetic (PK) modelling to improve tacrolimus dosing in paediatric SOT recipients. A systematic search of Medline, Embase and Cochrane databases identified studies published between March 2013 and March 2023 that investigated genotype- and PK model-informed tacrolimus dosing in children post-SOT. The Newcastle-Ottawa Scale assessed study quality. Seven studies encompassing paediatric kidney, heart, liver and lung transplants reported using genotype and model-informed dosing. A combination of clinical and genetic factors significantly impacts tacrolimus clearance and thus initial dose recommendation. Body size, transplant organ and co-medications were consistently important, while either time post-transplant or haematocrit emerged in some studies. Several models were identified, however, with limitations evident in some and with absence of evidence for their effectiveness in optimizing initial and subsequent dosing. This review highlights the development of PK models in paediatric SOT that integrate genotype and clinical covariates to personalize early tacrolimus dosing. While promising, prospective studies are needed to validate and confirm their effectiveness in improving time to therapeutic concentrations and reducing under- or overexposure. This approach has the potential to optimize tacrolimus therapy in paediatric SOT, thereby improving outcomes.

Tacrolimus related diabetic ketoacidosis and hyperglycaemic hyperosmolar nonketotic syndrome: an observational, retrospective, pharmacovigilance study.

BACKGROUND: Information on the incidence and risk factors for diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar nonketotic syndrome (HHNS) caused by tacrolimus has rarely been reported. This study aims to assess the spectrum of DKA/HHNS associated with tacrolimus. METHODS: We conducted an observational, retrospective pharmacovigilance study using the Food and Drug Administration adverse event reporting system (FAERS) database. We employed the information component (IC) and reporting odds ratio (ROR) to evaluate the association between tacrolimus and DKA/HHNS. RESULTS: A total of 232 events were identified as tacrolimus-related DKA/HHNS, 186 cases from DKA and 54 cases from HHNS. The frequency of tacrolimus-associated DKA and HHNS was found to be significantly higher compared to all other drugs. Specifically, HHNS was significantly associated with tacrolimus based on its ROR and IC. There were no significant differences in death and non-death cases in gender, age group, year of reporting and region of reporting. CONCLUSION: Our study showed that DKA and HHNS were associated with tacrolimus use. Healthcare professionals should be aware of the possibility of DKA/HHNS following tacrolimus administration, as they were associated with an increased risk of mortality in transplant recipients.

A randomized controlled trial comparing tacrolimus versus hydrocortisone for the treatment of atopic dermatitis in children: new perspectives on interferon gamma-induced protein and growth-related oncogene-α.

Introduction: Atopic dermatitis (AD) is a type of chronic inflammatory disorder that affects children. Aim: To investigate whether hydrocortisone or tacrolimus could be more effective for treating AD in children. Patients and methods: This clinical randomized investigation included 100 children with AD who met the eligibility criteria. AD patients were recruited from Tanta University's Dermatology Department and divided into two groups (n = 50)., For four months, group 1 (the hydrocortisone group) received topical hydrocortisone cream. Group 2 received topical tacrolimus for four months. A dermatologist evaluated the patients at the start and four months after the treatment had been initiated to measure serum concentrations of neutrophil chemoattractant growth-related oncogene-α (GRO-α), interferon gamma induced protein 10 (IP-10), tumor necrosis factor alpha (TNF-α), vascular adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1). All patients were examined using the modified Eczema Area and Severity Index (mEASI) score. Results: Tacrolimus group showed a significant reduction in serum levels of all measured biomarkers (p < 0.05) when compared to its baseline and when compared to the hydrocortisone group. Both groups displayed a significant decline in mEASI score in comparison with their baseline values (p < 0.05). Conclusion: In children with AD, tacrolimus reduces inflammatory biomarkers better than hydrocortisone, suggesting its potential as a more effective treatment option. Clinical trial registration: https://clinicaltrials.gov, identifier NCT05607901.

COMPARISON OF THREE STRATEGIES OF GVHD PROPHYLAXIS AFTER T-CELL REPLETE HAPLOIDENTICAL HEMATOPOIETIC TRANSPLANTATION: TACROLIMUS vs. CALCINEURIN INHIBITORS-MMF vs. SIROLIMUS-MMF.

Since the introduction of post-transplant cyclophosphamide (PTCy), haploidentical HSCT (HaploSCT) has become a real alternative for patients who lack other eligible donors. The standard GvHD prophylaxis after PTCy has been a calcineurin inhibitor plus MMF (up to day+35), but promising results with sirolimus (+/- MMF) and single-agent tacrolimus have been recently published. The current multicenter retrospective study compared the outcomes of 372 adult HaploSCT recipients who received TBF conditioning; PTCY and additional GVHD prophylaxis with one of three strategies, cohort-A: single-agent tacrolimus (N 222), cohort-B: CNI-MMF (N 49) and cohort-C: sirolimus-MMF (N 101). No differences in terms of grade II-IV (20%, 25%, and 30%) and III-IV (9%, 6%, and 15%) aGvHD at 100 days were found. However, cohort A had the lowest incidence of overall cGvHD [24%, 47%, and 52%, respectively (p 0.001)] and moderate-severe cGvHD [13%, 35%, and 33%, respectively (p 0.001)]. There were no differences in the 3-year overall survival, progression-free survival, NRM nor relapse among the cohorts. In conclusion, our study suggests that single-agent tacrolimus, CNI+MMF and sirolimus+MMF GvHD prophylaxis lead to similar outcomes following HaploSCT with TBF and PTCy, with low incidence of grade III-IV aGvHD, albeit possible differences in cGVHD require further investigation.

Pharmacogenetics of Calcineurin inhibitors in kidney transplant recipients: the African gap. A narrative review.

Calcineurin inhibitors (CNIs) are the mainstay of immunosuppression in kidney transplantation. Interpatient variability in the disposition of calcineurin inhibitors is a well-researched phenomenon and has a well-established genetic contribution. There is great diversity in the makeup of African genomes, but very little is known about the pharmacogenetics of CNIs and transplant outcomes. This review focuses on genetic variants of calcineurin inhibitors' metabolizing enzymes (CYP3A4, CYP3A5), related molecules (POR, PPARA) and membrane transporters involved in the metabolism of calcineurin inhibitors. Given the genetic diversity across the African continent, it is imperative to generate pharmacogenetic data, especially in the era of personalized medicine and emphasizes the need for studies specific to African populations. The study of allelic variants in populations where they have greater frequencies will help answer questions regarding their impact. We aim to fill the knowledge gaps by reviewing existing research and highlighting areas where African research can contribute.

Research on the pharmacogenetics of calcineurin inhibitors in kidney transplant recipients is truly wanting in data from the African continent. Given Africa's vast genetic diversity, it is necessary to intensify efforts to generate data from Africa in this field.

Reversible cerebral vasoconstriction syndrome post-cardiac transplantation: a therapeutic dilemma: case report.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by diffuse, multifocal segmental narrowing of cerebral arteries and can result in ischaemic stroke. Causal factors, identified in 60% of cases, include immunosuppressant pharmacotherapy. The few reports following heart transplantation are almost all in Asian recipients. We report on a Caucasian Australian patient with immunotherapy induced RCVS post heart transplantation to highlight the state of knowledge of the condition and the treatment dilemma it poses. CASE PRESENTATION: A 51-year-old female underwent orthotopic heart transplantation at our institution. Induction immunotherapy comprised basiliximab, mycophenolate mofetil and methylprednisolone. On day 6 post-transplantation the patient was transitioned to oral prednisolone and tacrolimus. On day 7 the patient began to experience bilateral, severe, transient occipital and temporal headaches. On day 9 tacrolimus dose was up-titrated. A non-contrast computed tomography brain (CTB) was normal. Endomyocardial biopsy on day 12 demonstrated moderate Acute Cellular Rejection (ACR), which was treated with intravenous methylprednisolone. That evening the patient experienced a 15-minute episode of expressive dysphasia. The following morning she became confused, aphasic, and demonstrated right sided neglect and right hemianopia. A CT cerebral perfusion scan demonstrated hypoperfusion in the left middle cerebral artery (MCA) territory and cerebral angiography revealed widespread, focal multi-segmental narrowing of the anterior and posterior circulations. A diagnosis of RCVS was made, and nimodipine was commenced. As both steroids and tacrolimus are potential triggers of RCVS, cyclosporin replaced tacrolimus and methylprednisolone dose was reduced. A further CTB demonstrated a large left MCA territory infarct with left M2 MCA occlusion. The patient made steady neurological improvement. She was discharged 34 days post-transplantation with mild residual right lower limb weakness and persistent visual field defect on verapamil, cyclosporine, everolimus, mycophenolate mofetil and prednisolone. CONCLUSION: Reversible cerebral vasoconstriction syndrome is rare after orthotopic heart transplantation. Until now, RCVS has been almost exclusively described in Asian recipients, and is typically caused by immunotherapy. The condition may lead to permanent neurological deficits, and in the absence of definitive treatments, early recognition and imaging based diagnosis is essential to provide the opportunity to remove the causal agent(s). Co-existent ACR, can pose unique treatment difficulties.

Can Pre-Transplant Psychometric Testing Predict Tacrolimus Intrapatient Variability After Living Kidney Transplantation?

OBJECTIVE: Tacrolimus intrapatient variability (Tac IPV) has been considered a marker for post-graft risk. We investigated pre-transplant psychometric testing to predict Tac IPV after living kidney transplantation. METHODS: Minnesota Multiphasic Personality Inventory-2 (MMPI-2) examined during pre-transplant evaluation by 102 recipients were analyzed. Subjects were divided into two groups, low IPV (L-IPV) and high IPV (H-IPV), by cutoffs of Tac IPV: median of 24 and value of 30. T-scores of MMPI-2 scales were used to analyze difference between L-IPV and H-IPV using independent t-tests. Stepwise multiple logistic regression was used to test whether MMPI-2 scales affected Tac IPV. Confusion matrix of logistic regression was used to explain statistical power. Cutoff values of significant scales for H-IPV were analyzed by constructing receiver operating characteristic curves. RESULTS: Hysteria (Hy) and depression (D) scale scores and Tac IPV were associated in IPV 24 (odds ratio [OR]: 1.08, p<0.01 for Hy; OR: 0.93, p<0.01 for D) and IPV 30 models (OR: 1.09, p<0.01 for Hy; OR: 0.92, p<0.01 for D). Paranoia (Pa) scale scores were associated with Tac IPV in IPV 24 model (OR=1.10, p<0.01) and were significantly higher in H-IPV 24 (p<0.01). F1 scores of confusion matrix in IPV 24 and 30 models were 0.70 and 0.71, respectively. Cutoffs of Hy, D, and Pa scales were 51, 57, and 47, respectively. CONCLUSION: MMPI-2 profile is suggested as a predictor for high Tac IPV after living kidney transplantation.

A tacrolimus-eluting nerve guidance conduit enhances regeneration in a critical-sized peripheral nerve injury rat model.

Critical-sized peripheral nerve injuries pose a significant clinical challenge and lead to functional loss and disability. Current regeneration strategies, including autografts, synthetic nerve conduits, and biologic treatments, encounter challenges such as limited availability, donor site morbidity, suboptimal recovery, potential immune responses, and sustained stability and bioactivity. An obstacle in peripheral nerve regeneration is the immune response that can lead to inflammation and scarring that impede the regenerative process. Addressing both the immunological and regenerative needs is crucial for successful nerve recovery. Here, we introduce a novel biodegradable tacrolimus-eluting nerve guidance conduit engineered from a blend of poly (L-lactide-co-caprolactone) to facilitate peripheral nerve regeneration and report the testing of this conduit in 15-mm critical-sized gaps in the sciatic nerve of rats. The conduit's diffusion holes enable the local release of tacrolimus, a potent immunosuppressant with neuro-regenerative properties, directly into the injury site. A series of in vitro experiments were conducted to assess the ability of the conduit to maintain a controlled tacrolimus release profile that could promote neurite outgrowth. Subsequent in vivo assessments in rat models of sciatic nerve injury revealed significant enhancements in nerve regeneration, as evidenced by improved axonal growth and functional recovery compared to controls using placebo conduits. These findings indicate the synergistic effects of combining a biodegradable conduit with localized, sustained delivery of tacrolimus, suggesting a promising approach for treating peripheral nerve injuries. Further optimization of the design and long-term efficacy studies and clinical trials are needed before the potential for clinical translation in humans can be considered.

Combination of reduced post-transplant cyclophosphamide and early tacrolimus initiation increases the incidence of chronic graft-versus-host disease in human leukocyte antigen-haploidentical peripheral blood stem-cell transplantation.

We evaluated the clinical impacts of the concurrent modification of post-transplant cyclophosphamide (PTCy) dose and tacrolimus (Tac)-initiation timing in 61 patients with human leukocyte antigen-haploidentical transplantation. Reduced-dose PTCy (80 mg/kg) was associated with a higher incidence of moderate-to-severe chronic graft-versus-host disease (GVHD) than standard-dose PTCy (100 mg/kg) (35.0% vs. 26.6%, p = 0.053). Notably, early-initiation Tac (day -1) increased moderate-to-severe chronic GVHD than standard-initiation Tac (day 5) in the reduced-dose PTCy group (p = 0.032), whereas Tac-initiation timing did not impact chronic GVHD in the standard-dose PTCy group. These data indicate that the combination of reduced-dose PTCy and early-initiation Tac can amplify chronic GVHD.

LCP-Tacrolimus Extended-Release (Envarsus XR) Use in Adolescent and Young Adult Solid Organ Transplant Recipients.

INTRODUCTION: Limited published experience describes once daily, extended-release tacrolimus (LCP-Tac) use in pediatric solid organ transplantation (SOT), particularly nonrenal SOT. LCP-Tac can simplify immunosuppression (IS) regimens, minimize immediate release-tacrolimus (IR-Tac)-associated adverse effects, and promote adherence. This study describes the successful use of LCP-Tac in adolescent and young adult (AYA) SOT populations. METHODS: A single-center, retrospective chart review of AYA SOT recipients (age < 25 years) converted from IR-Tac to LCP-Tac. Graft survival, biopsy-proven acute rejection (BPAR), infection rates, estimated glomerular filtration rate (eGFR), and pill burden were assessed at five time points postconversion (1, 3, 6, 12, and 24 months). Intrapatient variability of tacrolimus, as assessed by coefficient of variability (CV%), was also analyzed. RESULTS: Twenty-nine AYA SOT recipients (19 heart, 6 kidney, and 4 liver) were converted to LCP-Tac, with a median age of 17.4 years at conversion. Conversion, mainly due to perceived or identified medication nonadherence, occurred at a median of 5.4 years posttransplant. No graft loss occurred within 24 months of conversion, and BPAR incidence rate was consistent with previous reports for these populations. Only one patient experienced CMV infection. Renal function remained stable postconversion. CONCLUSION: Successful conversion from IR-Tac to LCP-Tac was demonstrated in AYA heart, kidney, and liver transplant recipients. These AYA SOT recipients experienced reduced pill burden and improved tacrolimus trough concentration variability. However, the impact on medication adherence warrants further investigation. Future research should explore the targeted use of LCP-Tac to enhance IS tolerability and medication adherence in young SOT populations.

Association between CYP3A5 Gene Polymorphism and Post-Transplant Acute Immune Rejection in Renal Transplant Recipients Receiving Tacrolimus Therapy: A Correlation Study.

BACKGROUND: Acute immune rejection remains a challenge in the post-transplant period, with approximately 7.8% of renal transplant recipients experiencing rejection episodes within the first year. Genetic polymorphisms in the CYP3A5 gene, which influences tacrolimus metabolism, have garnered interest regarding their association with clinical outcomes in renal transplantation. METHODS: This retrospective correlation study analysed clinical data from kidney transplant patients who received tacrolimus treatment at our hospital from June 2015 to June 2023. The presence of CYP3A5 gene polymorphisms, tacrolimus trough levels, and demographic and clinical data were collected and analysed. RESULTS: A total of 105 kidney transplant patients were included. Patients were divided into acute immune rejection (n = 56) and non-acute immune rejection (n = 49) groups. The distribution of CYP3A5 gene polymorphisms differed significantly between the acute rejection and non-acute rejection groups (p = 0.037). The acute rejection group exhibited a higher frequency of CYP3A5 *1/*1 or *1/*3 genotypes than the non-acute rejection group. No statistically significant differences were found in the tacrolimus trough levels between the two groups. Correlation analysis revealed a statistically significant correlation between CYP3A5 gene polymorphism and post-transplant acute immune rejection (r = 0.223, p < 0.05). CONCLUSIONS: This study demonstrated a significant association between CYP3A5 gene polymorphism and the risk of post-transplant acute immune rejection in renal transplant recipients receiving tacrolimus therapy. These findings highlighted the importance of genetic variability in tacrolimus metabolism when managing immunosuppressive therapy in transplant recipients.

Catatonia related to tacrolimus: a real world pharmacovigilance study of FDA adverse event reporting system (FAERS) database.

BACKGROUND: Emerging case reports have highlighted that catatonia may be a complication that is easily misdiagnosed. Our study aimed to summarize the clinical characteristics of patients with tacrolimus-induced catatonia and assess the association between tacrolimus and catatonia through disproportionality analysis. RESEARCH DESIGN AND METHODS: We conducted a retrospective pharmacovigilance study using the FAERS database, analyzing data up to the third quarter of 2023. The clinical characteristics of the reported cases were summarized using descriptive statistics. Information component (IC) and reporting odds ratio (ROR) were used to evaluate the association between tacrolimus and catatonia. RESULTS: There were 66 reports of tacrolimus-related catatonia, with the majority of cases occurring in the United States (78.79%). The risk signal for tacrolimus-related catatonia was significantly higher compared to all other drugs (ROR 3.222 [2.524, 4.111], IC 1.632 [1.273, 1.991]). A significant association was detected in both male and female, while the risk signal of tacrolimus-associated catatonia was only found in the subgroups aged over 40 years. CONCLUSIONS: Our study identified a safety signal for the association between tacrolimus and catatonia compared to all other drugs in FAERS database, particularly in patients aged 40 and above.

Cascading renal injury after brain death: Unveiling glycocalyx alteration and the potential protective role of tacrolimus.

Brain death (BD) is a complex medical state that triggers systemic disturbances and a cascade of pathophysiological processes. This condition significantly impairs both kidney function and structural integrity, thereby presenting considerable challenges to graft viability and the long-term success of transplantation endeavors. Tacrolimus (FK506), an immunosuppressive drug, was used in this study to assess its impact as a pretreatment on brain death-induced renal injury. This study aimed to investigate changes associated with brain death-induced renal injury in a 4-month-old female porcine model. The experimental groups included brain death placebo-pretreated (BD; n = 9), brain death tacrolimus-pretreated using the clinical dose of 0.25 mg/kg the day before surgery, followed by 0.05 mg/kg/day 1 hour before the procedure (BD + FK506; n = 8), and control (ctrl, n = 7) piglets, which did not undergo brain death induction. Furthermore, we aimed to assess the effect of FK506 on these renal alterations through graft preconditioning. We hypothesized that immunosuppressive properties of FK506 reduce tissue inflammation and preserve the glycocalyx. Our findings revealed a series of interconnected events triggered by BD, leading to a deterioration of renal function and increased proteinuria, increased apoptosis in the vessels, glomeruli and tubules, significant leukocyte infiltration into renal tissue, and degradation of the glycocalyx in comparison with ctrl group. Importantly, treatment with FK506 demonstrated significant efficacy in attenuating these adverse effects. FK506 helped reduce apoptosis, maintain glycocalyx integrity, regulate neutrophil infiltration, and mitigate renal injury following BD. This study offers new insights into the pathophysiology of BD-induced renal injury, emphasizing the potential of FK506 pretreatment as a promising therapeutic intervention for organ preservation, through maintaining endothelial function with the additional benefit of limiting the risk of rejection.

Enhanced eNOS/nitric oxide production by nebivolol interferes with TGF-ß1/Smad3 signaling and collagen I deposition in the kidney after prolonged tacrolimus administration.

AIMS: Tacrolimus is an effective immunosuppressant commonly used post-transplantation and in certain autoimmune diseases. However, its long-term administration is associated with renal fibrosis through transforming growth factor-beta/suppressor of mother against decapentaplegic (TGF-ß/Smad) signaling that could be partly attributed to endothelial dysfunction alongside decreased nitric oxide (NO) release. Our study aimed to investigate the prospective renal anti-fibrotic effect of enhanced NO production by nebivolol against tacrolimus stimulated TGF-ß1/Smad3 signaling. MATERIALS AND METHODS: To illustrate the proposed mechanism of nebivolol, Nω-nitro-L-arginine methyl ester (L-NAME); nitric oxide synthase inhibitor; was co-administrated with nebivolol. Rats were treated for 30 days as control, tacrolimus, tacrolimus/nebivolol, tacrolimus/L-NAME, and tacrolimus/nebivolol/L-NAME groups. KEY FINDINGS: Our results revealed that renal NO content was reduced in tacrolimus-treated rats, while treatment with tacrolimus/nebivolol enhanced NO content via up-regulated endothelial nitric oxide synthase (eNOS), but down-regulated inducible nitric oxide synthase (iNOS) expression. That participated in the inhibition of TGF-ß1/Smad3 signaling induced by tacrolimus, where the addition of L-NAME abolished the effects of nebivolol. Subsequently, the deposition of collagen I and alpha-smooth muscle actin (α-SMA) was retarded by nebivolol, emphasized by reduced Masson's Trichrome staining. In accordance, there was a strong negative correlation between eNOS and both TGF-ß1 and collagen I protein expression. The protective effects of nebivolol were further confirmed by the improvement in kidney function biomarkers and histological features. SIGNIFICANCE: It can be suggested that treatment with nebivolol along with tacrolimus could effectively suppress renal TGF-ß1/Smad3 fibrotic signaling via the enhancement of endothelial NO production, thus curbing renal fibrosis development.

Weight, CYP3A5 Genotype, and Voriconazole Co-administration Influence Tacrolimus Initial Dosage in Pediatric Lung Transplantation Recipients with Low Hematocrit based on a Simulation Model.

OBJECTIVE: The method of administering the initial doses of tacrolimus in recipients of pediatric lung transplantation, especially in patients with low hematocrit, is not clear. The present study aims to explore whether weight, CYP3A5 genotype, and voriconazole co-administration influence tacrolimus initial dosage in recipients of pediatric lung transplantation with low hematocrit based on safety and efficacy using a simulation model. METHODS: The present study utilized the tacrolimus population pharmacokinetic model, which was employed in lung transplantation recipients with low hematocrit. RESULTS: For pediatric lung transplantation recipients not carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-13, 13-19, 19-22, 22-35, 35-38, and 38-40 kg are 0.03, 0.04, 0.05, 0.06, 0.07, and 0.08 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-18, 18-30, and 30-40 kg are 0.06, 0.08, 0.11 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients not carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20 and 20-40 kg are 0.02 and 0.03 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20, 20-33, and 33-40 kg are 0.03, 0.04, and 0.05 mg/kg/day, which are split into two doses, respectively. CONCLUSION: The present study is the first to recommend the initial dosages of tacrolimus in recipients of pediatric lung transplantation with low hematocrit using a simulation model.

Effect of early post-hematopoietic stem cell transplant tacrolimus concentration on transplant outcomes in pediatric recipients: One facility's ten-year experience of immunosuppression with tacrolimus.

Acute graft-versus-host disease (GVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), ranking as the second leading cause of death among recipients, surpassed only by disease relapse. Tacrolimus is commonly used for GVHD prophylaxis, but achieving therapeutic blood levels is challenging, particularly in pediatrics, due to the narrow therapeutic window and the high interindividual variability. The retrospective study conducted at IRCCS "Burlo Garofolo" in Italy aimed to assess the impact of early post-HSCT tacrolimus levels on transplant-related outcomes in pediatric recipients. The population pharmacokinetic model (POP/PK) was set up to describe tacrolimus pharmacokinetics. Elevated tacrolimus (>12-15 ng/ml) levels within the initial weeks post-HSCT are associated with reduced post-transplant infections (p < 0.0001) and decreased incidence of early transplant-related events (p < 0.01), including a lower incidence of acute GVHD (p < 0.05 on day 0). High tacrolimus exposure can lead to an increased risk of chronic GVHD (p < 0.0001) and reduced overall survival (p < 0.01). Personalized dosing and therapeutic monitoring of tacrolimus are crucial to ensure optimal outcomes. POP/PK could help achieve this goal, giving us a model by which we can balance immunosuppression while looking at the patient's general well-being and providing the necessary treatment.

Recurrent rejections after liver transplantation for hepatocellular carcinoma with stem cell features in an adult patient.

Patients with hepatoblastoma featuring carcinoma characteristics have better outcomes after liver transplantation, than after chemotherapy and resection. Possibly this should be extrapolated to aggressive subtypes of hepatocellular carcinomas in non-cirrhotic livers, where early liver transplantation might also be indicated. However, the risks associated with liver transplantation and immunosuppressive treatment after liver transplantation are once again demonstrated by this case of a 32-year-old women with a negative personal and familial history of liver diseases. She underwent transplantation (DBD) for a hepatocellular carcinoma with stem cell features (HCC-HS; an aggressive 'hepatoblast subtype' of hepatocellular carcinoma) after chemotherapeutical downstaging techniques failed to sufficiently downstage the tumor. Despite being on conventional immunosuppressive regimens (tacrolimus and mycophenolate mofetil with initial corticosteroids tapered), this patient still developed two severe rejection episodes, one of which necessitated retransplantation (DCD). Both episodes were preceded by alterations in tacrolimus trough levels, either intentionally, when tacrolimus was reduced within a nephroprotective regimen, or unintentionally, when rifampicin, a CYP3A4 inducer, significantly lowered the trough levels. Together, these episodes stress the importance of therapeutic drug monitoring of tacrolimus. Furthermore, the patient experienced an everolimus-linked drug-induced thrombotic microangiopathy, underwent multiple ERCPs for an anastomotic stricture and only one and a half year after the first liver transplantation she already suffers from long-term immunosuppressive-related side effects such as impaired glucose tolerance, hypertension and a potential cardiomyopathy. At present, she is still alive and experienced no recurrence of her primary tumor. Her case underscores the significant challenges in post-liver transplantation care.

Abnormally Elevated Blood Tacrolimus Level Following the Concomitant Use of Nirmatrelvir/Ritonavir With Extended-Release Tacrolimus in a Post-lung Transplant Patient: A Case Report and a Literature Review.

Although nirmatrelvir/ritonavir (NMV/r) reportedly increases blood levels of tacrolimus (TAC) due to CYP3A4 inhibition and other factors, reports on the use of NMV/r in combination with tacrolimus hydrate extended-release capsules (TAC-ER) in lung transplant patients are limited. Herein, we present a case with post-lung transplantation of elevated blood trough levels of TAC after concomitant use of NMV/r. A woman in her 60s had undergone lung transplantation. She had coronavirus disease 2019 (COVID-19) and was co-administered NMV/r and TAC-ER, with the trough level controlled at approximately 4 µg/mL. Upon the co-administration of NMV/r and TAC-ER, the patient developed diarrhea and vomiting and was hospitalized. TAC-ER was discontinued on day 6, and TAC level was measured on day 8 and had risen above 100 ng/mL. This level gradually decreased to 17.8 ng/mL on day 11 and 2.4 ng/mL on day 15; therefore, TAC-ER was resumed at 2.5 mg/day. On day 18, the TAC level was 5.2 ng/mL, which was within the target range, and the patient was discharged on day 19. This is the first report of a post-lung transplant patient co-administered TAC-ER with NMV/r, who showed abnormally high blood TAC levels above the detection limit. In patients using TAC-ER after lung transplantation, it may be useful to confirm that the TAC blood level is below the effective therapeutic range before resuming TAC-ER safely.