Variability of Tacrolimus Trough Concentration in Liver Transplant Patients: Which Role of Inflammation?

Tacrolimus presents high intra and inter-individual variability in its blood trough concentration (Cmin). Knowledge of the factors that are involved in tacrolimus Cmin variability is thus clinically important to prevent or limit it. Inflammation can affect the pharmacokinetic properties of drugs. We evaluated the contribution of acute inflammation in the pharmacokinetic variability of tacrolimus blood Cmin in a large cohort of liver transplant patients. Demographic, biological, and clinical data from 248 liver transplant patients treated with tacrolimus from January 2010 to December 2016 were retrospectively collected from medical records. In total, 1573 Cmin/dose and concomitant C-reactive protein (CRP) measurements were analysed. In multivariate analysis, the log Cmin/dose of tacrolimus was significantly and positively associated with the hematocrit, ALAT, and CRP concentrations. CRP concentrations were higher (p = 0.003) for patients with tacrolimus overexposure (i.e., tacrolimus Cmin > 15 µg/L) (median CRP (10th–90th percentiles): 27 mg/L (3–149 mg/L), n = 91) than they were for patients with a tacrolimus Cmin ≤ 15 µg/L (13 mg/mL (3–95 mg/L), n = 1482)). CRP in the fourth quartile (49 to 334 mg/L) was associated with a 2.6-fold increased risk of tacrolimus Cmin overexposure. Our study provides evidence that inflammation contributes to tacrolimus Cmin variability and suggests that inflammation should be considered for the correct interpretation of tacrolimus blood concentration.

The use of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis post-liver transplant: a case series

Introduction Cystic fibrosis (CF) related liver disease (CFLD) manifests as a wide spectrum of hepatobiliary disease and can progress to need liver transplantation. Elexacaftor/tezacaftor/ivacaftor (elx/tez/iva) is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator which has superior efficacy compared to previously approved modulators. Use of elx/tez/iva, should be approached with caution in individuals with CFLD or following liver transplantation due to possible increases in LFTs and drug-drug interactions with several immunosuppressant medications. Objective The purpose of this case series was to explore if the use of elx/tez/iva is safe and tolerable in patients with CF post-liver transplantation. Methods A retrospective case series including patients prescribed elx/tez/iva following liver transplantation and an immunosuppressive regimen consisting of drug therapy metabolized by P-glycoprotein was completed. Results Ten patients at six CF centers with a median age of 22.1 years (range 14-43.4 years) and median time from transplant of 6.9 years (range 0.6-22 years) were included. Most patients (8, 80%) received a reduced or full dose of elx/tez/iva for a mean duration of 10.4 months (range 7-12 months). Fluctuations in LFTs occurred in all patients (10, 100%) and led to therapy discontinuation in two patients (20%). Elx/tez/iva initiation resulted in elevations in tacrolimus trough concentration in 7 patients (70%). Most patients who tolerated elx/tez/iva had symptomatic and quality of life improvement, increased body-mass-index, and maintained or improved lung function. Conclusion Initiation of elx/tez/iva in patients with CF who received a liver transplantation may be safe with clinical benefits.

Volumetric absorptive microsampling and dried blood spot microsampling vs. conventional venous sampling for tacrolimus trough concentration monitoring

ObjectivesMonitoring tacrolimus blood concentrations is important for preventing allograft rejection in transplant patients. Our hospital offers dried blood spot (DBS) sampling, giving patients the opportunity to sample a drop of blood from a fingerprick at home, which can be sent to the laboratory by mail. In this study, both a volumetric absorptive microsampling (VAMS) device and DBS sampling were compared to venous whole blood (WB) sampling.MethodsA total of 130 matched fingerprick VAMS, fingerprick DBS and venous WB samples were obtained from 107 different kidney transplant patients by trained phlebotomists for method comparison using Passing-Bablok regression. Bias was assessed using Bland-Altman. A multidisciplinary team pre-defined an acceptance limit requiring >80% of all matched samples within 15% of the mean of both samples. Sampling quality was evaluated for both VAMS and DBS samples.Results32.3% of the VAMS samples and 6.2% of the DBS samples were of insufficient quality, leading to 88 matched samples fit for analysis. Passing-Bablok regression showed a significant difference between VAMS and WB, with a slope of 0.88 (95% CI 0.81–0.97) but not for DBS (slope 1.00; 95% CI 0.95–1.04). Both VAMS (after correction for the slope) and DBS showed no significant bias in Bland-Altman analysis. For VAMS and DBS, the acceptance limit was met for 83.0% and 96.6% of the samples, respectively.ConclusionsVAMS sampling can replace WB sampling for tacrolimus trough concentration monitoring, but VAMS sampling is currently inferior to DBS sampling, both regarding sample quality and agreement with WB tacrolimus concentrations.

Potential Elevation of Tacrolimus Trough Concentrations with Concomitant Metronidazole Therapy

OBJECTIVE: To report the occurrence of a potential tacrolimus elevation in a renal transplant recipient after adding metronidazole to the medication regimen. CASE SUMMARY: A 24-year-old white man status post living-related renal transplant who had been stabilized on tacrolimus 4 mg twice daily (trough concentrations 7–10 ng/mL) for 2 months and prednisone 20 mg daily presented to the clinic with severe diarrhea. Stool cultures were positive for Clostridium difficile, and therapy with metronidazole 500 mg 4 times daily was initiated. Between days 4 and 14 of metronidazole therapy, the patient's tacrolimus trough concentration and serum creatinine level increased to maximum levels of 26.3 ng/mL and 3.3 mg/dL (baseline 1.6–1.8 mg/dL), respectively. Tacrolimus was withheld for one dose and then decreased to 1 mg twice daily. Two days after metronidazole discontinuation, tacrolimus trough concentrations dropped to 9.4 ng/mL and serum creatinine to 2.3 mg/dL, warranting a tacrolimus dose increase to 3 mg daily. DISCUSSION: As of April 15, 2005, one other case has been reported documenting an elevation in tacrolimus concentrations with the addition of metronidazole. The possible mechanism may be related to metronidazole's weak inhibition of CYP3A4 and, possibly, P-glycoprotein. According to the Naranjo probability scale, metronidazole was the probable cause of this adverse reaction. CONCLUSIONS: Coadministration of tacrolimus with metronidazole may result in elevated tacrolimus concentrations, possibly leading to tacrolimus toxicity. Practitioners should be aware of this potential interaction and closely monitor tacrolimus concentrations and renal function.