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

Abstract

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.

Induction of CYP3A activity by dexamethasone may not be strong, even at high doses: insights from a case of tacrolimus co-administration

“…Furthermore, although hematocrit levels and inflammatory responses are known to influence the pharmacokinetics of TAC [ 24 – 26 ], no association was observed between the C/D ratio of TAC and the course of hematocrit and C-reactive protein levels (an inflammatory response marker) in the present case.…”

A UPLC-MS/MS Method for Plasma Biological Monitoring of Nirmatrelvir and Ritonavir in the Context of SARS-CoV-2 Infection and Application to a Case

“…Moreover, a low concentration of ritonavir was still present after 4 days and thus could have decreased metabolism of tacrolimus resulting in increased concentrations. Tacrolimus was probably reintroduced prematurely; (2) tacrolimus binds to erythrocytes as well as to inflammation acute phase proteins (such as α1-acid glycoprotein), that are correlated with CRP blood levels . An episode of inflammation related to clinical infectious events may contribute to increase tacrolimus levels by altering plasma protein binding; (3) inflammation also induces transcriptional inhibition of drug-metabolizing enzymes, including CYP, and transporters, resulting in modulation of tacrolimus pharmacokinetics; (4) liver and renal function that may have already been impaired by the infection or antiviral treatment. − The clearance of tacrolimus would be greatly reduced, and its elimination half-life would also be increased.…”