Abstract
Tacrolimus is the cornerstone of the therapeutic immunosuppressive strategy in liver transplantation. The inter‐individual and intra‐individual variability of its trough blood concentrations is a surrogated biomarker of allograft rejection. Here we described two cases of patients with liver transplant who exhibited increases of tacrolimus blood trough concentration adjusted on the dose while experiencing acute inflammatory episodes. These case reports highlight the inhibitory effect of acute inflammation on tacrolimus metabolism and show that it accounts for the longitudinal intra‐individual variability of tacrolimus blood concentrations, beyond drug–drug interaction and observance.
Keywords: clinical pharmacology, drug safety, inflammation, therapeutic drug monitoring
1. INTRODUCTION
Tacrolimus is the cornerstone of therapeutic immunosuppression to prevent graft rejection after organ transplantation. Tacrolimus has a narrow therapeutic window, and intra‐individual variability of tacrolimus blood trough concentration (C0) is a surrogate biomarker of allograft rejection. 1 Therapeutic drug monitoring (TDM) of tacrolimus is thus recommended to adapt its dose. 2 Tacrolimus undergoes cytochrome P4503A4/5 (CYP3A4/5)‐mediated metabolism and is a substrate of P‐glycoprotein (Pgp). Consequently, genetic polymorphisms of CYP3A4/5 or ATP‐binding cassette subfamily B member 1, 3 co‐medication with a CYP3A4/5 inducer or inhibitor or a Pgp inhibitor, or liver dysfunction contribute to tacrolimus C0 variability. 4
Inflammation may also contribute to the pharmacokinetic variability of tacrolimus, as acute inflammation is associated with an increased plasma C0 of CYP substrates, such as voriconazole, 5 clozapine 6 and risperidone. 7 The underlying mechanisms involve down‐regulation of CYP or drug transporter transcription and activity due to acute inflammation, leading to enhanced exposure of CYP substrates. 8
We describe two cases of liver‐transplant patients who exhibited an increased tacrolimus C0 while experiencing acute inflammatory episodes. We used C‐reactive protein (CRP) and alanine aminotransferase (ALT) concentrations as biomarkers of inflammation and liver cytolysis, respectively. All presented data were collected from the medical charts; the tacrolimus C0 was measured during routine TDM by liquid chromatography–tandem mass spectrometry (LC–MS/MS).
Patient 1 (see Figure 1A) was a 31‐year‐old man who underwent liver transplantation (at day 0, D0) following chronic hepatitis B and D co‐infection. Although hepatic function recovered after the transplant, the tacrolimus C0 increased during two inflammatory episodes above the recommended therapeutic target window (10–15 μg L−1) 2 and the dose‐normalized tacrolimus C0 (C0/D [tacrolimus daily dose]) increased by 54% from D17 to D19 and by 141% from D25 to D28. The first event coincided with an episode of cholestasis at D15. The patient underwent a splenectomy and presented with an infection at D25 that was resolved by D36. Throughout this period, his medication compliance was good, and the C0/D strongly correlated with plasma CRP concentrations (r 2 = 0.78, P = 0.079, n = 7).
FIGURE 1.
Time course of dose‐normalized tacrolimus blood trough concentration (tacrolimus blood trough concentration adjusted for the preceding oral dose, C0/D) and plasma alanine aminotransferase (ALT) and C reactive protein (CRP) concentrations. Infectious clinical events and antimicrobial treatments are indicated above and below the graph, respectively. A, Patient 1, for whom the timeline was based on the day of his liver transplant (D0). B, Patient 2, for whom the timeline was based on the day of his second liver transplant (D0)
Patient 2 (see Figure 1B) was a 41‐year‐old man hospitalized for a second liver transplantation (at D0) after chronic hepatic rejection of the first liver graft. At D28, he presented with an episode of sepsis, which was diagnosed as Enterococcus faecium and Candida albicans infection on D38, with recurrence on D55. The tacrolimus C0 increased to above 20 μg L−1 on D44 and D45. Tacrolimus C0/D increased by 151% between D41 and D44 and by 92% between D44 and D45. The medical chart indicated a lack of medication compliance around D38 and between D54 and D59, possibly explaining the lack of increased tacrolimus C0, notably during the second sepsis episode (D55).
Observed changes in tacrolimus C0 were higher than the between‐day analytical precision of tacrolimus measure (which varied from 5.2% to 6.8% by our LC‐MS/MS method), excluding an analytical cause of tacrolimus C0 variations.
Dividing C0 by the preceding daily dose (C0/D) limited the influence of dose changes occurring during longitudinal TDM (see Figure 1) on tacrolimus blood exposure variations. The episode of liver cytolysis (ALT > 40 UI mL−1) at D2 for patient 2 (see Figure 1B) could have contributed to the enhanced tacrolimus exposure. However, an increase in the tacrolimus C0/D was also observed in the absence of liver cytolysis (ALT < 40 UI mL−1) for patient 1 and from D23 for patient 2. Moreover, neither patient suffered from other comorbidities (cancer) or clinical pathological conditions (diarrhoea), or was concomitantly treated by drugs known to increase the tacrolimus C0. 3 Finally, the route of administration remained unchanged.
Interestingly, tacrolimus C0/D–time profiles presented variations similar to the CRP concentration–time profiles for the compliant patient (patient 1), suggesting an association between acute inflammation and the increased tacrolimus C0/D. Inflammation has been reported to inhibit drug‐metabolizing enzymes and transporters (DMET) via two mechanisms: (i) early NO‐dependent activation of the proteasome pathway, leading to reduced activity of some DMET, and (ii) transcriptional inhibition of DMET mediated by pro‐inflammatory cytokines released during the acute phase of inflammation. 8 As tacrolimus is a substrate of Pgp and CYP3A4/5, we postulate that variations in its concentration during acute episodes of inflammation result from an inhibitory effect of inflammation on Pgp and CYP3A4 activity. We suggest that these mechanisms may contribute to reduce tacrolimus clearance and thereby to increase its concentrations. These data are consistent with the increase in the tacrolimus C0/D previously reported during a diarrhoeal episode related to rotavirus infection in a child. 9
In conclusion, these case reports highlight the influence of acute inflammation as a possible cause of alterations in the pharmacokinetics of tacrolimus and show that it accounts for the longitudinal intra‐individual variability of tacrolimus blood concentrations, beyond drug–drug interactions and compliance. Our data highlight the need to monitor CRP plasma concentrations during TDM of tacrolimus, as acute inflammation is likely to precede increases in tacrolimus blood C0. This point is of particular clinical relevance, as high intra‐patient variability of tacrolimus exposure is associated with poorer outcomes in liver transplant patients. 10 Further studies are required to confirm these findings on larger cohorts and propose a therapeutic strategy for tacrolimus dose adjustment in cases of acute inflammation.
1.1. Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY.
COMPETING INTERESTS
There are no competing interests to declare.
CONTRIBUTORS
E.B. contributed to data collection and analysis, and article writing. E.G.‐V. and X.F. contributed to drafting and revising the manuscript for important intellectual content. C.I., M.N.H. and M.B. contributed to data collection, analysis and interpretation. F.S.‐L. contributed to the conception of the letter, analysis and interpretation of data, and drafting of the manuscript. All the authors approved the present version to be published.
ACKNOWLEDGEMENT
We thank the patients for their written consents.
Bonneville E, Gautier‐Veyret E, Ihl C, et al. Unexpected overdose blood concentration of tacrolimus: Keep in mind the role of inflammation. Br J Clin Pharmacol. 2020;86:1888–1891. 10.1111/bcp.14292
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