High intrapatient variability of tacrolimus exposure associated with poorer outcomes in liver transplantation

Tacrolimus (TAC) is a dose‐dependent immunosuppressor with considerable intrapatient variability (IPV) in its pharmacokinetics. The aim of this work is to ascertain the association between TAC IPV at 6 months after liver transplantation (LT) and patient outcome. This single‐center cohort study retrospectively analyzed adult patients who underwent transplantation from 2015 to 2019 who survived the first 6 months with a functioning graft. The primary end point was the patient’s probability of death and the secondary outcome was the loss of renal function between month 6 and the last follow‐up. TAC IPV was estimated by calculating the coefficient of variation (CV) of the dose‐corrected concentration (C₀/D) between the third and sixth months post‐LT. Of the 140 patients who underwent LT included in the study, the low‐variability group (C₀/D CV < 27%) comprised 105 patients and the high‐variability group (C₀/D CV ≥ 27%) 35 patients. One‐, 3‐, and 5‐year patient survival rates were 100%, 82%, and 72% in the high‐variability group versus 100%, 97%, and 93% in the low‐variability group, respectively (p = 0.005). Moreover, significant impaired renal function was observed in the high‐variability group at 1 year (69 ± 16 ml/min/1.73 m² vs. 78 ± 16 ml/min/1.73 m², p = 0.004) and at 2 years post‐LT (69 ± 17 ml/min/1.73 m² vs. 77 ± 15 ml/min/1.73 m², p = 0.03). High C₀/D CV 3–6 months remained independently associated with worse survival (hazard ratio = 3.57, 95% CI = 1.32–9.67, p = 0.012) and loss of renal function (odds ratio = 3.47, 95% CI = 1.30–9.20, p = 0.01). Therefore, high IPV between the third and sixth months appears to be an early and independent predictor of patients with poorer liver transplant outcomes.

Abbreviations

BPAR

Biopsy proven acute rejection

BMI

Body mass index

CKD‐EPI

chronic kidney disease epidemiology collaboration

CV

coefficient of variation

C₀/D

dose‐corrected concentration

CMV

cytomegalovirus

eGFR

estimated glomerular filtration rate

HR

hazard ratio

HCC

hepatocellular carcinoma

ICU

intensive care unit

IPV

intrapatient variability

i.v.

intravenously

LC–MS/MS

liquid chromatography‐ tandem mass spectrometry

LT

liver transplantation

MELD

model for end‐stage liver disease

MMF

mycophenolate mofetil

NASH

Non‐Alcoholic Steatohepatitis

OR

odds ratio

PCR

polymerase chain reaction

SD

Standard Deviation

TAC

tacrolimus

3–6 M

three–six months

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

There is high intrapatient variability of tacrolimus and its correlation with liver transplantation (LT) outcomes.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Could the intrapatient variability of tacrolimus between months 3 and 6 post‐LT be a potential prognostic tool for poor outcomes?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Those patients with dose‐corrected concentration coefficient of variation greater than or equal to 27% between months 3 and 6 post‐LT have worst overall survival and impaired renal function.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

If we promptly identify those patients, a closer therapeutic drug monitoring program should be imperative with the possibility to make therapeutic interventions to improve outcomes.     

Spontaneous rupture of the membranes, functional dystocia, oxytocin treatment, and the route of delivery

The details of clinical management were examined in 96 nulliparous patients with functional dystocia who had spontaneous rupture of the membranes before admission and were treated with oxytocin in the first stage of labor. It was our hypothesis that if the allegedly "high" rate of cesarean sections was the result of mediocre or flawed practices, these should be most evident in patients delivered abdominally. A group of 59 patients delivered vaginally were compared with 37 patients delivered by cesarean section. The means of many variables were not statistically different. The cesarean section group was characterized by smaller stature, a lesser cervical dilatation rate both before and after oxytocin administration, a larger maximum oxytocin dose, a longer period of oxytocin administration, more frequent cessation of oxytocin administration or dose reduction because of hypercontractility or an abnormal fetal heart rate or both, and a higher incidence of intra-amniotic infection. We conclude that the decision to perform cesarean section in nulliparous women with functional dystocia arises from disabilities of the patient and not from differences in the application of our management principles, services, or treatments.     

Correction to: Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products

Journal of Thrombosis and Thrombolysis - In the original publication of the article, unfortunately the given name and family name of the author’s in the author group were inadvertently...