Orphan drugs! FDA approves terlipressin for hepatorenal syndrome

Guide

Hepatorenal syndrome (HRS) can occur in patients with advanced liver disease due to factors such as effective circulating volume depletion, decreased renal blood flow, endotoxemia, and decreased prostaglandin, and is significantly associated
with ascites.
At present, HRS survival is low, and there is no effective intervention other than liver and kidney transplantation
.

On September 14, 2022, terlipressin was approved by the FDA for use in HRS, the first drug approved for the treatment of HRS
.
This approval is closely related
to the results of a previous randomized double-blind study.
This article will introduce the study for the benefit of the reader
.

Study the design

Methods

The CONFIRM study was a 3-issue, multicenter, multi-country (U.
S.
and Canada) randomized, double-blind study
conducted between July 13, 2016 and July 24, 2019.

The inclusion criteria for the studies were (1) cirrhosis and the presence of ascites; (2) rapid deterioration of renal function, which is defined as serum creatinine level > 2.
25 mg / dL, and doubling of blood creatinine level within 2 weeks; (3) After discontinuation of diuretics, plasma volume enlargement with albumin, and no improvement in renal function within 48 hours (blood creatinine decreased by 20% or < 2.
25 mg / dL); (4) If the patient's conditions permit, midodrine or octreotide is applied before random grouping; (5) The age of the patient ≥ 18 years old<b10>.

The main exclusion criteria for the study were (1) serum creatinine levels > 7.
0 mg/dL; (2) At least 1 large-volume (4L) puncture within 2 days after random grouping; (3) sepsis and/or uncontrolled bacterial infection; (4) Shock; (5) use / exposure to nephrotoxic drugs; (6) Proteinuria > 500mg/d; (7) Hematuria or microscopic hematuria; (8) Pregnancy; (9) Receive kidney replacement therapy (RRT) within 4 weeks, etc
.

Patients in the included studies were divided into 2 groups, patients in the teripressin group were injected with telitpressin (0.
85 mg), the control group was injected with placebo (normal saline), and patients in 2 groups received injections
every 6 h.

Primary endpoint: Renal function remission rate in patients with HRS, defined as 2 consecutive serum creatinine levels ≤ 1.
5 mg/dL, with an interval of at least 2 h and sampling at least 24 h after
administration 。 The secondary endpoint was (1) serum creatinine compliance rate: 14 days or after discharge, the patient's serum creatinine level ≤ 1.
5 mg/dL; (2) HRS reversal rate: defined as 30 days after the patient's use of RRT; (3) Systemic inflammatory response improvement rate: it is defined as whether the patient's systemic inflammatory response syndrome (SIRS) is improving after 14 days or after discharge; (4) HRS no recurrence rate: HRS is confirmed for 15 days or after discharge to recover, and the patient does not recur
at 30 days.

Results of the study

Results

A total of 300 patients were included, and their mean age (SD) was 53.
8 (11.
49), and 59.
7%
were male.
The terlipressin group was superior to the control group in terms of renal function remission rate, serum creatinine compliance rate, HRS reversal rate, systemic inflammatory response improvement rate, and HRS non-recurrence rate (Table 1
).

Based on the results of this study, the drug instructions for terlipressin in the United States were updated
.
In the updated Teripressin instructions, terlipressin is indicated in HRS patients with rapidly declining renal function, but the benefit of terlipressin is limited
in patients with > 5 mg/dL of serum creatinine.
The instructions suggest that the starting dose of terlipressin is 0.
85 mg / time, 6 h injection once
.
At the 1st to 3rd day, the time of each intravenous injection should > 2 min
.
After the 4th day, the dose used should be adjusted according to the serum creatinine level
.

In addition, terlipressin may increase severe or fatal respiratory failure, is not recommended in patients with low oxygen levels, and oxygen monitoring
is recommended during treatment.
Because terlipressin therapy may cause partial tissue ischemia, it may make the patient unsuitable for liver and kidney transplantation
.
The use of the drug during pregnancy may cause damage to the fetus and should be considered
with caution in women with a birth plan.

References:

1.
FDA Announcement.
FDA approves treatment to improve kidney function in adults with hepatorenal syndrome.
Link: Trails.
gov.
Study To Confirm Efficacy and Safety of Terlipressin in Hepatorenal Syndrome (HRS) Type 1.
Link: FDA approved.
Terlipressin Label and Prescribing Information.
Link: