An evaluation of the safety and preliminary efficacy of peri- and post-operative treprostinil in preventing ischemia and reperfusion injury in adult orthotopic liver transplant recipients

Abstract

Background: Orthotopic liver transplantation (OLT) is the only treatment option for various end-stage liver diseases. Ischemia and reperfusion (I/R) injury is one of the unavoidable complications/conditions in OLT. In 2019, a total of 8896 livers were transplanted of which >94% organs were procured from deceased donors. An increase in the use of extended criteria donor (ECD) livers for transplantation further unraveled the role of hepatic I/R injury on short-term and long-term graft outcomes. Despite promising outcomes with the use of antioxidants, free radical scavengers, and vasodilators; I/R-mediated liver injury persists and significantly influences the overall clinical outcomes. Treprostinil, a synthetic prostacyclin I₂ (PGI₂ ) analog, due to its vasodilatory property, antiplatelet activity, and its ability to downregulate pro-inflammatory cytokines can potentially minimize I/R injury.

Aim: We investigated the safety and preliminary efficacy of continuous intravenous infusion of treprostinil in liver transplant recipients in a prospective, single-center, non-randomized, interventional study.

Material and methods: This was a dose escalation (3 + 3 design) phase 1/2 study. Deceased donor liver transplant recipients received 5 ng/kg/min for two days, or 2.5, 5, and 7.5 ng/min/kg for 5 days as a continuous infusion. Multiple blood samples were collected for biochemical parameter assessment and for measuring treprostinil levels. Indocyanine green plasma disappearance rate was used as a measure of hepatic functional capacity.

Results: Subjects tolerated continuous infusion of treprostinil up to 5 ng/kg/min for 120 h with no occurrence of primary graft non-function (PNF), minimized need for ventilation support, reduced hospitalization time, 100% graft and patient survival, and improved hepatobiliary excretory function comparable to normal healthy adults.

Discussion: Treprostinil can be administered to liver transplant patients safely during the perioperative period.

Conclusion: Based on this phase 1/2 study, further efficacy studies of treprostinil in preventing I/R injury of liver should be conducted to potentially increase the number of livers available for transplantation.

Keywords: ischemia reperfusion injury (IRI); liver transplantation; treprostinil.

FIGURE 1

Study design flowchart. The study starts with actively screening for new subjects, approaching them, describing the benefits and risks related to the study, and obtaining signed informed consent from the subject. Initially, treprostinil infusion was initiated after induction of general anesthesia (protocol 1). Subsequently, treprostinil infusion starts once the patient was hemodynamically stable and continued for up to 120 h (Protocol 2). During infusion, hemodynamic parameters and blood samples were collected and indocyanine green plasma disappearance rate (ICG‐PDR) test was conducted on days 2 and 5. Blood samples for post‐infusion treprostinil PK were collected on days 6 and 7. Subjects were followed up for approximately 180 days post‐transplantation to document graft and subject survivals

FIGURE 2

Study enrollment flowchart for the clinical study. This flowchart describes the patient enrollment in Remodulin clinical study at Montefiore hospital‐UPMC. The flowchart shows number of subjects screened and assessed for eligibility (n = 166). Subjects consented (n = 35) were evaluated throughout the study and were enrolled to three dose levels in a 3 + 3 dose escalating phase I design. Subjects were followed for up to 180 days post‐transplantation. * numbers in parenthesis [black (completed study), red (discontinued), and purple (early discharge)]

FIGURE 3

Heart rate and blood pressure parameters observed for 5 days in LTx patients. Panels A, C, and E depict HR, SBP, and DBP observed in respective dose groups over the 120 h from start of infusion and shaded areas represent the normal range for healthy subjects for the respective parameter. Panels B, D, and F plots show HR, SBP, and DBP observed in control and remodulin groups. Data are expressed as median and range

FIGURE 4

Hemodynamic parameters observed in patients receiving treprostinil infusion. Panels A, C, and E depict mean pulmonary arterial pressure, cardiac output, and cardiac index observed in LTx patients in respective treprostinil dose groups over two days and shaded areas represent the normal range for the respective parameter in healthy subjects. Panels B, D, and F plots show mPAP, CO, and observed in control and remodulin groups. Data are expressed as median and range

FIGURE 5

Time course of hepatic injury markers during first week after LTx. Panels A, C, and E show ALT, AST, and total bilirubin levels observed in LTx patients in respective treprostinil dose groups during the first‐week post‐LTx. Shaded areas represent the normal range for the respective parameter in healthy subjects. Panels B, D, and F plots show ALT, AST, and Total bilirubin levels observed in control (open circles) and remodulin groups (closed circles). Data are expressed as median and range

FIGURE 6

Time course of blood coagulation and kidney function markers for 7 days post‐LTx. Panels A, C, and E show time course of serum creatinine levels, platelet counts, and prothrombin time observed in LTx patients in respective treprostinil dose groups during the first‐week post‐LTx. The shaded areas represent normal ranges of each parameter in healthy subjects. Panels B, D, and F show serum creatinine, platelet counts, and prothrombin time observed in control (open circles) and remodulin groups (closed circles). Data are expressed as median and range

FIGURE 7

Area under the concentration time curves (AUC) for liver and kidney biomarkers over 7 days post‐LTx. AUCs for ALT (A), AST (B), total bilirubin (C), and SCr (D) observed in control (open circles) and remodulin groups (closed circles) in first week after LTx. Data are expressed as median and range

FIGURE 8

ICG‐PDR observed on Day2 and Day5 post‐LTx. Left panel illustrates ICG‐PDR values observed in respective treprostinil dose groups on day 2 post‐LTx and right panel illustrates ICG‐PDR values observed in respective treprostinil dose groups on day 5, respectively. The shaded areas represent the normal range observed in healthy subjects, and dotted line is the lowest threshold below which the liver is deemed non‐functional or compromised. Data are expressed as median and range. *ICG‐PDR values for healthy and control subjects were obtained from previous study