Pharmacokinetic Analysis of Continuous Intravenous Infusion of Lipo-Prostaglandin E1 As a Prophylaxis of Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation
Authors: Hong Che Ry , Choi Yewon , Oh Jaeseong , Sunwoo Jung , Hong Kyung Taek , Choi Jung Yoon , Yu Kyung-Sang , Park Kyung Duk , Shin Hee Young , Kang Hyoung Jin 
Published: October 2019

Introduction: Prostaglandin E1 (PEG1) has various pharmacological effects such as vasodilation, inhibition of platelet aggregation, inhibition of superoxide anion generation, activation of the fibrinolytic system and inhibition of vascular smooth muscle cell proliferation. Continuous intravenous infusion of PGE1 as a prophylaxis of hepatic veno-occlusive disease (VOD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) have previously been shown to be effective. Further study has been done with continuous intravenous infusion of lipo-prostaglandin E1 (lipo-PGE1) because it can be used in smaller doses to avoid toxicities since it is a form of PGE1 dissolved in the lipid emulsion of soybean oil and thus has greater and long lasting effects. However, it has not been evaluated pharmacokinetically.

Methods: We performed a prospective explorative pharmacokinetic study on patients who received continuous intravenous infusion of lipo-PGE1 at a dose of 1mcg/kg/day as a prophylaxis of VOD during HSCT at Seoul National University Children's Hospital. Eligible patients were those at high risk of developing VOD (previous abdominal irradiation, liver function abnormality, busulfan or total body irradiation based conditioning, age under 18 years old) but who cannot use low dose heparin due to low platelet count, bleeding tendency or allergy. Dose of lipo-PGE1 could be increased to 1.5mcg/kg/day if patients showed clinical symptoms of VOD, before the establishment of VOD diagnosis. Lipo-PGE1 level was measured before the start of infusion (B level), between 1 hour and 72 hours after the start of infusion (P1 level), and after neutrophil engraftment (P2 level). Additional samplings were done if the dose of infusion was changed or if the condition of the patient changed significantly. Patients were evaluated for the occurrence and severity of VOD. VOD was diagnosed without limitation of onset time, when patients had 2 or more of the following features: serum total bilirubin of greater than 2 mg/dL, hepatomegaly or right upper quadrant pain of liver origin, or unexplained weight gain of greater than 2% over baseline.

Results: Thirty patients were enrolled between January 2015 and May 2016 and all of them were eligible for analysis. Patients underwent HSCT at median age of 12.2 years old for hematologic malignancies, solid tumors, brain tumors, and non-malignant diseases. Donors and stem cell sources were variable. Twenty patients received busulfan-based conditioning and 1 patient received total body irradiation based conditioning. Continuous intravenous infusion of lipo-PGE1 was started at median 1 day before the start of the conditioning regimen and was administered for a median duration of 29 days (range, 23-56 days). Dose of lipo-PGE1 was adjusted to 1.5mcg/kg/day in 2 patients at median 18 days (range, 14-21 days) from start of continuous infusion due to increasing serum total bilirubin or tender hepatomegaly. B level and P1 level were measured in all enrolled patients and P2 level was measured in all 28 of the patients who achieved neutrophil engraftment. The P1 level was 6.60 ± 2.88 (mean ± standard deviation) pg/mL and the clearance was 308.48 ± 233.04 L/h. The P2 level was significantly lower than P1 level at 5.55 ± 2.06 pg/mL (P=0.005) and the clearance was greater at 392.64 ± 302.78 L/h but it was not statistically significant (P=0.109). The coefficient of variability (CV%) of lipo-PGE1 level and clearance were 43.64% and 75.54% respectively at P1 and 37.12% and 77.11% respectively at P2. Between-subject variability of lipo-PGE1 level and clearance (11.18 and 51.65 %) were higher than intra-subject variability (7.19 and 7.40 %). No significant relationship was found between the level or clearance of lipo-PGE1 and occurrence or severity of VOD. VOD developed in 2 patients (6.7%) but both resolved completely with antithrombin-III based treatment at median 38 days from diagnosis. There was no adverse event or death related to lipo-PGE1 prophylaxis and there were no deaths related to VOD.

Conclusions: We herein provide the first prospective explorative pharmacokinetic data of continuous infusion of lipo-PGE1 as a prophylaxis of VOD in patients undergoing HSCT. We also suggest that lipo-PGE1 is efficient and safe as a prophylaxis of VOD in patients undergoing HSCT.

Disclosures

No relevant conflicts of interest to declare.