Pharmacokinetics and Tolerance of the Phage Endolysin-Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers

Abstract

This study was a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service [https://cris.nih.go.kr/cris/] under identifier KCT0000968.).

Keywords: SAL200; phage endolysin; phase 1 clinical study; staphylococcal infections.

Copyright © 2017 Jun et al.

Figures

FIG 1

Consolidated Standards of Reporting Trials (CONSORT) diagram. Exclusion criteria (1), subjects with evidence or history of clinically significant hepatic, renal, neurologic, endocrine, pulmonary, hematological, neoplastic, cardiovascular, or psychiatric disease. Exclusion criteria (6), subjects who have systolic blood pressure 150 mmHg or diastolic blood pressure >100 mmHg when measured at a sitting position after resting for 3 min. Exclusion criteria (13), subjects who are evaluated as ineligible for study participation for other reasons, including clinical laboratory test results.

FIG 2

Mean single-dose serum concentration-time profiles of SAL200. Linear (A) and log-transformed (B) profiles are shown. •, 0.1 mg/kg; ○, 0.3 mg/kg; ▼, 1 mg/kg; △, 3 mg/kg; ■, 10 mg/kg. Error bars denote SDs.