Safety, Tolerability, Pharmacokinetics, and Drug Interaction Potential of SPR741, an Intravenous Potentiator, after Single and Multiple Ascending Doses and When Combined with β-Lactam Antibiotics in Healthy Subjects

Abstract

SPR741 is a novel polymyxin B derivative, with minimal intrinsic antibacterial activity and reduced nonclinical nephrotoxicity compared to levels with polymyxin B, that interacts with the outer membrane of Gram-negative bacteria, enhancing penetration of coadministered antibiotics. The safety, tolerability, and pharmacokinetics (PK) of SPR741 were evaluated in two studies, after single and multiple intravenous (i.v.) doses in healthy adult subjects and after coadministration with partner antibiotics. In the single and multiple ascending-dose study, SPR741 or placebo was administered as a 1-h infusion at single doses of 5 to 800 mg and in multiple doses of 50 to 600 mg every 8 h (q8h) for 14 days. In the drug-drug interaction study, a single 400-mg i.v. dose of SPR741 was administered alone and in combination with piperacillin-tazobactam, ceftazidime, and aztreonam. PK parameters for SPR741 and partner antibiotics were determined using noncompartmental analysis. After single doses, a dose-linear and proportional increase in mean maximum concentration in plasma (Cmax) and area under the concentration-time curve (AUC) was observed. At doses of 100 to 800 mg, >50% of the dose was excreted in the urine in the first 4 h postdose. After multiple doses, the mean half-life was 2.2 h on day 1 and up to 14.0 h on day 14, with no evidence of accumulation after 14 days of dosing up to 400 mg. The PK profile of SPR741 and partner antibiotics was unchanged with coadministration. SPR741 was generally well tolerated at doses up to 1,800 mg/day. These data support further clinical development of SPR741 for treating serious infections due to resistant bacteria. (These studies have been registered at ClinicalTrials.gov under identifiers NCT03022175 and NCT03376529.)

Emerging Treatment Options for Infections by Multidrug-Resistant Gram-Positive Microorganisms

“…In the presence of other antibiotics, there was no increase or decrease in the clearance or half-life of SPR741, suggesting a lack of drug-drug interaction [183]. Both single and multiple doses of SPR741 was well tolerated in healthy adult subjects [183]. In the single-ascending dose part, 34 treatment-emergent adverse events were reported in 15/48 (31%) of the subjects, compared to 5/16 (31%) in placebo-treated subjects [183].…”

“…SPR-741 demonstrated a peak of mean plasma concentrations one hour after a single intravenous dose which declined over 24 h [183]. A linear and proportional pharmacokinetic profile was associated when a single one hour intravenous infusion at doses up to 800 mg was administered [183]. SPR-741 was found to have a half-life ranging from 2.0 to 3.8 h with no evidence of accumulation or time-dependent changes in plasma exposure [183].…”

“…A phase I study was conducted in 2017 to assess the safety, tolerability and pharmacokinetics of single and multiple intravenous doses of SPR-741 in healthy adult volunteers (NCT03022175) [182]. SPR-741 demonstrated a peak of mean plasma concentrations one hour after a single intravenous dose which declined over 24 h [183]. A linear and proportional pharmacokinetic profile was associated when a single one hour intravenous infusion at doses up to 800 mg was administered [183].…”

“…A linear and proportional pharmacokinetic profile was associated when a single one hour intravenous infusion at doses up to 800 mg was administered [183]. SPR-741 was found to have a half-life ranging from 2.0 to 3.8 h with no evidence of accumulation or time-dependent changes in plasma exposure [183]. In the presence of other antibiotics, there was no increase or decrease in the clearance or half-life of SPR741, suggesting a lack of drug-drug interaction [183].…”

“…SPR-741 was found to have a half-life ranging from 2.0 to 3.8 h with no evidence of accumulation or time-dependent changes in plasma exposure [183]. In the presence of other antibiotics, there was no increase or decrease in the clearance or half-life of SPR741, suggesting a lack of drug-drug interaction [183]. Both single and multiple doses of SPR741 was well tolerated in healthy adult subjects [183].…”