Pharmacokinetics, Safety, and Tolerability Evaluation of Single and Multiple Doses of GSK3342830 in Healthy Volunteers

Abstract

This was a first‐time‐in‐human randomized, double‐blind, single‐center, placebo‐controlled dose‐escalation study to determine the safety, tolerability, and pharmacokinetic (PK) profiles of GSK3342830 after single and repeat intravenous doses in healthy adult subjects (NCT0271424). Sixty‐two subjects were enrolled: 48 subjects in part 1 (single dose) and 14 subjects in part 2 (multiple doses). Following single intravenous infusions, total systemic exposure of GSK3342830 was dose proportional over the 250‐ to 6000‐mg dose range evaluated, whereas peak exposure was approximately dose proportional over the dose range. Following repeat intravenous infusions 3 times a day, GSK3342830 showed time invariance with no drug accumulation. Steady state was reached before day 3, and approximately 90% of GSK3342830 was excreted unchanged in urine. All 48 subjects in part 1 (100.0%) completed the study. In part 2, 9 subjects (64.3%) completed the study, and 5 subjects, all receiving GSK3342830, discontinued early (35.7%), 4 after experiencing fever, headache, and malaise, whereas 1 subject met predefined criteria for drug discontinuation because of transaminitis. GSK3342830 demonstrated PK consistent with other cephalosporin‐class antibiotics but poor tolerability following multiple doses in healthy volunteers.

Leaks in the Pipeline: a Failure Analysis of Gram-Negative Antibiotic Development from 2010 to 2020

“…Phase 1 GSK3342830 trials began in 2017 ( 32 ). In the SAD component, pharmacokinetic (PK) properties were consistent with those of other cephalosporins, including cefiderocol, and no severe adverse events were detected at doses of up to 6 g ( 33 ). In the MAD study, 11 subjects received 1 g GSK3342830 as a single i.v.…”

“…Four participants discontinued the treatment due to headache, malaise, and/or fever, and 1 had high ALT levels leading to automatic discontinuation. The 6 subjects remaining in the study experienced malaise, headache, and fever with onset at between 9 and 10 days and a general decrease in platelet counts ( 33 ). While symptoms could be related to known off-target binding to the 5HT-3 serotonin receptor, this interaction seemed physiologically unlikely ( 33 ).…”

“…The 6 subjects remaining in the study experienced malaise, headache, and fever with onset at between 9 and 10 days and a general decrease in platelet counts ( 33 ). While symptoms could be related to known off-target binding to the 5HT-3 serotonin receptor, this interaction seemed physiologically unlikely ( 33 ). GSK3342830 was discontinued following these results in 2018.…”

The Role of Iron and Siderophores in Infection, and the Development of Siderophore Antibiotics

“…More recently, Shionogi and GlaxoSmithKline (GSK) ran a joint discovery program around such conjugated cephalosporins. GSK registered a phase 1 trial to evaluate safety, tolerability, and pharmacokinetics of an ascending intravenous single-dose and repeat dose of GSK3342830 (NCT02751424) [74]; however, the trial was suspended, and no details of activity or structure of the compound are available. Shionogi pursued S-649266 (previously also known as GSK2696266), now called cefiderocol (Figure 3, compound 6), which has progressed satisfactorily through clinical trials (see below).…”

Developments for the Treatment of Invasive Infections Due to Multidrug-resistant Acinetobacter baumannii

“…However, a phase I dose-escalation study was stopped early. It is important to note that 35.7% of subjects discontinued the study drug during the multi-dose arm due to fever, headache, malaise or transaminitis [132].…”