A Phase 1 Study of Intravenous Plazomicin in Healthy Adults to Assess Potential Effects on the QT/QTc Interval, Safety, and Pharmacokinetics

Abstract

Plazomicin is an aminoglycoside with in vitro activity against multidrug‐resistant Enterobacteriaceae. A phase 1, randomized, double‐blind, crossover study assessed the potential effects of plazomicin on cardiac repolarization (NCT01514929). Fifty‐six healthy adults (24 men, 32 women) received a single therapeutic dose of plazomicin (15 mg/kg administered by 30‐minute intravenous infusion), a single supratherapeutic dose of plazomicin (20 mg/kg administered by 30‐minute intravenous infusion), placebo, or oral moxifloxacin (400 mg). The primary end point was the baseline‐adjusted, placebo‐corrected QTc interval using the Fridericia formula (ΔΔQTcF). Assay sensitivity was concluded if the lower limit of a 1‐sided 95%CI (adjusted for multiplicity using the Hochberg procedure) for moxifloxacin ΔΔQTcF was >5 milliseconds at ≥1 prespecified time points. No QT prolongation effect for plazomicin was concluded if the largest mean effect was <5 milliseconds, and the upper limit of a 2‐sided 90%CI for plazomicin ΔΔQTcF was <10 milliseconds at all time points. Assay sensitivity was demonstrated based on moxifloxacin ΔΔQTcF. No QT prolongation effect for plazomicin was concluded because the largest mean ΔΔQTcF for plazomicin was 3.5 milliseconds, and the highest upper limit was 5.6 milliseconds. No clinically relevant changes were observed in electrocardiograms. For the 15‐ and 20‐mg/kg dose levels of plazomicin, mean peak plasma concentration values were 76.0 and 96.6 mg/L, and mean values of the area under the concentration‐time curve over 24 hours were 263 and 327 mg·h/L, respectively. Model‐derived pharmacokinetic parameters and safety findings were generally consistent with previously reported plazomicin studies. In conclusion, therapeutic and supratherapeutic doses of plazomicin had no clinically significant effect on cardiac repolarization and were generally well tolerated.

No Effect of Plazomicin on the Pharmacokinetics of Metformin in Healthy Subjects

“…The PK profile of plazomicin 15 mg/kg IV when administered with metformin 850 mg orally was consistent with previous data for plazomicin alone in healthy subjects (Table ) . At the clinically intended plazomicin dose, the geometric mean C max was 84.6 µg/mL (geometric coefficient of variation, 12.4); with plazomicin human plasma protein binding of approximately 20%, the corresponding C max,u was 67.7 µg/mL.…”

“…In vitro, plazomicin was shown to be an inhibitor of OCT2, MATE1, and MATE2‐K transporters. Unbound plasma concentrations achieved in healthy subjects from a previously conducted phase 1 study were 84‐fold, 21‐fold, and 5.6‐fold lower than the IC 50 for OCT2, MATE1, and MATE2‐K, respectively. Based on recent FDA guidance, the potential for an investigational drug to inhibit transporters in vivo cannot be ruled out if C max,u /IC 50 is ≥0.1 for OCT2 or ≥0.02 for MATEs .…”

“…The usual starting dose of metformin is 500 mg twice daily or 850 mg once daily, with titration up to a maximum of 2000 mg daily in divided oral doses . The recommended dose of plazomicin for patients with normal renal function is 15 mg/kg as a 30‐minute IV infusion once daily . This dose is associated with the efficacy and safety outcomes observed in phase 2 and 3 clinical trials in patients with complicated urinary tract infections or serious infections due to carbapenem‐resistant Enterobacteriaceae .…”

“…The PK profile of plazomicin 15 mg/kg IV when administered with metformin 850 mg orally was consistent with previous data for plazomicin alone in healthy subjects (Table 3). 10 At the clinically intended plazomicin dose, the geometric mean C max was 84.6 µg/mL (geometric coefficient of variation, 12.4); with plazomicin human plasma protein binding of approximately 20%, 11 the corresponding C max,u was 67.7 µg/mL. AUC 0-Ý , area under the concentration-time curve extrapolated to infinity; AUC 0-tlast , AUC from time zero to the last quantifiable concentration; CL T , total plasma clearance after intravenous plazomicin administration; C max , maximum observed plasma concentration; g%CV, geometric coefficient of variation; k el , apparent terminal elimination rate constant; PK, pharmacokinetic; SD, standard deviation; t 1/2 , apparent terminal elimination half-life; T max , time to reach C max ; V z , volume of distribution during the elimination phase after intravenous administration; V ss , volume of distribution estimated at steady state.…”

“…The pharmacokinetic (PK) profile of plazomicin has been extensively characterized in healthy subjects and in subjects with renal impairment . Plazomicin concentration‐time profiles decline in a multiphasic manner after single and repeated doses administered via 30‐minute intravenous (IV) infusion, consistent with the aminoglycoside class of antibiotics . Plazomicin is largely unmetabolized; approximately 90% of the dose is excreted as unchanged drug in the urine via glomerular filtration, with negligible active renal secretion …”