Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a β-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants

Rhee, Elizabeth G.; Rizk, Matthew L.; Calder, Nicole; Nefliu, Marcela; Warrington, Steven; Schwartz, Michael S.; Mangin, Eric; Boundy, Keith; Bhagunde, Pratik; Colon-Gonzalez, Francheska; Jumes, Patricia; Liu, Yang; Butterton, Joan R.

doi:10.1128/aac.00280-18

Cited by 42 publications

(55 citation statements)

References 31 publications

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“…IMI‐REL pharmacokinetic properties are summarized in Table 2. Researchers studied the effects of single and multiple doses of IMI‐REL in 106 healthy adult males, 16 elderly patients, and 8 healthy adult females . The healthy adult males were aged 18–45 years, weighed ≥ 60 kg, had a body mass index (BMI) ≤ 30 kg/m 2 , and had a CrCL > 80 ml/minute.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…The subject who was unable to complete the study reported nausea, vomiting, and diarrhea. Two phase I, randomized, double‐blind, placebo‐controlled studies of relebactam with and without imipenem were completed in 106 and 24 healthy subjects, respectively . Study one consisted single and multiple doses (parts I–IV) administered to adult men, and study two was a multidose study in adult women as well as elderly men and women.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

“…Researchers studied the effects of single and multiple doses of IMI-REL in 106 healthy adult males, 16 elderly patients, and 8 healthy adult females. 75 The healthy adult males were aged 18-45 years, weighed ≥ 60 kg, had a body mass index (BMI) ≤ 30 kg/m 2 , and had a CrCL > 80 ml/minute. The 106 male subjects were given single doses of intravenous relebactam ranging from 25-1150 mg.…”

Section: Resistancementioning

confidence: 99%

“…Two phase I, randomized, doubleblind, placebo-controlled studies of relebactam with and without imipenem were completed in 106 and 24 healthy subjects, respectively. 75 Study one consisted single and multiple doses (parts I-IV) administered to adult men, and study two was a multidose study in adult women as well as elderly men and women. In study one (part 1), no serious adverse drug events (ADEs) were reported, and there were no clinically significant abnormalities.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

“…Multiple-Dose Pharmacokinetics of Imipenem-Relebactam in 22 Healthy Volunteers75,76 = area under the concentration-time curve from 0-6 hours after drug administration; C max = maximum concentration; t 1/2 = half-life; Vd = volume of distribution.…”

mentioning

confidence: 99%

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Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

2020

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Imipenem‐cilastatin‐relebactam (IMI‐REL) is a novel β‐lactam–β‐lactamase inhibitor combination recently approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs). Relebactam is a β‐lactamase inhibitor with the ability to inhibit a broad spectrum of β‐lactamases such as class A and class C β‐lactamases, including carbapenemases. The addition of relebactam to imipenem restores imipenem activity against several imipenem‐resistant bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Clinical data demonstrate that IMI‐REL is well tolerated and effective in the treatment of cUTIs and cIAIs due to imipenem‐resistant bacteria. In a phase III trial comparing IMI‐REL with imipenem plus colistin, favorable clinical response was achieved in 71% and 70% of patients, respectively. Available clinical and pharmacokinetic data support the approved dosage of a 30‐minute infusion of imipenem 500 mg–cilastatin 500 mg–relebactam 250 mg every 6 hours, along with dosage adjustments based on renal function. In this review, we describe the chemistry, mechanism of action, spectrum of activity, pharmacokinetics and pharmacodynamics, and clinical efficacy, and safety and tolerability of this new agent. The approval of IMI‐REL represents another important step in the ongoing fight against multidrug‐resistant gram‐negative pathogens.

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Section: Pharmacokineticsmentioning

confidence: 99%

Section: Safety and Tolerabilitymentioning

confidence: 99%

Section: Resistancementioning

confidence: 99%

Section: Safety and Tolerabilitymentioning

confidence: 99%

mentioning

confidence: 99%

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Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

2020

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Thorough QTc Study of a Single Supratherapeutic Dose of Relebactam in Healthy Participants

Boundy

Liu

Bhagunde

et al. 2020

Clinical Pharm in Drug Dev

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The effects of supratherapeutic doses of intravenous (IV) relebactam on duration of ventricular depolarization and subsequent repolarization were assessed in a thorough QT/corrected QT study. This was a single-dose, double-blind (relebactam only), randomized, placebo-and positive-controlled, 3-period, balanced crossover study in healthy participants. Participants received in randomized order, and separated by a washout (ࣙ4 days), a single dose of IV relebactam 1150 mg, oral moxifloxacin 400 mg (open-label positive control), and IV placebo. Least squares mean and 2-sided 90% confidence interval for change from baseline in population-derived corrected QT intervals for relebactam, moxifloxacin, and placebo were estimated for 24 hours. The upper limit of the 90% confidence interval of all least squares mean population-derived corrected QT treatment differences from placebo was not >10 milliseconds at any time point for 24 hours. Corrected QT assay sensitivity was confirmed with moxifloxacin treatment. Analysis of electrocardiogram parameters resulted in no additional cardiac safety concerns. Overall, a supratherapeutic dose of relebactam yielded no cardiac safety events; the 1150-mg supratherapeutic dose (4.6-fold above the 250-mg therapeutic dose) was not associated with QT prolongation or other abnormal cardiodynamic parameters. This study lends additional support to relebactam's use as a β-lactamase inhibitor in antimicrobial therapy.

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Simplification of Imipenem Dosing by Removal of Weight‐Based Adjustments

Lala

Brown

Kantesaria

et al. 2018

The Journal of Clinical Pharma

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In patients with renal insufficiency, dose adjustments based on creatinine clearance and body weight have been a component of imipenem dosage instructions. The objective of the current analysis was to provide revised dosing recommendations by evaluating the impact of creatinine clearance and body weight on the pharmacokinetics of imipenem. A population pharmacokinetics model was developed with data from 465 patients and 3300 pharmacokinetic samples. Simulations provided data to support revision of the dosing recommendations to remove body weight-adjusted dosing, and the analysis formed the basis for updates that are reflected on the current imipenem label for both the United States and Europe. The optimized regimen provided an advantage in terms of improved target attainment at breakpoint minimum inhibitory concentration values of 1 and 2 μg/mL, as low-body-weight patients maintained >90% probability of target attainment compared to <90% probability of target attainment achieved with the previously approved regimen. It was concluded that additional dose adjustments for body weight were not necessary and the new scheme would simplify dosing while maintaining patient safety and efficacy.

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Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Relebactam, a β-Lactamase Inhibitor, in Combination with Imipenem and Cilastatin in Healthy Participants

Cited by 42 publications

References 31 publications

Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

Imipenem‐Cilastatin‐Relebactam: A Novel β‐Lactam–β‐Lactamase Inhibitor Combination for the Treatment of Multidrug‐Resistant Gram‐Negative Infections

Thorough QTc Study of a Single Supratherapeutic Dose of Relebactam in Healthy Participants

Simplification of Imipenem Dosing by Removal of Weight‐Based Adjustments

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