A translational pharmacokinetic/pharmacodynamic model to characterize bacterial kill in the presence of imipenem-relebactam

Bhagunde, Pratik; Zhang, Zufei; Racine, Fred; Carr, Donna; Jin, Wei; Young, Katherine; Rizk, Matthew L.

doi:10.1016/j.ijid.2019.08.026

Cited by 37 publications

(21 citation statements)

References 23 publications

(43 reference statements)

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“…A sensitivity analysis was performed with relebactam f AUC 0–24 hours /MIC ≥ 7.5 because this is the f AUC 0–24 hours /MIC required to achieve 2‐log kill in an HF model . Historically, for imipenem monotherapy, ~ 30% f T > MIC is required to achieve 1‐log kill to 2‐log kill in in vivo animal models .…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Analysis for Imipenem–Relebactam in Healthy Volunteers and Patients With Bacterial Infections

Bhagunde

Patel²,

Lala

et al. 2019

CPT Pharmacom & Syst Pharma

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Relebactam is a small-molecule β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin. The pharmacokinetics of relebactam and imipenem across 10 clinical studies were analyzed using data from adult healthy volunteers and patients with bacterial infections. Renal function estimated by creatinine clearance significantly affected the clearance of both compounds, whereas weight and health status were of less clinical significance. Simulations were used to calculate probability of joint target attainment (ratio of free drug area under the curve from 0 to 24 hours to minimum inhibitory concentration (MIC) for relebactam and percentage of time the free drug concentration exceeded the MIC for imipenem) for the proposed imipenem/relebactam dose of 500/250 mg, with adjustments for patients with renal impairment, administered as a 30-minute intravenous infusion four times daily. These dosing regimens provide sufficient antibacterial coverage (MIC ≤ 4 μg/mL) for all renal groups.Relebactam is a small-molecule β-lactamase inhibitor active against classes A and C β-lactamases that is being developed as a fixed-dose combination with imipenem/cilastatin (PRIMAXIN, Whitehouse Station, NJ). 1,2 Imipenem is an approved carbapenem β-lactam antibacterial agent that covers many gram-negative organisms and certain gram-positive organisms and anaerobes. 2 Cilastatin alone has no antibacterial activity, but prevents the metabolism of imipenem by renal dehydropeptidase produced in vivo.In vitro susceptibility and hollow fiber (HF) time-kill studies found that relebactam restored the activity of subinhibitory concentrations of imipenem against imipenem-resistant isolates. [3][4][5] Animal studies further confirmed the activity of relebactam, and integrated translational pharmacokinetic/ pharmacodynamic (PK/PD) modeling suggested that the combination of imipenem/relebactam would be efficacious against the majority of imipenem-resistant strains at clinically achievable doses and concentrations. 6,7 From these

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Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Analysis for Imipenem–Relebactam in Healthy Volunteers and Patients With Bacterial Infections

Bhagunde

Patel²,

Lala

et al. 2019

CPT Pharmacom & Syst Pharma

Self Cite

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“…IMI‐REL at a simulated dose of IMI 500 mg–REL 250 mg achieved time above MIC with each dosing interval of > 65% of the interval based on these dynamic MIC values, which is greater than the accepted pharmacodynamic marker of efficacy for carbapenems of > 40% time above MIC . In another hollow‐fiber in vitro model, Bhagunde and colleagues again demonstrated the ratio of AUC for free drug to MIC ( f AUC/MIC) as the primary marker of efficacy . In their model, the authors simulated an imipenem dose of 500 mg every 6 hours with relebactam doses ranging from 0–3000 mg daily.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

“…80 In another hollow-fiber in vitro model, Bhagunde and colleagues again demonstrated the ratio of AUC for free drug to MIC (fAUC/MIC) as the primary marker of efficacy. 81 In their model, the authors simulated an imipenem dose of 500 mg every 6 hours with relebactam doses ranging from 0-3000 mg daily. Their primary efficacy analyses were based on the clinically evaluated IMI-REL dose of IMI 500 mg-REL 250 mg every 6 hours.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

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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“…f T >MIC is the best pharmacokinetic/pharmacodynamic index correlating with imipenem clinical outcomes [11] . Although a significant association between PD exposure and microbiological or clinical outcomes was not found for imipenem, changing the infusion regimens and obtaining a proper f T >MIC is especially necessary for the treatment of critically ill patients [4] .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of imipenem pharmacokinetic/pharmacodynamic parameters and the impact on antimicrobial outcomes in critically ill patients

Zhang¹,

Chen²,

Xu³

et al. 2020

Preprint

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Aims: Imipenem is a widely used antibiotic for the treatment of critically ill patients with severe infections. Here, we present a translational pharmacokinetic/pharmacodynamic mathematical model to assess fT>MIC and evaluate the clinical outcomes of imipenem treatment in critically ill patients. Methods: Critically ill patients with severe infections were included in our study. Blood samples at different time points were collected after imipenem plasma concentration reached a steady state in vivo. A one-compartment model was used for pharmacokinetic profiles. PK/PD parameters were calculated separately with or without a mathematical model. Clinical results were mainly defined as the microbiological results. The resolution of fever and the decrease in PCT and WBC levels were also considered. Results: A total of 54 patients were enrolled in our study. The fT>MIC calculated by the mathematical model was 67.26±39.96%, and the fT>MIC was 73.75±23.11% without the model. The PK/PD parameters calculated between the two groups were not significantly different. Regarding clinical outcomes, 35 (64.3%) patients were defined as having clinical success. The fT>MIC was 83.33±12.90% in the clinical success group and 59.42±19.11% in the clinical failure group. The fT>MIC was significantly different between the two groups (p=0.022). Based on the regimens, the PCT level decreased to at least 20% of the peak level and the WBC level decreased during the first 3 days when patients' fT>MIC was greater than 70%. Conclusion: The pharmacokinetic mathematical model may be used for PK/PD parameter evaluation. To treat critically ill patients, achieving fT>MIC greater than 70% may be necessary.

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A translational pharmacokinetic/pharmacodynamic model to characterize bacterial kill in the presence of imipenem-relebactam

Cited by 37 publications

References 23 publications

Population Pharmacokinetic Analysis for Imipenem–Relebactam in Healthy Volunteers and Patients With Bacterial Infections

Population Pharmacokinetic Analysis for Imipenem–Relebactam in Healthy Volunteers and Patients With Bacterial Infections

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

Evaluation of imipenem pharmacokinetic/pharmacodynamic parameters and the impact on antimicrobial outcomes in critically ill patients

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