Model‐Informed Drug Development for Antimicrobials: Translational PK and PK/PD Modeling to Predict an Efficacious Human Dose for Apramycin

Sou, Tomás; Hansen, Jens Munk; Liepinsh, Edgars; Backlund, Maria; Ercan, Onur; Grı̄nberga, Solveiga; Cao, Sha; Giachou, Paraskevi; Petersson, Anna; Tomczak, Magdalena; Urbaś, Małgorzata; Żabicka, Dorota; Lundberg, Carina Vingsbo; Hughes, Diarmaid; Hobbie, Sven N.; Friberg, Lena E.

doi:10.1002/cpt.2104

Cited by 28 publications

(50 citation statements)

References 43 publications

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“…Apramycin, which is in Phase I clinical trials, has been shown to be active against Enterobacterales that produce 16S-RMTases, which confer resistance to all other currently available aminoglycosides. 116 , 117 Although limited data about apramycin against MBL-producing Enterobacterales is currently available, it holds potential to become a therapeutic option for MBL-producing Enterobacterales based on its spectrum of activity.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales

Tan

Kim

Baugh

et al. 2021

IDR

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The spread of metallo-β-lactamase (MBL)-producing Enterobacterales worldwide without the simultaneous increase in active antibiotics makes these organisms an urgent public health threat. This review summarizes recent advancements in diagnostic and treatment strategies for infections caused by MBL-producing Enterobacterales. Adequate treatment of patients infected with MBL-producing Enterobacterales relies on detection of the β-lactamase in the clinic. There are several molecular platforms that are currently available to identify clinically relevant MBLs as well as other important serine-β-lactamases. Once detected, there are several antibiotics that have historically been used for the treatment of MBL-producing Enterobacterales. Antimicrobials such as aminoglycosides, tetracyclines, fosfomycin, and polymyxins often show promising in vitro activity though clinical data are currently lacking to support their widespread use. Ceftazidime-avibactam combined with aztreonam is promising for treatment of infections caused by MBL-producing Enterobacterales and currently has the most clinical data of any available antibiotic to support its use. While cefiderocol has displayed promising activity against MBL-producing Enterobacterales in vitro and in preliminary clinical studies, further clinical studies will better shed light on its place in treatment. Lastly, there are several promising MBL inhibitors in the pipeline, which may further improve the treatment of MBL-producing Enterobacterales.

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Section: Introductionmentioning

confidence: 99%

Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales

Tan

Kim

Baugh

et al. 2021

IDR

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“…In our model, the EBL-1003 exposure in plasma and ELF (fAUC plasma and fAUC ELF , respectively) achieved by doses corresponding to the predicted therapeutic dose for systemic Escherrichia coli infections in humans (30 mg/kg) were considerably higher than the predicted target values for A. baumannii [17]. PK/PD predictions suggested >99•9% PTA for MIC ≤8 µg/mL in the lung of healthy individuals and even higher PTA in patients with a reduced (80 mL/min) creatinine clearance, representative of typical patients in the target patient population [27,28].…”

Section: Pkpd and Probability Of Target Attainment (Pta) Analysismentioning

confidence: 83%

“…The AUC plasma of 339 h×μg/mL for this dose in mice roughly corresponds to the expected therapeutic AUC in humans ( Figure 3B). The human dose predicted to achieve a similar AUC plasma exposure level is approximately 30 mg/kg [17].…”

Section: Lung Efficacy Dose Fractionation Studies Lung Pk and Maldi-mentioning

confidence: 99%

“…In the absence of a model for the human PK of EBL-1003, human concentration time profiles were simulated from a model of human PK of gentamicin. While being an assumption, this hypothesis is backed up by the chemical similarity of the two molecules and the similarity of their PK in various animal species [17].…”

Section: Pkpd and Probability Of Target Attainment (Pta) Analysismentioning

confidence: 99%

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Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice

Becker

Aranzana-Climent

Cao

et al. 2021

Clinical Microbiology and Infection

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“…In line with these earlier studies, we recently found T > MIC to have a higher correlation than AUC/ MIC in the thigh infection mouse model for the aminoglycoside apramycin, currently in clinical development. 18 Correlations for the two indices were, however, similar when only data from the q2h to q8h intervals were considered. There is consequently a dependence on the PK profile and the dosing interval in relation to the half-life of the drug for the correlations obtained.…”

Section: Limitation Of Static Pk/pd Targets For Translationmentioning

confidence: 85%

Pivotal Role of Translation in Anti‐Infective Development

Friberg

2021

Clin Pharma and Therapeutics

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The value of model‐based translation in drug discovery and development is now effectively being recognized in many disease areas and among various stakeholders. Such quantitative approaches are expected to facilitate the selection on which compound to prioritize for successful development, predict the human efficacious dose based on preclinical data with adequate precision, guide design, and de‐risk later development stages. The importance of time‐dependencies, which are typically species‐dependent due to different turnover rates of biological processes, is, however, often neglected. For bacterial infections, the choice of dosing regimen is typically relying on preclinical pharmacokinetic (PK) and pharmacodynamic (PD) data, because the bacterial load and disease severity, and consequently the PK/PD relationship, cannot be quantified well on clinical data, given the low‐information end points used. It is time to recognize the limitations of using time‐collapsed approaches for translation (i.e., methods where targets are based on summary measures of exposure and response). Models describing the full time‐course captures important quantitative information of drug distribution, bacterial growth, antibiotic killing, and resistance development, and can account for species‐differences in the PK profiles driving the killing. Furthermore, with a model‐based approach for translation, we can take a holistic approach in development of a joint model for in vitro, in vivo, and clinical data, as well as incorporating information on the contribution of the immune system. Such advancements are anticipated to facilitate rational decision making during various stages of drug development and in the optimization of treatment regimens for different groups of patients.

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Model‐Informed Drug Development for Antimicrobials: Translational PK and PK/PD Modeling to Predict an Efficacious Human Dose for Apramycin

Cited by 28 publications

References 43 publications

Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales

Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales

Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice

Pivotal Role of Translation in Anti‐Infective Development

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