Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia

Aranzana-Climent, Vincent; Hughes, Diarmaid; Cao, Sha; Tomczak, Magdalena; Urbaś, Małgorzata; Żabicka, Dorota; Lundberg, Carina Vingsbo; Hansen, Jens Munk; Lindberg, Johan; Hobbie, Sven N.; Friberg, Lena E.

doi:10.1016/j.cmi.2022.05.003

Cited by 11 publications

(8 citation statements)

References 27 publications

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“…Our results are in support of previous connotations that apramycin may represent a new generation of therapeutic aminoglycoside antibiotics that evades the widespread antimicrobial resistance that compromises the clinical utility of 4,6-disubstituted 2-deoxystreptamines such as gentamicin, tobramycin, netilmicin, amikacin, plazomicin, arbekacin, etimicin, and others. The apramycin MIC values reported in this study are well aligned with the apramycin PKPD targets modelled previously for once-daily intravenous infusion in humans [15,[17][18][19]. The present study complements these prior reports by expanding our knowledge to specifically include 470 blood culture isolates and an isolate panel of well-defined geographic origin.…”

Section: Discussionsupporting

confidence: 86%

“…Clinical resistant breakpoints for apramycin do not exist. The amikacin breakpoints were tentatively applied as interpretative cut-off values for apramycin in this study, based on previous reports indicating the in-vitro potency and PKPD of apramycin resembles that of amikacin in models using amikacin-susceptible strains [17][18][19]. For the aminoglycoside plazomicin, the FDA-Identified Susceptibility Test Interpretive Criteria (STIC) for Enterobacterales were applied.…”

Section: Ast Interpretationmentioning

confidence: 99%

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Apramycin susceptibility of multidrug-resistant Gram-negative blood culture isolates in five countries in Southeast Asia

Gysin

Hon

Tan

et al. 2022

International Journal of Antimicrobial Agents

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Section: Discussionsupporting

confidence: 86%

Section: Ast Interpretationmentioning

confidence: 99%

Apramycin susceptibility of multidrug-resistant Gram-negative blood culture isolates in five countries in Southeast Asia

Gysin

Hon

Tan

et al. 2022

International Journal of Antimicrobial Agents

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“…In earlier stages of drug development, we made use of gentamicin PPK to predict the human efficacious dose since the PK of gentamicin and apramycin have been shown to be similar in preclinical studies. 9 , 16 , 17 This illustrates how model-informed drug development can be used to support drug development 41 before patient information is available. Defining the dose for Phase II based on a reduced eGFR also reduces the risk to suggest a dosing strategy that may lead to exposures above the studied range in Phase I and thereby increase the risk of toxicity.…”

Section: Discussionmentioning

confidence: 99%

“… 9 , 16 This dose regimen was also recently predicted to be efficacious in clinical pneumonia caused by Gram-negative bacteria based on translational in vitro and in vivo PKPD modelling. 17 …”

Section: Introductionmentioning

confidence: 99%

Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose

Zhao

Chirkova²,

Rosenborg

et al. 2022

Journal of Antimicrobial Chemotherapy

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Background Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure. Objectives To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial. Methods The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis. Results A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min. Conclusions The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily.

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“…The reliability of the transferability of in vitro growth characteristics to human in vivo conditions to achieve a direct translation of the bacterial burden in patients is still a subject of research. One study, for example, analysed the same bacterial strain in vitro and in vivo and showed that model parameters may need to be adjusted to enable quantitative translation of the bacterial concentrations [ 40 ]. However, PKPD models allow for the drawing of inferences regarding which dosing regimen and shape of human concentration-time profile influence bacterial killing in the most favourable way.…”

Section: Discussionmentioning

confidence: 99%

Model-Informed Translation of In Vitro Effects of Short-, Prolonged- and Continuous-Infusion Meropenem against Pseudomonas aeruginosa to Clinical Settings

et al. 2022

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Pharmacokinetic-pharmacodynamic (PKPD) models have met increasing interest as tools to identify potential efficacious antibiotic dosing regimens in vitro and in vivo. We sought to investigate the impact of diversely shaped clinical pharmacokinetic profiles of meropenem on the growth/killing patterns of Pseudomonas aeruginosa (ARU552, MIC = 16 mg/L) over time using a semi-mechanistic PKPD model and a PK/PD index-based approach. Bacterial growth/killing were driven by the PK profiles of six patient populations (infected adults, burns, critically ill, neurosurgery, obese patients) given varied pathogen features (e.g. EC50, growth rate, inoculum), patient characteristics (e.g. creatinine clearance), and ten dosing regimens (including two dose levels and 0.5-h, 3-h and continuous-infusion regimens). Conclusions regarding the most favourable dosing regimen depended on the assessment of (i) the total bacterial load or fT>MIC (time that unbound concentrations exceed the minimum inhibitory concentration); (ii) the median or P0.95 profile of the population; and (iii) 8 h or 24 h time points. Continuous infusion plus loading dose as well as 3-h infusions (3-h infusions: e.g. for scenarios associated with low meropenem concentrations, P0.95 profiles, and MIC ≥ 16 mg/L) appeared superior to standard 0.5-h infusions at 24 h. The developed platform can serve to identify promising strategies of efficacious dosing for clinical trials.

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Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia

Cited by 11 publications

References 27 publications

Apramycin susceptibility of multidrug-resistant Gram-negative blood culture isolates in five countries in Southeast Asia

Apramycin susceptibility of multidrug-resistant Gram-negative blood culture isolates in five countries in Southeast Asia

Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose

Model-Informed Translation of In Vitro Effects of Short-, Prolonged- and Continuous-Infusion Meropenem against Pseudomonas aeruginosa to Clinical Settings

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