1392. Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses to Support Inhaled ME1100 Dose Selection
Session: Poster Abstract Session: PK/PD Studies
Friday, October 5, 2018
Room: S Poster Hall
Posters
  • 00439_me1100_pkpd_ta_IDWeek18_28sep18.pdf (688.8 kB)
  • Background: ME1100 (arbekacin inhalational solution) is an inhaled aminoglycoside being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). PK-PD target attainment analyses were undertaken to evaluate ME1100 regimens for patients with HABP/VABP arising from Klebsiella pneumoniae (KP), Pseudomonas aeruginosa (PA) and Staphylococcus aureus (SA), including those with renal impairment.

    Methods:  Data used included a population pharmacokinetic (PPK) model developed using Phase 1 and post-marketing PK data, non-clinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and MIC data. Using parameter estimates from the PPK model (4-compartment model with 1st-order elimination), total-drug epithelial lining fluid concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr; mL/min/1.73 m2) and by CLcr group. Twice daily (BID) ME1100 regimens ranging from 300 to 900 mg were assessed in simulated patients with CLcr >80 to ≤120 mL/min/1.73 m2.  Percent probabilities of PK‑PD target attainment by MIC were determined based on total-drug ELF AUC:MIC ratio targets associated with 1‑ and 2-log10 CFU reductions from baseline for KP, PA and SA using  Day 1 AUC. Regimens in simulated patients with renal impairment that best matched the BID regimen in the normal CLcr group with high percent probabilities of PK-PD target attainment and a low percent probability of Cmin > 2mg/L were identified.  

    Results: ME1100 600 mg BID in simulated patients with CLcr >80 to ≤120 mL/min/1.73 m2, with 600 mg once daily, 450 mg BID and 600 mg BID in simulated patients with CLcr of 0 to ≤30, >30 to ≤50 and >50 to ≤80 mL/min/1.73 m2, respectively, achieved high percent probabilities of PK-PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at relevant MIC values for KP, PA and SA, and relatively lower Cmin values. In simulated patients with varying CLcr who received these regimens, high percent probabilities of PK-PD target attainment were achieved for KP, PA and SA at the upper margins of the MIC distributions (Figures 1-3).

    Conclusion: The data provide support for ME1100 dose selection for patients with HABP/VAPB.

     

    Sujata M. Bhavnani, Pharm.D., M.S.1, Jeffrey P. Hammel, M.S., B.S.1, Elizabeth A. Lakota, Pharm.D., M.S.1, Brian D. VanScoy, B.S.1, Yu Nagira, M.S.2, Christopher M. Rubino, Pharm.D.1, Nobuo Sato, Ph.D.2, Tomokazu Koresawa, M.S.2, Kenichiro Kondo, Ph.D.2 and Paul G. Ambrose, Pharm.D., FIDSA1, (1)ICPD, Schenectady, NY, (2)Meiji Seika Pharma Co., Ltd., Chuo-ku Tokyo, Japan

    Disclosures:

    S. M. Bhavnani, Meiji Seika Pharma Co.Ltd.: Research Contractor , Research support .

    J. P. Hammel, Meiji Seika Pharma Co. Ltd.: Research Contractor , Research support .

    E. A. Lakota, Meiji Seika Pharma Co. Ltd.: Research Contractor , Research support .

    B. D. VanScoy, Meiji Seika Pharma Co. Ltd.: Research Contractor , Research support .

    Y. Nagira, Meiji Seika Pharma Co.Ltd.: Employee , Salary .

    C. M. Rubino, Meiji Seika Pharma Co.Ltd.: Research Contractor , Research support .

    N. Sato, Meiji Seika Pharma Co. Ltd.: Employee , Salary .

    T. Koresawa, Meiji Seika Pharma Co. Ltd.: Employee , Salary .

    K. Kondo, Meiji Seika Pharma Co. Ltd.: Employee , Salary .

    P. G. Ambrose, Meiji Seika Pharma Co. Ltd.: Research Contractor , Research support .

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