Benzylpenicillin (PCG; 180 micromol/kg), a classic beta-lactam antibiotic, was intravenously given to Sprague-Dawley (SD) rats and multidrug resistance-associated protein 2 (Mrp2)-deficient Eisai hyperbilirubinemic rats (EHBR). A percentage of the [(3)H]PCG was excreted into the bile of the rats within 60 min (SD rats: 31.7% and EHBR: 4.3%). Remarkably, a transient increase in the bile flow ( approximately 2-fold) and a slight increase in the total biliary bilirubin excretion were observed in SD rats but not in the EHBR after PCG administration. This suggests that the biliary excretion of PCG and its choleretic effect are Mrp2-dependent. Positive correlations were observed between the biliary excretion rate of PCG and bile flow (r(2) = 0.768) and more remarkably between the biliary excretion rate of GSH and bile flow (r(2) = 0.968). No ATP-dependent uptake of [(3)H]PCG was observed in Mrp2-expressing Sf9 membrane vesicles, whereas other forms of Mrp2-substrate transport were stimulated in the presence of PCG. GSH efflux mediated by human MRP2 expressed in Madin-Darby canine kidney II cells was enhanced in the presence of PCG in a concentration-dependent manner. In conclusion, the choleretic effect of PCG is caused by the stimulation of biliary GSH efflux as well as the concentrative biliary excretion of PCG itself, both of which were Mrp2 dependent.
Tebipenem pivoxil (TBPM-PI, ME1211) has been under development as the world's first oral carbapenem for treatment of otolaryngological/respiratory infections caused by drug-resistant S. pneumoniae in pediatric patients. In order to treat these infections effectively, it is important to design optimal dosing regimens based on the pharmacokinetics/pharmacodynamics (PK/PD) relationships, which can be characterized by clarifying the pharmacokinetics of tebipenem (TBPM) in the pediatric population. We therefore performed an population pharmacokinetic analysis using plasma TBPM concentrations obtained from pediatric patients with otolaryngological infection or bacterial pneumonia (0.5-16 years old; n=217, 395 points), after repeated oral administration of TBPM-PI at a dose of 4 or 6 mg/kg b.i.d. A one-compartment model with first-order absorption was adopted. In analysis, weight-normalized creatinine clearance (Ccr) and age were the most significant covariates that respectively explained inter-subject variability in weight-normalized apparent clearance (CL/F) and volume of distribution (Vd/F) of TBPM. The CL/F of TBPM increased with Ccr, and the Vd/F decreased with age. Based on the results of the present analysis, validity of the presently recommended dosage regimen of TBPM-PI in pediatric patients is discussed.
ME1100, an inhalation solution of arbekacin, an aminoglycoside, is being developed for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia. The objective of these analyses was to develop a population pharmacokinetic model to describe the arbekacin concentration-time profile in plasma and epithelial lining fluid (ELF) following ME1100 administration. Data were obtained from a postmarketing study for an intravenous (i.v.) formulation of arbekacin, a phase 1 study of ME1100 in healthy volunteers, and a phase 1b study of ME1100 in mechanically ventilated subjects with bacterial pneumonia. Data from the postmarketing study were utilized to develop a population pharmacokinetic model following i.v. administration, and this model was subsequently utilized as the foundation for development of the model characterizing arbekacin disposition following inhalation of ME1100. The final model utilized two compartments for both plasma and ELF disposition, with movement of arbekacin between the ELF and plasma parameterized using linear first-order rate constants. A bioavailability term was included for the inhalational route of administration, which was estimated to be 19.5% for a typical subject. The model included normalized creatinine clearance (CLcrn) and weight as covariates on arbekacin clearance: CL ϭ (weight/52.2) 0.855 ·[(CLcrn-77)·0.0289 ϩ 2.32]. The model simultaneously described arbekacin concentrations following both i.v. and inhaled administration and provided acceptable fits to the plasma and ELF data (r 2 of 0.922 and 0.557 for observed versus fitted concentrations, respectively). The developed model will be useful for conducting future analyses to support ME1100 dose selection.
ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. Data used included a population pharmacokinetic (PPK) model 4-compartment model with 1st-order elimination, non-clinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr; mL/min/1.73 m2). Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC:MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PK-PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/mL), P. aeruginosa (4 μg/mL), and S. aureus (0.5 μg/mL) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr >80 to ≤120 mL/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, 600 mg once daily in simulated patients with CLcr of >50 to ≤80, >30 to ≤50 and 0 to ≤30 mL/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.
BackgroundME1100 (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.MethodsData used included a population pharmacokinetic (PPK) model developed using Phase 1 and post-marketing PK data, nonclinical PK-PD targets from one compartment in vitro and/or in vivo infection models, and MIC data. Using parameter estimates from the PPK model (four-compartment model with first-order elimination), total-drug epithelial lining fluid concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr; mL/minute/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/minute/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 > 2 mg/L were identified.ResultsME1100 600 mg BID in simulated patients with CLcr >80 to ≤120 mL/minute/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/minute/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). ConclusionThe data provide support for ME1100 dose selection for patients with HABP/VAPB.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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