Modeling & Simulation Exercise to Recommend Dosage Regimens for Patients with End-Stage Renal Disease Receiving Hemodialysis
Holly Kimko, Donna Skee, Joseph Massarella, Iolanda Cirillo
Janssen Pharmaceutical Companies of Johnson & Johnson
Objectives: End-stage-renal-disease (ESRD) is a condition when kidney does not adequately excrete wastes via urine to regulate hormones and chemicals in the body, which requires hemodialysis. Due to kidney failure, drug exposure in the body is higher than that of subjects with normal renal function; hence dose adjustment is necessary in ESRD patients. Ceftobiprole  is a first broad-spectrum cephalosporin to treat bacterial infections including those caused by methicillin-resistant Staphylococcus aureus. This modeling and simulation exercise was performed in order to recommend ceftobiprole dosage regimens for ESRD patients who require hemodialysis thrice a week.
Methods: A final population PK model , developed from Phase 1/2/3 subjects, was used to evaluate the PK profiles of a separate ESRD subject study. After model qualification, PK profiles (median and 90 % interval) of various dosage regimens were simulated by superpositioning to account for drug extraction (60% extraction ratio) by hemodialysis. Corresponding % Time-above-MIC as a PK/PD target were calculated. A logistic regression of nausea events with respect to Cmax was conducted.
Results: The PK model predicted the observed ESRD study PK results well. Three dosage regimens were identified as viable options, considering %T>MIC, probability of causing nausea and patient-convenience. To be conservative, the lower band of 90% prediction interval of PK profiles should yield higher than 50 %T>MIC. The incidences of observed and model-predicted nausea events increased around ceftobiprole concentration of 40 ug/ml. None of the simulated dosage regimen yielded a highest median concentration above 40 ug/ml.
Conclusions: Based on modeling and simulation three dosage regimens may be suitable for patients with ESRD: (1) 250 mg, 1-hr infusion, Q24h, (2) 500mg, 1-hr infusion, Q48h with an additional 250 mg 1-hr infusion on the 7th day, and (3) 500mg, 1-hr infusion, Q48h, twice, followed by 750 mg, 1-hr infusion on the 5th day. Each regimen will achieve > 50% T>MIC over the dosing intervals. Maximum predicted ceftobiprole concentrations do not exceed those that have been observed previously.
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