1975. Population Pharmacokinetic (PPK) Analysis for Intravenous (IV) and Oral (PO) Delafloxacin Using Data from Phase 1 Studies
Session: Poster Abstract Session: Antimicrobial Pharmacokinetics and Pharmacodynamics
Saturday, October 29, 2016
Room: Poster Hall
Background: Delafloxacin is an investigational IV and PO anionic quinolone being developed for acute skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). To assist with future dose selection assessments for CABP, the objectives of these analyses were to refine a previously-developed PPK model [ICAAC 2010, A1-682] and to explore covariates predictive of pharmacokinetic (PK) variability using pooled IV and PO data from Phase 1 studies.

Methods: PK data were obtained from healthy subjects and those with renal impairment after delafloxacin IV and PO (under fed and fasted conditions) administration. Delafloxacin daily doses ranged from 300 to 900 mg. Alterations to the structural model were evaluated and covariates (e.g., renal function, body size) associated with interindividual variability in delafloxacin exposure were explored.

Results: The analysis dataset contained 6211 plasma concentrations from 157 subjects with creatinine clearance (CLcr) ranging from 17.2 to 175.4 mL/min/1.73 m2 and body weight (WTKG) ranging from 51 to 140.4 kg. A three-compartment model with mixed linear plus saturable elimination and two parallel first-order absorption processes provided unbiased estimates of delafloxacin exposure (r2= 0.902). Additionally, the good agreement between simulated and observed plasma concentrations from Phase 2 patients with ABSSSI after IV delafloxacin provided support for using this model to predict exposures for patients with CABP (Figure 1). Covariate analyses revealed 3 statistically significant relationships: 1) the linear portion of clearance decreased with decreasing baseline CLcr; 2) the volume of the central compartment increased with increasing WTKG; and 3) the absorption rate was slower after a high-fat meal compared to fasted conditions. Of these, only that for CLcr demonstrated a clinically meaningful effect on delafloxacin exposure (Figure 2).

Conclusion: The final PPK model provided precise fits to delafloxacin PK data after IV and PO administration in healthy subjects and patients with ABSSSI. CLcr exerted a clinically relevant influence on delafloxacin exposure. This model will be useful to assess delafloxacin dosing recommendations for patients with mild to severe renal impairment.  


Li Zhang, M.D., Ph.D.1, Sujata Bhavnani, Pharm.D., M.S.1, Paul G. Ambrose, Pharm.D., FIDSA1, Sue K. Cammarata, M.D.2 and Christopher M. Rubino, Pharm.D.1, (1)Institute for Clinical Pharmacodynamics, Schenectady, NY, (2)Melinta Therapeutics, Inc., New Haven, CT

Disclosures:

L. Zhang, Melinta Therapeutics Inc.: Research Contractor , Research support

S. Bhavnani, Melinta Therapeutics Inc.: Research Contractor , Research support

P. G. Ambrose, Melinta Therapeutics Inc.: Research Contractor , Research support

S. K. Cammarata, Melinta Therapeutics Inc.: Employee , Salary

C. M. Rubino, Melinta Therapeutics Inc.: Research Contractor , Research support

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