CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 206494Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) CLINICAL PHARMACOLOGY REVIEW NDA: 206-494 Submission Date(s): 06/25/2014 Drug Ceftazidime-Avibactam Trade Name AVICAZ® Injection OCP Reviewers Seong H, Jang, Ph.D. OCP Team Leader Kimberly Bergman, Pharm.D. OCP PM Team Reader Jeffry Florian, Ph.D. OCP Division DCP4 OND Division DAIP Sponsor Cerexa, Inc Relevant IND(s) IND 101,307 Submission Type; Code Original; 1S; Priority Review Formulation; Strength(s) Powder for IV Injection (2 g ceftazidime and 0.5 g avibactam) in a single-use, clear glass vial Indication Treatment of infections proven or suspected to be caused by AVICAZ- susceptible organisms (including ceftazidime resistant, β-lactamase-producing, Gram-negative bacteria) in the following indications: Complicated Intra-abdominal Infection Complicated Urinary Tract Infection, including Acute Pyelonephritis Limited Use Indication: Aerobic Gram-negative Infections with Limited Treatment Options in patients ≥ 18 years of age Dosage and 2.5 g (2 g ceftazidime and 0.5 g avibactam) administered every 8 hours by Administration intravenous (IV) infusion over 2 hours Table of Contents 1. Executive Summary ........................................................................................................... 2 1.1. Recommendation ............................................................................................................ 3 1.2. Phase 4 Commitments .................................................................................................. 3 1.3. Summary of Important Clinical Pharmacology findings ........................................... 3 2. Question-Based Review ........................................................................................................ 8 2.1. General attributes of the drug ..................................................................................... 8 2.2. General Clinical Pharmacology ................................................................................ 11 2.3. Intrinsic Factors .......................................................................................................... 39 2.4. Extrinsic factors........................................................................................................... 50 2.6. Analytical Section ........................................................................................................ 53 3. Labeling Recommendation ............... 58 4. Appendix .............................................................................................................................. 92 4.1. Pharmcometrics Review .................................................................................................. 92 1 Reference ID: 3689069 1. Executive Summary The sponsor submitted this NDA for the use of ceftazidime in combination with avibactam (CAZ-AVI) in the treatment of complicated urinary tract infection (cUTI) and complicated intra- abdominal infection (cIAI). The recommended dosage of CAZ-AVI is 2.5 g (2 g ceftazidime + 0.5 g avibactam) administered every 8 hours (q8h) by intravenous (IV) infusion over 2 hours in patients ≥ 18 years of age with normal renal function or mild renal impairment (creatinine clearance [CRCL] > 50 mL/min). Dose adjustments for patients with moderate and severe renal impairment and patients with end-stage renal disease requiring hemodialysis are recommended (see below). Ceftazidime, the bactericidal β-lactam component of CAZ-AVI, is approved for the treatment of bacterial infections caused by susceptible pathogens. Included among these are cUTI caused by Pseudomonas aeruginosa, Enterobacter spp., Proteus spp., Klebsiella spp., and Escherichia coli and serious intra-abdominal infections, including peritonitis, caused by E. coli, Klebsiella spp., Staphylococcus aureus (methicillin-susceptible strains), and polymicrobial infections caused by aerobic and anaerobic organisms. Resistance to cephalosporins due to β-lactamase-producing bacteria is increasing in various regions worldwide. Avibactam, a β-lactamase inhibitor, is intended to extend the activity of ceftazidime to include Gram-negative bacteria that are non- susceptible to ceftazidime alone due to the production of a β-lactamase. As a β-lactamase inhibitor, avibactam has a spectrum of activity against Ambler class A extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemase class A (KPC) enzymes, Ambler class C enzymes, and some class D β-lactamases. Avibactam has no meaningful antibacterial activity at achievable concentrations in humans. Avibactam is not approved in any markets worldwide. Clinical studies have been conducted with avibactam in combination with ceftazidime, ceftaroline fosamil, and aztreonam. The clinical development program for CAZ-AVI includes 10 completed Phase 1 clinical pharmacology studies, 1 completed Phase 2 study in patients with cUTI, and 1 completed Phase 2 study in patients with cIAI. In addition, avibactam pharmacokinetic (PK) data from 4 completed Phase 1 clinical pharmacology studies in the ceftaroline fosamil-avibactam (CXL) development program are included in this submission. The proposed dosing regimens provides ~100% of the probability of the PK/PD targets (i.e., 50%fT > MIC for ceftazidime and 50%fT > 1.0 mg/L) at up to 8 µg/mL of CAZ-AVI MIC (i.e., measured using a fixed concentration of avibactam of 4 mg/L). Together with the efficacy results of Phase 2 studies, the proposed dosing regimen of CAZ-AVI appears to be appropriate for organisms with MIC values up to 8 µg/mL of CAZ-AVI MIC. However, the originally proposed dosing regimens for patients with moderate or severe renal impairment are recommended to be revised because (a) the ongoing Phase 3 cIAI study showed a lower clinical cure rate in patients with moderate (CrCL 31-50 mL/min) renal impairment who received the originally proposed dosing regimen and (b) the originally proposed dosing regimens are predicted to result in substantially lower exposure of ceftazidime and avibactam in moderate and severe renal impairment patients compared with patients with normal renal function. 2 Reference ID: 3689069 1.1. Recommendation From a Clinical Pharmacology perspective, we support the approval of AVICAZ injection for the proposed indications in patients ≥ 18 years of age. However, we recommend the originally proposed dosing regimens for patients with moderate and severe renal impairments be revised as follows. Estimated Creatinine Recommended Dosage Regimen for AVICAZ Clearance (mL/min)a > 30 to ≤ 50 1.25 g (1.0 g ceftazidime + 0.25 g avibactam) IV (over 2 hours) every 8 hours > 15 to ≤ 30 0.94 g (0.75 g ceftazidime + 0.188 g avibactam) IV (over 2 hours) every 12 hours > 5 to ≤ 15b 0.94 g (0.75 g ceftazidime + 0.188 g avibactam) IV (over 2 hours) every 24 hours ≤ 5b 0.94 g (0.75 g ceftazidime + 0.188 g avibactam) IV (over 2 hours) every 48 hours a As calculated using the Cockcroft-Gault formula. b Both ceftazidime and avibactam are hemodialyzable; thus, AVICAZ should be administered after hemodialysis on hemodialysis days. 1.2. Phase 4 Commitments Conduct a study to evaluate the efficacy and safety of the alternatively recommended dosages of AVYCAZ in patients with complicated intra-abdominal infection with CRCL ≤50 mL/min. 1.3. Summary of Important Clinical Pharmacology findings Summary of Pharmacokinetics The PK of ceftazidime and avibactam are linear, with Cmax and AUC increasing in proportion to dose. Both avibactam and ceftazidime undergo limited metabolism and there is no evidence of a drug-drug interaction (DDI) between ceftazidime and avibactam. No appreciable accumulation of ceftazidime or avibactam was observed after multiple dose administration of CAZ-AVI for 11 days. Both ceftazidime and avibactam are eliminated primarily by the kidney, with the majority of the dose (80-90% ceftazidime and 85% avibactam) recovered as unchanged drug in urine. The terminal elimination half-life (T½) of ceftazidime and of avibactam is approximately 2 h in patients with normal renal function and substantially prolonged in patients with renal impairment, necessitating reduction of dose and prolongation of the dosing interval in patients with creatinine clearance (CrCL) less than 50 mL/min. A Phase 1 study conducted with CAZ- AVI in healthy adult subjects demonstrated that ceftazidime and avibactam are able to penetrate into bronchial epithelial lining fluid (ELF) to a similar extent and with similar kinetics. The exposure of both drugs in the lung was approximately 30-35% of the exposure in plasma. Less than 10% of ceftazidime is protein bound. The degree of protein binding is independent of concentration. The binding of avibactam to human plasma proteins is also low (5.7% to 8.2%) and similar across the range of concentrations tested in vitro (0.5 to 50 mg/L). The potential for DDIs with CAZ-AVI is low based on the following: both ceftazidime and avibactam undergo limited metabolism; avibactam showed no significant inhibition or induction of cytochrome P450 (CYP) enzymes in vitro, and ceftazidime also showed no CYP induction potential; both avibactam and ceftazidime have low binding to human plasma proteins; and, 3 Reference ID: 3689069 avibactam and ceftazidime did not inhibit any major renal or hepatic transporters in vitro in the clinically relevant exposure range. Avibactam was shown to be a substrate of human organic anion transporter (OAT)1 and OAT3 in vitro, which may contribute to its