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Clinical Pharmacology and Biopharmaceutics Review(S) CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 200327 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) CLINICAL PHARMACOLOGY REVIEW NDA: 200-327 Submission Date(s): • 30 Dec 2009 (SDN 1) • 30 Apr 2010 (SDN 14) • 04 Feb 2010 (SDN 7) • 18 Jun 2010 (SDN 19) • 23 Apr 2010 (SDN 10) • 06 Aug 2010 (SDN 31) • 29 Apr 2010 (SDN 13) • 18 Aug 2010 (SDN 34) Drug Ceftaroline Fosamil for Injection Trade Name TEFLARO™ (proposed) OCP Reviewer Aryun Kim, Pharm.D. OCP Team Leader Charles Bonapace, Pharm.D. PM Reviewer Yongheng Zhang, Ph.D. PM Team Leader Pravin Jadhav, Ph.D. OCP Division DCP4 OND division DAIOP (520) Sponsor Cerexa, Inc., Oakland, CA Relevant IND(s) IND 71,371 Submission Type; Code Original New Drug Application (New Molecular Entity), 1S Formulation; Strength(s) Sterile (b) (4) of ceftaroline fosamil and L-arginine supplied as powder in single-use, 20-cc, clear, Type I glass vials containing 600 mg or 400 mg of ceftaroline fosamil Indication For the treatment of complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) caused by designated susceptible isolates of Gram-positive and Gram-negative microorganisms Dosage and 600 mg administered every 12 hours by intravenous infusion over 1 hour Administration in patients ≥18 years of age • for 5-14 days for treatment of cSSSI • for 5-7 days for treatment of CABP 1. EXECUTIVE SUMMARY 5 1.1 Recommendations 5 1.2 Phase 4 Commitments 6 1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics Findings 6 2. QUESTION-BASED REVIEW 11 2.1 General Attributes of the Drug 11 2.2 General Clinical Pharmacology 13 2.3 Intrinsic Factors 37 2.4 Extrinsic Factors 56 2.5 General Biopharmaceutics 58 2.6 Analytical Section 58 3. DETAILED LABELING RECOMMENDATIONS 62 4. APPENDICES 85 4.1 Individual Study Report Reviews 85 1 4.1.1 In Vitro Studies 85 4.1.2 General Pharmacokinetics/Pharmacodynamics 103 Study P903-01 104 Study P903-13 119 Study P903-14 129 4.1.3 Intrinsic Factors 138 Study P903-02 139 Study P903-04 156 Study P903-11 170 Study P903-15 182 Study P903-18 193 4.1.4 Extrinsic Factors 208 4.2 Pharmacometrics Review 218 2 Abbreviations Ae, cumulative amount excreted in urine AUC, area under plasma concentration-time curve AUC24, area under plasma concentration-time curve over 24 hours AUCinf, area under plasma concentration-time curve from time 0 to infinity AUCtau, area under plasma concentration-time curve over dosing interval AZT, aztreonam Cmax, maximum observed plasma concentration Ctr, trough plasma concentration CABP, community-acquired bacterial pneumonia CART, classification and regression tree analysis CE, clinically evaluable analysis population CI, confidence interval CL, plasma clearance CLNon-R, non-renal clearance CLR, renal clearance CLSI, Clinical and Laboratory Standards Institute CrCL, creatinine clearance CRO, ceftriaxone cSSSI, complicated skin and skin structure infections CV, coefficient of variation CYP450, cytochrome P450 DC-TEAE, discontinuation due to treatment-emergent adverse event ESBL, extended-spectrum β-lactamase ESRD, end-stage renal disease f, free unbound (i.e., microbiologically active) drug fT>MIC, time of free drug concentrations above the minimum inhibitory concentration HD, hemodialysis HPLC, high performance liquid chromatography IM, intramuscular IRT, Interdisciplinary Review Team for QT Studies IV, intravenous LC-MS/MS, liquid chromatography with tandem mass spectrometry LLOQ, lower limit of quantification MIC, minimum inhibitory concentration MIC50, minimum inhibitory concentration for 50% of bacterial population MIC90, minimum inhibitory concentration for 90% of bacterial population MITT, modified intent-to-treat analysis population MITTE, modified intent-to-treat efficacy analysis population MRSA, methicillin-resistant Staphylococcus aureus MSSA, methicillin-susceptible Staphylococcus aureus NDA, new drug application P-gp, P-glycoprotein PAE, post-antibiotic effect PBP, penicillin-binding protein PD, pharmacodynamics 3 PISP, penicillin-intermediate Streptococcus pneumoniae PK, pharmacokinetics PK-PD, pharmacokinetics-pharmacodynamics PRSP, penicillin-resistant Streptococcus pneumoniae PSSP, penicillin-susceptible Streptococcus pneumoniae Q12h, every 12 hours Q24h, every 24 hours QC, quality control QTcIb, QT interval corrected for heart rate using individual subject correction formula based on baseline QT-RR slope ∆QTcIb, change in QTcIb from baseline ∆∆QTcIb, between-treatment difference in ∆QTcIb SAE, serious adverse event SD, standard deviation t1/2, elimination half-life Tmax, time of maximum observed plasma concentration TEAE, treatment-emergent adverse event TOC, test-of-cure visit ULOQ, upper limit of quantification Vc, apparent volume of distribution of the central compartment Vp, apparent volume of distribution of the peripheral compartment Vss, apparent steady-state volume of distribution Vz, apparent volume of distribution of the terminal phase VAN, vancomycin 4 1. EXECUTIVE SUMMARY Cerexa Inc., submitted a New Drug Application (NDA) for ceftaroline fosamil for the treatment of complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) caused by susceptible organisms. Ceftaroline fosamil is a semi-synthetic cephalosporin prodrug that is converted in vivo to the microbiologically active ceftaroline. The proposed clinical dosing regimen for ceftaroline fosamil is 600 mg every 12 hours (Q12h) by intravenous (IV) infusion over 1 hour in adults ≥18 years of age for 5-14 days for treatment of cSSSI and for 5-7 days for treatment of CABP. Clinical components of the ceftaroline fosamil NDA are summarized as follows: • Seven in vitro studies with human biomaterials were submitted, evaluating plasma protein binding, biotransformation of prodrug in plasma, metabolism in hepatic microsomes, and inhibition/induction of cytochrome P450 (CYP450) isoenzymes. • Eleven Phase 1 studies evaluating pharmacokinetics of ceftaroline fosamil and relevant metabolites, including the bioactive ceftaroline, were submitted. Studies included single- and multiple-dose pharmacokinetics; metabolism and elimination via mass balance and metabolite profiling; effect of renal impairment (mild, moderate, severe, and end-stage renal disease [ESRD] on intermittent hemodialysis [HD]), age (elderly and adolescent), and gender; and impact on intestinal microflora and QT prolongation. All Phase 1 studies were conducted with IV infusions of ceftaroline fosamil except for one which utilized intramuscular [IM] administration. • Two supportive Phase 2 trials evaluating safety/efficacy of ceftaroline fosamil versus active comparators in the treatment of cSSSI were submitted. In P903-03, ceftaroline fosamil 600 mg Q12h as a 1-hour IV infusion was compared to vancomycin with optional aztreonam. In P903-19, ceftaroline fosamil 600 mg Q12h as IM injection was compared to linezolid with optional aztreonam. • Four pivotal Phase 3 trials evaluating safety/efficacy of ceftaroline fosamil versus active comparators in the treatment of cSSSI and CABP were submitted. For cSSSI, ceftaroline fosamil 600 mg Q12h as a 1-hour IV infusion was compared to vancomycin 1 g IV Q12h + aztreonam 1 g IV Q12h for 5-14 days in two Phase 3 trials (P903-06 and P903-07). For CABP, ceftaroline fosamil 600 mg Q12h as a 1-hour IV infusion was compared to ceftriaxone 1 g IV Q24h for 5-7 days in two Phase 3 trials (P903-08 and P903-09). 1.1 Recommendations The Office of Clinical Pharmacology, Division 4 has reviewed NDA 200-327, and it is acceptable from a clinical pharmacology perspective. The Reviewer’s recommendations for dose adjustment for renal impairment should be incorporated in the label as indicated in Table 1.1-1. 5 Table 1.1-1 Dose recommendations for ceftaroline fosamil by renal function Renal Function Creatinine Clearance Recommended Ceftaroline Fosamil Regimensa (mL/min) By Sponsor By Reviewer Normal renal function >80 (b) (4) 600 mg Q12h Mild renal impairment >50 to ≤80 600 mg Q12h Moderate renal impairment >30 to ≤50 400 mg Q12h Severe renal impairment ≤30 300 mg Q12h End-stage renal disease (On hemodialysis [HD]) 200 mg Q12h, (ESRD) dose post-HD on HD days a All doses are as 1-h IV infusions 1.2 Phase 4 Commitments None. 1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics Findings 1.3.1 Exposure-Response Efficacy: Characteristic of β-lactams, % fT>MIC (i.e., percentage of the dosing interval that free drug concentrations are greater than the MIC) for ceftaroline was best associated with in vivo efficacy in a neutropenic murine thigh model against S. aureus (n=4, methicillin-susceptible [MSSA] and -resistant [MRSA]) and S. pneumoniae (n=5). Median % fT>MIC ≥51 was associated with 2-log kill (99% reduction) against S. aureus and S. pneumoniae strains, in accordance with historical PK-PD data of cephalosporins (optimal % fT>MIC, 50-70). Median % fT>MIC associated with bacteriostasis against S. aureus and S. pneumoniae isolates were ≥26 and ≥35, respectively. Exposure-response analysis with population PK models indicated a significant positive relationship (p=0.027) between % fT>MIC and per-patient microbiological response in microbiologically evaluable (ME) patients with mono- or poly-microbial S. aureus or S. pyogenes cSSSI (n=449). Unlike for cSSSI, an exposure-response relationship was not identified for CABP, as majority of Phase 3 patients had a high and limited range of ceftaroline exposures (91.7-100% fT>MIC). Based on PK-PD target attainment analyses by Monte Carlo
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