CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-311 PHARMACOLOGY REVIEW(S) MEMORANDUM Mozobil (plerixafor injection) Date: December 3, 2008 To: File for NDA 22-311 From: John K. Leighton, PhD, DABT Associate Director for Pharmacology Office of Oncology Drug Products I have examined the labeling and pharmacology/toxicology supporting reviews and memoranda provided by Drs. Shwu-Luan Lee and Haleh Saber and concur with their conclusions that Mozobil may be approved. No additional pharmacology/toxicology studies are necessary for the proposed indication. --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- John Leighton 12/3/2008 09:55:45 AM PHARMACOLOGIST MEMORANDUM Date: December 2, 2008 From: Haleh Saber, Ph.D. Pharmacology Acting Team Leader Division of Drug Oncology Products To: File for NDA #22,311 Mozobil (plerixafor injection) Re: Approvability for Pharmacology and Toxicology Nonclinical studies that investigated the pharmacology and toxicology of plerixafor were provided in support of the NDA. Mozobil (plerixafor injection) is a hematopoietic stem cell mobilizer, and is indicated in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkins lymphoma and multiple myeloma. “Hematopoietic stem cell mobilizer” is used in the highlight section of the label to describe the pharmacologic class of this drug. Selection of this term was based on a CDER initiative to use terms to provide scientifically valid information that will be meaningful to prescribers. Plerixafor blocks the interaction between CXCR4 receptor and its ligand, stromal-derived factor-1 (SDF-1). SDF-1 and CXCR4 are involved in the trafficking and homing of CD34+ cells to the marrow. Plerixafor enhanced G-CSF- induced mobilization and engraftment of hematopoeitic stem cells and progenitor cells in irradiated mice and dogs. Pharmacology, safety pharmacology, pharmacokinetic/ ADME, and toxicology studies supporting the marketing application of plerixafor for the proposed indication were conducted in in vitro systems and in animal species. The general toxicology studies were conducted using the administration route, and dosing schedule and duration that adequately addressed safety concerns for the indicated patient population and the intended duration of administration. General toxicology studies of longer than 4 weeks were not conducted and are not required, since the maximum duration of plerixafor treatment in patients will be 7 days. Non-clinical studies defined the target organs/tissues of plerixafor as the hematopoietic system (leucocytosis), bone (bone mineral and/or volume loss), liver (increased hematopoiesis), spleen (increased weight, increased hematopoiesis), and cardiovascular (e.g. changes in the blood pressure and heart rate) and central nervous systems. The effects in the respiratory system (reduced tidal volume and respiratory rate) and in the cardiovascular system, may have been at least partially CNS-related. Injection site reactions included hemorrhage and inflammation. Plerixafor was negative for evidence of genetic toxicity in the standard battery of tests described by ICH S2. Carcinogenicity studies were not conducted, nor are they needed for use in this patient population or for this short period of clinical administration (generally 4 days, maximum of 7 days). Plerixafor was teratogenic in rats; therefore, Pregnancy Category D is recommended for Mozobil label. Teratogenic effects were also observed in rabbits in a dose range-finding 1 developmental toxicity study. Embryo-fetal toxicities appear to be a direct pharmacologic effect of plerixafor; the role of SDF-1/CXCR4 in embryo-fetal development has been described in the literature. If the indication changes, a GLP- compliant reproductive toxicology study in rabbits may be needed, to fully explore the effects of plerixafor on embryo-fetal development. Fertility and pre- and post-natal reproductive toxicity studies have not been conducted and are not required for the proposed indication. The nonclinical studies were reviewed in detail by Dr. Shwu-Luan Lee. The nonclinical findings are summarized in the “Executive Summary” and “Discussion and Conclusions” of the review, and reflected in the product label. Recommendation: I concur with Dr. Lee’s conclusion that pharmacology and toxicology data support the approval of NDA 22,311 for Mozobil. There are no outstanding non-clinical issues related to the approval of Mozobil for the proposed indication. 2 --------------------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------------------- /s/ --------------------- Haleh Saber 12/3/2008 09:44:24 AM PHARMACOLOGIST DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION NDA NUMBER: 22,311 SERIAL NUMBER: 000 DATE RECEIVED BY CENTER: 6/16/2008 PRODUCT: Mozobil (plerixafor) subcutaneous injection INTENDED CLINICAL POPULATION: Enhancing mobilization of hematopoietic stem cells in combination with granulocyte-colony stimulating factor (G-CSF) in patients with non- Hodgkins lymphoma and multiple myeloma SPONSOR: Genzyme Corporation DOCUMENTS REVIEWED: Pharmacology/Toxicology REVIEW DIVISION: Division of Drug Oncology Products PHARM/TOX REVIEWER: Shwu-Luan Lee, Ph.D. PHARM/TOX SUPERVISOR: Haleh Saber, Ph.D. DIVISION DIRECTOR: Robert Justice, M.D., M.S. PROJECT MANAGER: Susan Jenney Date of review submission to Division File System (DFS): November 14, 2008 TABLE OF CONTENTS EXECUTIVE SUMMARY .............................................................................................. 3 2.6 PHARMACOLOGY/TOXICOLOGY REVIEW................................................... 6 2.6.1 INTRODUCTION AND DRUG HISTORY................................................................... 6 2.6.2 PHARMACOLOGY....................................................................................................... 11 2.6.2.1 Brief summary ...................................................................................................................... 11 2.6.2.2 Primary pharmacodynamics ................................................................................................. 12 2.6.2.3 Secondary pharmacodynamics ............................................................................................. 24 2.6.2.4 Safety pharmacology ............................................................................................................ 25 2.6.2.5 Pharmacodynamic drug interactions..................................................................................... 33 2.6.3 PHARMACOLOGY TABULATED SUMMARY....................................................... 33 2.6.4 PHARMACOKINETICS/TOXICOKINETICS .......................................................... 35 2.6.4.2 Methods of Analysis.............................................................................................................36 2.6.4.3 Absorption ............................................................................................................................ 36 2.6.4.4 Distribution........................................................................................................................... 54 2.6.4.5 Metabolism........................................................................................................................... 69 2.6.4.6 Excretion............................................................................................................................... 73 2.6.4.7 Pharmacokinetic drug interactions........................................................................................ 73 2.6.4.8 Other Pharmacokinetic Studies............................................................................................. 76 2.6.4.9 Discussion and Conclusions ................................................................................................. 80 2.6.4.10 Tables and figures to include comparative TK summary ..................................................... 82 2.6.5 PHARMACOKINETICS TABULATED SUMMARY............................................... 83 2.6.6 TOXICOLOGY .............................................................................................................. 86 2.6.6.1 Overall toxicology summary ................................................................................................ 86 2.6.6.2 Single-dose toxicity .............................................................................................................. 87 2.6.6.3 Repeat-dose toxicity ............................................................................................................. 90 2.6.6.4 Genetic toxicology..............................................................................................................123