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Pharmacology Review(S) CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 22-465 PHARMACOLOGY REVIEW(S) 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, 465 SERIAL NUMBER: 000 DATE RECEIVED BY CENTER: 12/19/2008 PRODUCT: Pazopanib INTENDED CLINICAL POPULATION: Renal Cell Carcinoma SPONSOR: GlaxoSmithKline DOCUMENTS REVIEWED: Electronic Submission REVIEW DIVISION: Oncology Drug Products PHARM/TOX REVIEWER: Robeena Aziz, MPH, PhD/ Whitney Helms, Ph.D PHARM/TOX SUPERVISOR: Leigh Verbois, PhD DIVISION DIRECTOR: Robert Justice, MD PROJECT MANAGER: Kim Robertson Date of review submission to Division File System (DFS): 9/17/2009 TABLE OF CONTENTS EXECUTIVE SUMMARY .............................................................................................. 3 2.6 PHARMACOLOGY/TOXICOLOGY REVIEW................................................... 8 2.6.1 INTRODUCTION AND DRUG HISTORY................................................................... 8 2.6.2 PHARMACOLOGY....................................................................................................... 20 2.6.2.1 Brief summary..................................................................................................................... 20 2.6.2.2 Primary pharmacodynamics ................................................................................................ 23 2.6.2.3 Secondary pharmacodynamics ............................................................................................ 57 2.6.2.4 Safety pharmacology ........................................................................................................... 57 2.6.2.5 Pharmacodynamic drug interactions.................................................................................... 68 2.6.3 PHARMACOLOGY TABULATED SUMMARY....................................................... 73 2.6.4 PHARMACOKINETICS/TOXICOKINETICS .......................................................... 75 2.6.4.1 Brief summary..................................................................................................................... 75 2.6.4.2 Methods of Analysis ........................................................................................................... 78 2.6.4.3 Absorption .......................................................................................................................... 78 2.6.4.4 Distribution ......................................................................................................................... 98 2.6.4.5 Metabolism ...................................................................................................................... 105 2.6.4.6 Excretion............................................................................................................................ 134 2.6.4.7 Other PK studies………………........................................................................................ 138 2.6.4.8 Pharmacokinetics tabulated summary ............................................................................... 138 2.6.4.9 Tables and figures to include comparative TK summary………………………………… 145 2.6.5 PHARMACOKINETICS TABULATED SUMMARY............................................. 145 2.6.6 TOXICOLOGY ............................................................................................................ 147 2.6.6.1 Overall toxicology summary ............................................................................................. 147 2.6.6.2 Single-dose toxicity:.......................................................................................................... 156 2.6.6.3 Repeat-dose toxicity .......................................................................................................... 158 2.6.6.4 Genetic toxicology............................................................................................................. 193 2.6.6.5 Reproductive toxicology.................................................................................................... 204 2.6.6.6 Carcinogenicity ................................................................................................................. 229 2.6.6.7 Local tolerance .................................................................................................................. 229 2.6.6.8 Special toxicology studies ................................................................................................ 229 2.6.6.9 Discussion and Conclusions .............................................................................................. 229 2.6.6.10 Tables and Figures ............................................................................................................ 227 2.6.7 TOXICOLOGY TABULATED SUMMARY ............................................................ 232 OVERALL CONCLUSIONS AND RECOMMENDATIONS............................................. 239 2 Robeena M. Aziz MPH, PhD./Whitney S. Helms, Ph.D. NDA 22465 EXECUTIVE SUMMARY I. Recommendations A. Recommendation on approvability Approvable. The non-clinical studies with pazaponib support the safety of its use in renal cell carcinoma. B. Recommendation for nonclinical studies No additional non-clinical studies are required for pazopanib C. Recommendations on labeling The recommendations to the sponsor’s proposed labeling are given, with a detailed report regarding the rationale for the recommended changes, in a subsequent review. II. Summary of nonclinical findings A. Brief overview of nonclinical findings The nonclinical findings have shown the target sites of toxicity with pazopanib to be the teeth, bone marrow, gastrointestinal, and reproductive systems. Many of these toxicities are seen clinically and are thought to be direct effects of the pharmacology of pazopanib. Pazopanib was not mutagenic or clastogenic in the in vitro assays. Pazopanib was not clastogenic (induction of micronuclei) in the in vivo rat micronucleus assay (highest dose = 2000 mg/kg; 12,000 mg/m2). Pazopanib did not impair fertility when administered to male rats. Female rats showed reduced fertility at doses ≥ 30 mg/kg (180 mg/m2). Pazopanib was found to be teratogenic in the rat and induced embryo-fetal toxicity in both rats and rabbits at doses significantly below those that caused maternal toxicity. B. Pharmacologic activity The major pharmacological activity of pazopanib is inhibition of angiogenic signaling pathways through a panel of growth factors and receptors, primarily the VEGF receptor family. Inhibition of these growth factors and/or their receptors results in the inhibition of neovascularization, disruption of existing tumor vascularization, and inhibition of proangiogenic growth factor release. In nonclinical studies, pazopanib inhibited vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-α and -β, fibroblast growth factor receptor (FGFR) -1 and -3, cytokine receptor (Kit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), transmembrane glycoprotein receptor tyrosine kinase (c-Fms), and mitogen-activated protein kinase (P38). 3 Robeena M. Aziz MPH, PhD./Whitney S. Helms, Ph.D. NDA 22465 Pazopanib inhibited autophosphorylation of VEGFR-2, c-Kit and PDGFR-β receptors in human umbilical vein endothelial cells (HUVEC), NCI-H526 (human small cell lung carcinoma), human foreskin fibroblast (HFF) and RS4;11 cells (human B-cell acute lymphoblastic leukemia). Pazopanib showed modest activity (IC50 values < 1 nM ) in 282 human cell lines obtained from AML, myeloma, colon carcinoma, kidney leiomyoblastoma, thyroid carcinoma, rhabdomyosarcoma, CML, lymphoma cutaneous T- cell, and stomach carcinoma. When evaluated in imatinib-resistant c-Kit mutant cell lines (V654A, T670I, Y816V, Y823D, K642E), and in CHO-K1 cells transiently-transfected with wild type c-Kit, pazopanib inhibited wild-type c-Kit activation (IC50 values of 3 nM). In vivo studies in mouse lung stimulated with VEGF showed that pazopanib inhibited VEGF-induced phosphorylation at 8, 16, and 24 hours post-dosing and at doses of 10, 30, and 100 mg/kg (30, 90, and 300 mg/m2). Pazopanib showed an improved dose- dependent inhibition of tumors in CB-17 SCID mice compared to Swiss mice at doses >10 mg/kg/day (30 mg/m2) when both mouse models were injected with renal cell carcinoma tumor xenografts (CAKI-2 and A498). Pazopanib also showed modest inhibition of tumor growth at >10 mg/kg/day (30 mg/m2) when the human renal cell cancer xenograft (ACHN) was injected in Swiss nude mice. Compared to the dihydrchloride form, the monohydrochloride form of the drug was not as effective at inhibiting tumors in a mouse model of angiogenesis; however, there was significant tumor inhibition when the monohydrochloride was administered at ≥30 mg/kg (90 mg/m2). The drug does not appear to disrupt delivery of other anti-angiogenic agents to tumor tissues when given in combination. The pharmacological classification of pazopanib is a kinase inhibitor. This is consistent with other drugs of this class that act by competitively inhibiting tyrosine kinase function. C. Nonclinical safety issues relevant to clinical use The nonclinical safety issues observed in the toxicology program with pazopanib included toxicities in the bone marrow, gastrointestinal and reproductive system, hepatic system and teeth (mice and rats only)
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