Plerixafor 24 mg/1.2mL Solution, 1 vial — NDC 71288-155-01 (Billing 71288-0155-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Plerixafor is an inhibitor of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1α (SDF-1α). SDF-1α and CXCR4 are recognized to play a role in the trafficking and homing of human hematopoietic stem cells (HSCs) to the marrow compartment. Once in the marrow, stem cell CXCR4 can act to help anchor these cells to the marrow matrix, either directly via SDF-1α or through the induction of other adhesion molecules.

Treatment with plerixafor resulted in leukocytosis and elevations in circulating hematopoietic progenitor cells in mice, dogs and humans. CD34+ cells mobilized by plerixafor were capable of engraftment with long-term repopulating capacity up to one year in canine transplantation models.

12.2Pharmacodynamics Data on the fold increase in peripheral blood CD34+ cell count (cells/mcL) by apheresis day were evaluated in two placebo-controlled clinical studies in patients with NHL and MM (Study 1 and Study 2, respectively). The fold increase in CD34+ cell count (cells/mcL) over the 24-hour period starting from the day prior to the first apheresis and ending the next morning just before the first apheresis is summarized in Table 3 . During this 24-hour period, a single dose of plerixafor or placebo was administered 10 to 11 hours prior to apheresis.

Table 3: Fold Increase in Peripheral Blood CD34+ Cell Count Following Pretreatment with Filgrastim and Administration of Plerixafor Study Plerixafor and Filgrastim Placebo and Filgrastim Median Mean (SD) Median Mean (SD) Study 1 5.0 6.1 (5.4) 1.4 1.9 (1.5) Study 2 4.8 6.4 (6.8) 1.7 2.4 (7.3) In pharmacodynamic studies of plerixafor in healthy volunteers, peak mobilization of CD34+ cells was observed between 6 and 9 hours after administration. In pharmacodynamic studies of plerixafor in conjunction with filgrastim in healthy volunteers, a sustained elevation in the peripheral blood CD34+ count was observed from 4 to 18 hours after plerixafor administration with a peak CD34+ count between 10 and 14 hours.

QT/QTc Prolongation There is no indication of a QT/QTc prolonging effect of plerixafor in single doses up to 0.40 mg/kg. In a randomized, double-blind, crossover study, 48 healthy subjects were administered a single subcutaneous dose of plerixafor (0.24 mg/kg and 0.40 mg/kg) and placebo. Peak concentrations for 0.40 mg/kg plerixafor were approximately 1.8-fold higher than the peak concentrations following the 0.24 mg/kg single subcutaneous dose.

12.3Pharmacokinetics The single-dose pharmacokinetics of plerixafor 0.24 mg/kg were evaluated in patients with NHL and MM following pretreatment with filgrastim (10 mcg/kg once daily for 4 consecutive days). Plerixafor exhibits linear kinetics between the 0.04 mg/kg to 0.24 mg/kg dose range. The pharmacokinetics of plerixafor was similar across clinical studies in healthy subjects who received plerixafor alone and NHL and MM patients who received plerixafor in combination with filgrastim.

A population pharmacokinetic analysis incorporated plerixafor data from 63 subjects (NHL patients, MM patients, subjects with varying degrees of renal impairment, and healthy subjects) who received a single SC dose (0.04 mg/kg to 0.24 mg/kg) of plerixafor. A two-compartment disposition model with first order absorption and elimination was found to adequately describe the plerixafor concentration-time profile. Significant relationships between clearance and creatinine clearance (CL CR ), as well as between central volume of distribution and body weight were observed.

The distribution half-life (t 1/2α ) was estimated to be 0.3 hours and the terminal population half-life (t 1/2β ) was 5.3 hours in patients with normal renal function. The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUC 0-24h ) with increasing body weight. In order to compare the pharmacokinetics and pharmacodynamics of plerixa… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Plerixafor is an inhibitor of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1α (SDF-1α). SDF-1α and CXCR4 are recognized to play a role in the trafficking and homing of human hematopoietic stem cells (HSCs) to the marrow compartment. Once in the marrow, stem cell CXCR4 can act to help anchor these cells to the marrow matrix, either directly via SDF-1α or through the induction of other adhesion molecules.

Treatment with plerixafor resulted in leukocytosis and elevations in circulating hematopoietic progenitor cells in mice, dogs and humans. CD34+ cells mobilized by plerixafor were capable of engraftment with long-term repopulating capacity up to one year in canine transplantation models.

12.3Pharmacokinetics The single-dose pharmacokinetics of plerixafor 0.24 mg/kg were evaluated in patients with NHL and MM following pretreatment with filgrastim (10 mcg/kg once daily for 4 consecutive days). Plerixafor exhibits linear kinetics between the 0.04 mg/kg to 0.24 mg/kg dose range. The pharmacokinetics of plerixafor was similar across clinical studies in healthy subjects who received plerixafor alone and NHL and MM patients who received plerixafor in combination with filgrastim.

A population pharmacokinetic analysis incorporated plerixafor data from 63 subjects (NHL patients, MM patients, subjects with varying degrees of renal impairment, and healthy subjects) who received a single SC dose (0.04 mg/kg to 0.24 mg/kg) of plerixafor. A two-compartment disposition model with first order absorption and elimination was found to adequately describe the plerixafor concentration-time profile. Significant relationships between clearance and creatinine clearance (CL CR ), as well as between central volume of distribution and body weight were observed.

The distribution half-life (t 1/2α ) was estimated to be 0.3 hours and the terminal population half-life (t 1/2β ) was 5.3 hours in patients with normal renal function. The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUC 0-24h ) with increasing body weight. In order to compare the pharmacokinetics and pharmacodynamics of plerixafor following 0.24 mg/kg-based and fixed (20 mg) doses, a follow-up trial was conducted in patients with NHL (N=61) who were treated with 0.24 mg/kg or 20 mg of plerixafor.

The trial was conducted in patients weighing 70 kg or less. The fixed 20 mg dose showed 1.43-fold higher exposure (AUC 0-10h ) than the 0.24 mg/kg dose ( Table 4 ). The fixed 20 mg dose also showed numerically higher response rate (5.2% [60.0% vs 54.8%] based on the local lab data and 11.7% [63.3% vs 51.6%] based on the central lab data) in attaining the target of ≥5 × 10 6 CD34+ cells/kg than the mg/kg-based dose.

However, the median time to reach ≥5 × 10 6 CD34+ cells/kg was 3 days for both treatment groups, and the safety profile between the groups was similar. Based on these results, further analysis was conducted by FDA reviewers and a body weight of 83 kg was selected as an appropriate cut-off point to transition patients from fixed to weight based dosing. Table 4: Systemic Exposure (AUC 0-10h ) Comparisons of Fixed and Weight-Based Regimens Regimen Geometric Mean AUC Fixed 20 mg (n=30) 3991.2 0.24 mg/kg (n=31) 2792.7 Ratio (90% CI) 1.43 (1.32,1.54) There is limited experience with the 0.24 mg/kg dose of plerixafor in patients weighing above 160 kg.

Therefore, the dose should not exceed that of a 160 kg patient (i.e., 40 mg/day if CL CR is greater than 50 mL/min and 27 mg/day if CL CR is less than or equal to 50 mL/min) [see D osage and Administration (2.1 , 2.3 )] . Absorption Peak plasma concentrations occurred at approximately 30 to 60 minutes after a SC dose. Distribution Plerixafor is bound to human plasma proteins up to 58%.

The apparent volume of distribution of plerixafor in humans is

0.3L/kg demonstrating that plerixafor is largely confined to, but not limited to, the extravascular fluid space. Metabolism The metabolism of plerixafor was evaluated with in vitro assays. Plerixafor is not metabolized as shown in assays using human liver microsomes or human primary hepatocytes and does not exhibit inhibitory activity in vitro towards the major drug metabolizing cytochrome P450 enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4/5).

In in vitro studies with human hepatocytes, plerixafor does not induce CYP1A2, CYP2B6, or CYP3A4 enzymes. These findings suggest that plerixafor has a low potential for involvement in cytochrome P450-dependent drug-drug interactions. Elimination The major route of elimination of plerixafor is urinary.

Following a 0.24 mg/kg dose in healthy volunteers with normal renal fu… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Data on the fold increase in peripheral blood CD34+ cell count (cells/mcL) by apheresis day were evaluated in two placebo-controlled clinical studies in patients with NHL and MM (Study 1 and Study 2, respectively). The fold increase in CD34+ cell count (cells/mcL) over the 24-hour period starting from the day prior to the first apheresis and ending the next morning just before the first apheresis is summarized in Table 3 . During this 24-hour period, a single dose of plerixafor or placebo was administered 10 to 11 hours prior to apheresis.

Table 3: Fold Increase in Peripheral Blood CD34+ Cell Count Following Pretreatment with Filgrastim and Administration of Plerixafor Study Plerixafor and Filgrastim Placebo and Filgrastim Median Mean (SD) Median Mean (SD) Study 1 5.0 6.1 (5.4) 1.4 1.9 (1.5) Study 2 4.8 6.4 (6.8) 1.7 2.4 (7.3) In pharmacodynamic studies of plerixafor in healthy volunteers, peak mobilization of CD34+ cells was observed between 6 and 9 hours after administration. In pharmacodynamic studies of plerixafor in conjunction with filgrastim in healthy volunteers, a sustained elevation in the peripheral blood CD34+ count was observed from 4 to 18 hours after plerixafor administration with a peak CD34+ count between 10 and 14 hours.

QT/QTc Prolongation There is no indication of a QT/QTc prolonging effect of plerixafor in single doses up to 0.40 mg/kg. In a randomized, double-blind, crossover study, 48 healthy subjects were administered a single subcutaneous dose of plerixafor (0.24 mg/kg and 0.40 mg/kg) and placebo. Peak concentrations for 0.40 mg/kg plerixafor were approximately 1.8-fold higher than the peak concentrations following the 0.24 mg/kg single subcutaneous dose.

14 CLINICAL STUDIES The efficacy and safety of plerixafor in conjunction with filgrastim in non-Hodgkin’s lymphoma (NHL) Study AMD 3100-3101 (referred to as study 1) ( NCT00103610 ) and multiple myeloma (MM) Study AMD 3100-3102 (referred to as study 2) ( NCT00103662 ) were evaluated in two placebo-controlled studies (Studies 1 and 2). Patients were randomized to receive either plerixafor 0.24 mg/kg or placebo on each evening prior to apheresis. Patients received daily morning doses of filgrastim 10 mcg/kg for 4 days prior to the first dose of plerixafor or placebo and on each morning prior to apheresis.

Two hundred and ninety-eight (298) NHL patients were included in the primary efficacy analyses for Study 1. The mean age was 55 years (range 29-75) and 58 years (range 22-75) in the plerixafor and placebo groups, respectively, and 93% of subjects were Caucasian. In study 2, 302 patients with MM were included in the primary efficacy analyses.

The mean age (58 years) and age range (28-75) were similar in the plerixafor and placebo groups, and 81% of subjects were Caucasian. In Study 1, 59% of NHL patients who were mobilized with plerixafor and filgrastim collected ≥5 × 10 6 CD34+ cells/kg from the peripheral blood in four or fewer apheresis sessions, compared with 20% of patients who were mobilized with placebo and filgrastim (p <0.001). Other CD34+ cell mobilization outcomes showed similar findings ( Table 5 ).

Table 5: Study 1 Efficacy Results - CD34+ Cell Mobilization in NHL Patients a p-value calculated using Pearson’s Chi-Squared test Efficacy Endpoint Plerixafor and Filgrastim (n=150) Placebo and Filgrastim (n=148) p-value a Patients achieving ≥5 × 10 6 cells/kg in ≤4 apheresis days 89 (59%) 29 (20%) <0.001 Patients achieving ≥2 × 10 6 cells/kg in ≤4 apheresis days 130 (87%) 70 (47%) <0.001 The median number of days to reach ≥5 × 10 6 CD34+ cells/kg was 3 days for the plerixafor group and not evaluable for the placebo group.

Table 6 presents the proportion of patients who achieved ≥5 × 10 6 CD34+ cells/kg by apheresis day. Table 6: Study 1 Efficacy Results - Proportion of Patients Who Achieved ≥5 × 10 6 CD34+ cells/kg by Apheresis Day in NHL Patients a Percents determined by Kaplan Meier method b n includes all patients who received at least one day of apheresis Days Proportion a in Plerixafor and Filgrastim (n=147 b ) Proportion a in Placebo and Filgrastim (n=142 b ) 1 27.9% 4.2% 2 49.1% 14.2% 3 57.7% 21.6% 4 65.6% 24.2% In Study 2, 72% of MM patients who were mobilized with plerixafor and filgrastim collected ≥6 × 10 6 CD34+ cells/kg from the peripheral blood in two or fewer apheresis sessions, compared with 34% of patients who were mobilized with placebo and filgrastim (p <0.001).

Other CD34+ cell mobilization outcomes showed similar findings ( Table 7 ). Table 7: Study 2 Efficacy Results - CD34+ Cell Mobilization in Multiple Myeloma Patients a p-value calculated using Pearson’s Chi-Squared test Efficacy Endpoint Plerixafor and Filgrastim (n=148) Placebo and Filgrastim (n=154) p-value a Patients achieving ≥6 × 10 6 cells/kg in ≤2 apheresis days 106 (72%) 53 (34%) <0.001 Patients achieving ≥6 × 10 6 cells/kg in ≤4 apheresis days 112 (76%) 79 (51%) <0.001 Patients achieving ≥2 × 10 6 cells/kg in ≤4 apheresis days 141 (95%) 136 (88%) 0.028 The median number of days to reach ≥6 × 10 6 CD34+ cells/kg was 1 day for the plerixafor group and 4 days for the placebo group.

Table 8 presents the proportion of patients who achieved ≥6 × 10 6 CD34+ cells/kg by apheresis day. Table 8: Study 2 - Proportion of Patients Who Achieved ≥6 × 10 6 CD34+ cells/kg by Apheresis Day in MM Patients a Percents determined by Kaplan Meier method b n includes all patients who received at least one day of apheresis Days Proportion a in Plerixafor and Filgrastim (n=144 b ) Proportion a in Placebo and Filgrastim (n=150 b ) 1 54.2% 17.3% 2 77.9% 35.3% 3 86.8% 48.9% 4 86.8% 55.9% Multiple factors can influence time to engraftment and graft durability follow… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with plerixafor have not been conducted. Plerixafor was not genotoxic in an in vitro bacterial mutation assay (Ames test in Salmonella ), an in vitro chromosomal aberration test using V79 Chinese hamster cells, or an in vivo bone marrow micronucleus test in rats after subcutaneous doses up to 25 mg/kg (150 mg/m 2 ). The effect of plerixafor on human fertility is unknown.

The effect of plerixafor on male fertility was not studied in designated reproductive toxicology studies. The staging of spermatogenesis measured in a 28-day repeated dose toxicity study in rats revealed no abnormalities considered to be related to plerixafor. No histopathological evidence of toxicity to male or female reproductive organs was observed in 28-day repeated dose toxicity studies.

No adverse effects on estrus or reproductive indices were observed in an investigative fertility study in female rats administered plerixafor at doses up to 90 mg/m 2 (15mg/kg/day) or approximately 10 times the recommended human dose of 0.24 mg/kg when compared on a mg/m 2 basis.