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Mozobil (Plerixafor Subcutaneous) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Mozobil (plerixafor injection) is a sterile, preservative-free, clear, colorless to pale yellow, isotonic solution for subcutaneous injection. Each mL of the sterile solution contains 20 mg of plerixafor.  Each single-use vial is filled to deliver 1.2 mL of the sterile solution that contains 24 mg of plerixafor and 5.9 mg of sodium chloride in Water for Injection adjusted to a pH of 6.0 to 7.5 with hydrochloric acid and with sodium hydroxide, if required. 

Plerixafor is a hematopoietic stem cell mobilizer with a chemical name 1, 1'-[1,4-phenylenebis (methylene)]-bis-1,4,8,11- tetraazacyclotetradecane.  It has the molecular formula C28H54N8.  The molecular weight of plerixafor is 502.79 g/mol. The structural formula is provided in Figure 1.

Figure 1: Structural Formula

Plerixafor is a white to off-white crystalline solid.  It is hygroscopic. Plerixafor has a typical melting point of 131.5 °C. The partition coefficient of plerixafor between 1-octanol and pH 7 aqueous buffer is < 0.1.


CLINICAL PHARMACOLOGY

Mechanism 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.

Pharmacodynamics

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 Mozobil or placebo was administered 10 to 11 hours prior to apheresis.

Table 3: Fold Increase in Peripheral Blood CD34+ Cell Count Following Pretreatment with G-CSF and Administration of Plerixafor
 
 Study
Mozobil® and G-CSF Placebo and G-CSF
   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 Mozobil in healthy volunteers, peak mobilization of CD34+ cells was observed between 6 and 9 hours after administration. In pharmacodynamic studies of Mozobil in conjunction with G-CSF 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.

Pharmacokinetics

The single-dose pharmacokinetics of plerixafor 0.24 mg/kg were evaluated in patients with NHL and MM following pre-treatment with G-CSF (10 micrograms/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 were similar across clinical studies in healthy subjects who received plerixafor alone and NHL and MM patients who received plerixafor in combination with G-CSF.

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 (CLCR), as well as between central volume of distribution and body weight were observed.  The distribution half-life (t1/2α) was estimated to be 0.3 hours and the terminal population half-life (t1/2β) 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 (AUC0-24h) with increasing body weight.  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 CLCR is > 50 mL/min and 27 mg/day if CLCR is ≤ 50 mL/min).  [see Dosage and Administration (2.1 2.3) ]

Absorption
Peak plasma concentrations occurred at approximately 30 - 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 0.3 L/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, 2C9, 2C19, 2D6, 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 function, approximately 70% of the dose was excreted in the urine as the parent drug during the first 24 hours following administration. In studies with healthy subjects and patients, the terminal half-life in plasma ranges between 3 and 5 hours. At concentrations similar to what are seen clinically, plerixafor did not act as a substrate or inhibitor of P-glycoprotein in an in vitro study with MDCKII and MDCKII-MDR1 cell models.

Renal Impairment
Following a single 0.24 mg/kg SC dose, plerixafor clearance was reduced in subjects with varying degrees of renal impairment and was positively correlated with CLCR.  The mean AUC0-24h of plerixafor in subjects with mild (CLCR 51-80 mL/min), moderate (CLCR 31-50 mL/min), and severe (CLCR < 31 mL/min) renal impairment was 7%, 32%, and 39% higher than healthy subjects with normal renal function, respectively.  Renal impairment had no effect on Cmax. A population pharmacokinetic analysis indicated an increased exposure (AUC0-24h) in patients with moderate and severe renal impairment compared to patients with CLCR > 50 mL/min. These results support a dose reduction of one-third in patients with moderate to severe renal impairment (CLCR ≤ 50 mL/min) in order to match the exposure in patients with normal renal function. The population pharmacokinetic analysis showed that the mg/kg-based dosage results in an increased plerixafor exposure (AUC0-24h) with increasing body weight; therefore if CLCR is ≤ 50 mL/min the dose should not exceed 27 mg/day.  [see  Dosage and Administration ]

Since plerixafor is primarily eliminated by the kidneys, coadministration of plerixafor with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of plerixafor or the coadministered drug.  The effects of coadministration of plerixafor with other drugs that are renally eliminated or are known to affect renal function have not been evaluated.

Race
Clinical data show similar plerixafor pharmacokinetics for Caucasians and African-Americans, and the effect of other racial/ethnic groups has not been studied. 

Gender
Clinical data show no effect of gender on plerixafor pharmacokinetics.

Age
Clinical data show no effect of age on plerixafor pharmacokinetics.

QT/QTc Prolongation

There is no indication of a QT/QTc prolonging effect of Mozobil 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 Mozobil (0.24 mg/kg and 0.40 mg/kg) and placebo. Peak concentrations for 0.40 mg/kg Mozobil were approximately 1.8-fold higher than the peak concentrations following the 0.24 mg/kg single subcutaneous dose.

NONCLINICAL TOXICOLOGY

Carcinogenesis, 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/m2).

The effect of plerixafor on human fertility is unknown.  The effect of plerixafor on male or female 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.

CLINICAL STUDIES

The efficacy and safety of Mozobil in conjunction with G-CSF in non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM) were evaluated in two placebo-controlled studies (Studies 1 and 2).  Patients were randomized to receive either Mozobil 0.24 mg/kg or placebo on each evening prior to apheresis. Patients received daily morning doses of G-CSF 10 micrograms/kg for 4 days prior to the first dose of Mozobil 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 55.1 years (range 29-75) and 57.5 years (range 22-75) in the Mozobil and placebo groups, respectively, and 93% of subjects were Caucasian. Three hundred and two (302) MM patients were included in the primary efficacy analyses for Study 2. The mean age was 58.2 years (range 28-75) and 58.5 years (range 28-75) in the Mozobil and placebo groups, respectively, and 81% of subjects were Caucasian.

In Study 1, 59% of NHL patients who were mobilized with Mozobil and G-CSF collected ≥ 5 X 106 CD34+ cells/kg from the peripheral blood in four or fewer apheresis sessions, compared with 20% of patients who were mobilized with placebo and G-CSF (p < 0.001). Other CD34+ cell mobilization outcomes showed similar findings (Table 4). 


Table 4: Study 1 Efficacy Results - CD34+ Cell Mobilization in NHL Patients
 Efficacy Endpoint Mozobil® and
G-CSF
(n = 150)
Placebo and
G-CSF
(n = 148)
p-value 1   
Patients achieving ≥ 5 X 106 cells/kg in ≤ 4 apheresis days 89 (59%) 29 (20%) < 0.001
Patients achieving ≥ 2 X 106 cells/kg in ≤ 4 apheresis days 130 (87%) 70 (47%) < 0.001

1   p-value calculated using Pearson's Chi-Squared test

The median number of days to reach ≥ 5 x 106 CD34+ cells/kg was 3 days for the Mozobil group and not evaluable for the placebo group.  Table 5 presents the proportion of patients who achieved ≥ 5 x 106 CD34+ cells/kg by apheresis day.


Table 5: Study 1 Efficacy Results - Proportion of Patients Who Achieved ≥ 5 x 106 CD34+ cells/kg by Apheresis Day in NHL Patients
Days Proportion 1   
in Mozobil® and G-CSF
(n=147 2)
 Proportion  
in Placebo and G-CSF
(n = 142)
1 27.9% 4.2%
2 49.1% 14.2%
3 57.7% 21.6%
4 65.6% 24.2%

1   Percents determined by Kaplan Meier method
2   n includes all patients who received at least one day of apheresis

In Study 2, 72% of MM patients who were mobilized with Mozobil and G-CSF collected ≥ 6 X 106 CD34+ cells/kg from the peripheral blood in two or fewer apheresis sessions, compared with 34% of patients who were mobilized with placebo and G-CSF (p < 0.001). Other CD34+ cell mobilization outcomes showed similar findings (Table 6). 

Table 6: Study 2 Efficacy Results - CD34+ Cell Mobilization in Multiple Myeloma Patients
 Efficacy Endpoint     Mozobil® and
G-CSF
(n=148)
Placebo and
G-CSF
(n=154)
  p-value 1  
Patients achieving ≥ 6 X 106 cells/kg in ≤ 2 apheresis days  106 (72%)  53 (34%)  < 0.001
Patients achieving ≥ 6 X 106 cells/kg in ≤ 4 apheresis days   112 (76%) 79 (51%)  < 0.001
Patients achieving ≥ 2 X 106 cells/kg in ≤ 4 apheresis days    141 (95%)  136 (88%)  0.028

1   p-value calculated using Pearson's Chi-Squared test

The median number of days to reach ≥ 6 x 106 CD34+ cells/kg was 1 day for the Mozobil group and 4 days for the placebo group.  Table 7 presents the proportion of patients who achieved ≥ 6 x 106 CD34+ cells/kg by apheresis day.

Table 7: Study 2 – Proportion of Patients Who Achieved ≥ 6 x 106 CD34+ cells/kg by Apheresis Day in MM Patients
Days  Proportion 1   
in Mozobil® and G-CSF
(n=144 2
 Proportion  
in Placebo and G-CSF
(n=150)
 1  54.2%  17.3%
 2  77.9%  35.3%
 3  86.8%  48.9%
 4  86.8%  55.9%

1   Percents determined by Kaplan Meier method
2   n includes all patients who received at least one day of apheresis

Multiple factors can influence time to engraftment and graft durability following stem cell transplantation. For transplanted patients in the Phase 3 studies, time to neutrophil and platelet engraftment and graft durability were similar across the treatment groups.


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