Plerixafor Dailymed

10 Overdosage

Based on limited data at doses above the recommended dose of 0.24 mg/kg SC, the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher.

11 Description

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-dose 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 1,4-Bis((1,4,8,11-tetraazacyclotetradecan-1-yl)methyl)benzene.  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.

12 Clinical Pharmacology

12.1 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.

12.2 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 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 Â	 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.

12.3 Pharmacokinetics

The single-dose pharmacokinetics of plerixafor 0.24 mg/kg were evaluated in patients with NHL and MM following pretreatment with filgrastim (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 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 × 10⁶ CD34+ cells/kg than the mg/kg-based dose. However, the median time to reach ≥5 × 10⁶ 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 Dosage 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 0.3 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, 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 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.

Special Populations

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 CL_CR.  The mean AUC_0–24h of plerixafor in subjects with mild (CL_CR 51–80 mL/min), moderate (CL_CR 31–50 mL/min), and severe (CL_CR <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 C_max. A population pharmacokinetic analysis indicated an increased exposure (AUC_0–24h)_ in patients with moderate and severe renal impairment compared to patients with CL_CR >50 mL/min. These results support a dose reduction of one-third in patients with moderate to severe renal impairment (CL_CR ≤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 (AUC_0–24h) with increasing body weight; therefore, if CL_CR is ≤50 mL/min the dose should not exceed 27 mg/day [see Dosage and Administration (2.3)].

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.

13.1 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 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 90mg/m² (15mg/kg/day) or approximately 10 times the recommended human dose of 0.24 mg/kg when compared on a mg/m² basis.

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 micrograms/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 × 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 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

Efficacy Endpoint	Plerixafor and Filgrastim(n=150)	Placebo and Filgrastim(n=148)	p-valuep-value calculated using Pearson's Chi-Squared test Â
Patients achieving ≥5 × 106 cells/kg in ≤4 apheresis days	89 (59%)	29 (20%)	<0.001
Patients achieving ≥2 × 106 cells/kg in ≤4 apheresis days	130 (87%)	70 (47%)	<0.001

The median number of days to reach ≥5 × 10⁶ 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 × 10⁶ CD34+ cells/kg by apheresis day.

Table 6: Study 1 Efficacy Results – Proportion of Patients Who Achieved ≥5 × 10⁶ CD34+ cells/kg by Apheresis Day in NHL Patients

Days	ProportionPercents determined by Kaplan Meier method in Plerixafor and Filgrastim(n=147n includes all patients who received at least one day of apheresis)	Proportion in Placebo and Filgrastim(n=142)
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 × 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 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

Efficacy Endpoint	Plerixafor and Filgrastim(n=148)	Placebo and Filgrastim(n=154)	p-valuep-value calculated using Pearson's Chi-Squared testÂ
Patients achieving ≥6 × 106 cells/kg in ≤2 apheresis days	 106 (72%)	 53 (34%)	 <0.001
Patients achieving ≥6 × 106 cells/kg in ≤4 apheresis days Â	112 (76%)	79 (51%)	<0.001
Patients achieving ≥2 × 106 cells/kg in ≤4 apheresis days  Â	141 (95%)	136 (88%)	0.028

The median number of days to reach ≥6 × 10⁶ 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 × 10⁶ CD34+ cells/kg by apheresis day.

Table 8: Study 2 – Proportion of Patients Who Achieved ≥6 × 10⁶ CD34+ cells/kg by Apheresis Day in MM Patients

DaysÂ	ProportionPercents determined by Kaplan Meier method in Plerixafor and Filgrastim(n=144n includes all patients who received at least one day of apheresis)Â	Proportion in Placebo and Filgrastim(n=150)
 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 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.

16 How Supplied/storage And Handling

Plerixafor injection 24 mg/1.2 mL (20 mg/mL) is a sterile, preservative-free, clear, colorless to pale-yellow solution supplied in a 2 mL clear glass single-dose vial.

NDC Number: 65219-284-12

STORAGE AND HANDLING SECTION

Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). [see USP Controlled Room Temperature]

17 Patient Counseling Information

Advise patients of the potential for anaphylactic reactions, including signs and symptoms such as urticaria, periorbital swelling, dyspnea, or hypoxia during and following plerixafor injection and to report these symptoms immediately to a healthcare professional [see Adverse Reactions (6.1, 6.2)].

Advise patients to contact healthcare professional immediately if they experience left upper abdominal pain and/or scapular or shoulder pain [see Adverse Reactions (6.1, 6.2)].

Advise patients to inform a healthcare professional immediately if symptoms of vasovagal reactions such as orthostatic hypotension or syncope occur during or shortly after their plerixafor injection [see Adverse Reactions (6.1)].

Advise patients who experience itching, rash, or reaction at the site of injection to notify a healthcare professional, as these symptoms have been treated with over-the-counter medications during clinical trials [see Adverse Reactions (6.1)].

Advise patients that plerixafor may cause gastrointestinal disorders, including diarrhea, nausea, vomiting, flatulence, and abdominal pain. Patients should be told how to manage specific gastrointestinal disorders and to inform their healthcare professional if severe events occur following plerixafor injection [see Adverse Reactions (6.1)].

Advise females of reproductive potential of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with plerixafor [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)].

Advise females and males of reproductive potential to use effective contraceptive methods during plerixafor use and for 1 week following cessation of treatment [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)].

Advise women not to breastfeed during treatment with plerixafor and for 1 week following the last dose [Use in Specific Populations (8.2)].

Manufactured for:Fresenius Kabi USA, LLCLake Zurich, IL 60047

Principal Display Panel - 24 Mg/1.2 Ml Vial Label

Plerixaforinjection

24 mg/1.2 mL(20 mg/mL)

Rx only

For subcutaneousinjection only

Manufactured for:Fresenius Kabi USA, LLCLake Zurich, IL 60047

NDC 6521-9284-12

Lot.Exp.

XXXXXX

403963

Principal Display Panel - 24 Mg/1.2 Ml Vial Carton

NDC 6521-9284-12621878

Plerixaforinjection

24 mg/1.2 mL(20 mg/mL)

For subcutaneousinjection only

One single-dose vial.Discard unused portion.

Rx only

FRESENIUSKABI