CLINICAL PHARMACOLOGY SECTION

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-lα (SDF-1α). SDF-lα 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 G-CSF and Administration of Plerixafor

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 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 (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. 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 (AUC0-10h) than the 0.24 mg/kg dose (Table 4). The fixed 20 mg dose also showed numerically higher response rate (5.2% [60% 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 (AUC0-10h) Comparisons of Fixed and Weight-Based Regimens

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 greater than 50 mL/min and 27 mg/day if CLCR 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 CLCR. The mean AUC0-24h of plerixafor in subjects with mild (CLCR 51 to 80 mL/min), moderate (CLCR 31 to 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 ( 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.

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WARNINGS AND PRECAUTIONS SECTION

Highlight: * Anaphylactic Shock and Serious Hypersensitivity Reactions have occurred. Monitor patients during and after completion of plerixafor injection administration. (5.1)

• Tumor Cell Mobilization in Leukemia Patients: Plerixafor injection may mobilize leukemic cells and should not be used in leukemia patients. (5.2)
• Hematologic Effects: Increased circulating leukocytes and decreased platelet counts have been observed. Monitor blood cell counts and platelet counts during plerixafor injection use. (5.3)
• Potential for Tumor Cell Mobilization: Tumor cells may be released from marrow during HSC mobilization with plerixafor injection and filgrastim. Effect of reinfusion of tumor cells is unknown. (5.4)
• Splenic Rupture: Evaluate patients who report left upper abdominal and/or scapular or shoulder pain. (5.5)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise women not to become pregnant when taking plerixafor injection. (5.6, 8.1)

5 WARNINGS AND PRECAUTIONS

5.1 Anaphylactic Shock and Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening with clinically significant hypotension and shock have occurred in patients receiving plerixafor [see Adverse Reactions (6.2)]. Observe patients for signs and symptoms of hypersensitivity during and after plerixafor injection administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer plerixafor injection when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.

In clinical studies, mild or moderate allergic reactions occurred within approximately 30 minutes after plerixafor administration in less than 1% of patients [see Adverse Reactions (6.1)].

5.2 Tumor Cell Mobilization in Leukemia Patients

For the purpose of HSC mobilization, plerixafor injection may cause mobilization of leukemic cells and subsequent contamination of the apheresis product. Therefore, plerixafor injection is not intended for HSC mobilization and harvest in patients with leukemia.

5.3 Hematologic Effects

Leukocytosis

Administration of plerixafor injection in conjunction with filgrastim increases circulating leukocytes as well as HSC populations. Monitor white blood cell counts during plerixafor injection use [see Adverse Reactions (6.1)].

Thrombocytopenia

Thrombocytopenia has been observed in patients receiving plerixafor injection. Monitor platelet counts in all patients who receive plerixafor injection and then undergo apheresis.

5.4 Potential for Tumor Cell Mobilization

When plerixafor injection is used in combination with filgrastim for HSC mobilization, tumor cells may be released from the marrow and subsequently collected in the leukapheresis product. The effect of potential reinfusion of tumor cells has not been well-studied.

5.5 Splenic Enlargement and Rupture

Higher absolute and relative spleen weights associated with extramedullary hematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor SC administration in rats at doses approximately 4-fold higher than the recommended human dose based on body surface area. The effect of plerixafor on spleen size in patients was not specifically evaluated in clinical studies. Cases of splenic enlargement and/or rupture have been reported following the administration of plerixafor in conjunction with filgrastim. Evaluate individuals receiving plerixafor injection in combination with filgrastim who report left upper abdominal pain and/or scapular or shoulder pain for splenic integrity.

5.6 Embryo-Fetal Toxicity

Based on findings from animal reproduction studies, plerixafor can cause fetal harm when administered to a pregnant woman. Plerixafor administration to pregnant rats during organogenesis resulted in embryo-fetal mortality, structural abnormalities, and alterations to growth at exposures approximately 10 times the exposure at the recommended human dose.

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use an effective form of contraception during treatment with plerixafor injection and for one week after the final dose [see Use in Specific Populations (8.1)].

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

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

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INFORMATION FOR PATIENTS SECTION

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 injection 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 injection [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 injection 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 injection and for 1 week following the last dose [Use in Specific Populations (8.2)].

Rx only

Distributor:

Dr. Reddy’s Laboratories Inc.,

Princeton, NJ 08540

Made in India

Issued: 09/2023

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