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 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 Filgrastim and Administration of Plerixafor
Study	Mozobil and Filgrastim		Placebo and Filgrastim
Study	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 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 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 plerixafor (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.

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% [60.0% 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 (AUC0–10h) 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 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 51–80 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 (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.