Aphexda (motixafortide acetate)

Motixafortide acetate, a C-X-C motif chemokine receptor 4 (CXCR4) inhibitor, is a hematopoietic stem cell mobilizer.

Motixafortide is an inhibitor of the C-X-C Motif Chemokine Receptor 4 (CXCR4) that blocks the binding of its cognate ligand, stromal-derived factor-1alpha (SDF-1alpha)/C-X-C Motif Chemokine Ligand 12 (CXCL12). Both SDF-1alpha and CXCR4 play an important role in the trafficking of hematopoietic stem cells to the bone marrow, with CXCR4 helping to anchor stem cells to the marrow matrix (either directly via SDF-1alpha or through the induction of other adhesion molecules).

In humans and animal models, treatment with motixafortide resulted in leukocytosis and elevations in circulating hematopoietic stem and progenitor cells into the peripheral circulation, facilitating their collection for the purposes of autologous transplantation. Stem cells mobilized by motixafortide were capable of engraftment with long-term repopulating capacity in a rodent transplantation model.

Motixafortide occupies the CXCR4 receptor for >72 hours. Mobilization ofCD34+ cells to peripheral blood was observed in all clinical studies that evaluated the pharmacodynamics of the drug. Following administration of motixafortide as monotherapy to healthy volunteers, CD34+ cell counts increased with time and peaked 16 hours postdose; the counts declined slightly thereafter but remained elevated well above baseline at the last observation at 24-hours postdose.

In healthy volunteers, motixafortide prolonged the QT interval corrected for rate (QTc) in a concentration-dependent manner.

The pharmacokinetic characteristics of motixafortide following subcutaneous administration were similar across various populations, including healthy volunteers, patients with acute myeloid leukemia, and patients with multiple myeloma. Motixafortide pharmacokinetics following subcutaneous administration were adequatelydescribed by a 3-compartment model with first-order absorption, dose-dependentrelative bioavailability, and linear elimination kinetics. Following once-daily dose administration, minimal to no drug accumulation was observed; therefore, the single-dose pharmacokinetic profile is considered representative of a steady state profile.

After subcutaneous injection as either a single or repeated dose at 0.24-2 mg/kg, the time to peak plasma concentration of motixafortide was approximately 0.25-1.17 hours.

Motixafortide is >99% bound to human plasma proteins. Motixafortide undergoes non-specific degradation via catabolic pathways in bothblood and liver microsomes into small peptides and individualamino acids and their derivatives. In vitro studies using human and animal biomaterials did not identify any prominent unique human metabolites.

The effective half-life of motixafortide in human plasma is approximately 2 hours. The elimination kinetics were similar in healthy subjects and patients with multiple myeloma. In studies performed in rats and dogs, the total amount of14C-labeled motixafortide-related material excreted in urine was approximately 80% and 82%, respectively, of the dose administered; no parent drug was detected in urine.

In both species, nometabolite exceeded 30% of total clearance. Animal data suggest that the main excretion pathway of motixafortide metabolites is via the kidneys and that biliary excretion is minimal.

In a population pharmacokinetic analysis, there washigher relative bioavailability and 10% higher exposure in female patients compared with males for a weight-based dose of motixafortide; this was not considered clinically important. Age and race/ethnicity were not found to be statistically important predictors of motixafortide pharmacokinetics.

USES: Motixafortide is used by people with a certain type of cancer (multiple myeloma) to prepare for stem cell transplant. Stem cells, which are found mainly in the bone marrow, turn into red blood cells, white blood cells, and platelets. Motixafortide is used to help stem cells move from the bone marrow to the bloodstream so that the cells can be collected and stored.

The stem cells are then given back to you by infusion after chemotherapy or radiation.

Generic name: motixafortide acetate
Drug class: CXCR4 Chemokine Receptor Antagonists
Therapeutic class: Hematological Agents

The following indications are listed for Aphexda:

• Peripheral Mobilization Of Hematopoietic Stem Cells