Mavorixafor

Mavorixafor is a CXC Chemokine Receptor 4 (CXCR4) antagonist that blocks the binding of the CXCR4 ligand, stromal-derived factor-1α (SDF-1α)/CXC Chemokine Ligand 12 (CXCL12). SDF-1/CXCR4 plays a role in trafficking and homing of leukocytes to and from the bone marrow compartment. Gain of function mutations in the CXCR4 receptor gene that occur in patients with WHIM syndrome lead to increased responsiveness to CXCL12 and retention of leukocytes in the bone marrow. Mavorixafor inhibits the response to CXCL12 in both wild‑type and mutated CXCR4 variants associated with WHIM syndrome. Treatment with mavorixafor results in increased mobilisation of neutrophils and lymphocytes and monocytes from the bone marrow into peripheral circulation.

Absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) peaked at 4 hours after mavorixafor dosing and returned towards baseline within 24 h after dosing. Over mavorixafor doses of 50 mg (0.125 times the maximum recommended dose) to 400 mg once daily, higher mavorixafor exposure at steady state was associated with longer mean time (hours) above ANC threshold (TAT_ANC) of 500 cells/μL and longer mean time (hours) above ALC threshold (TAT_ALC) of 1 000 cells/μL over a 24-hour period.

Mavorixafor pharmacokinetic parameters are presented as geometric mean (CV%) in adults with WHIM syndrome unless otherwise specified. Mavorixafor steady state C_max is 3 304 (58.6%) ng/mL and the AUC from 0 to 24 hours (AUC_0-24h) is 13 970 (58.4%) ng×h/mL following 400 mg once daily.

Absorption

Mavorixafor median (range) time to C_max (t_max) is 2.8 hours (1.9 to 4 hours) at the highest approved recommended dose.

Effect of food

High fat meal: Mavorixafor C_max decreased by 66% and AUC decreased by 55% following single-dose administration of mavorixafor 400 mg with a high‑fat meal (1 000 calories, 50% fat) to healthy subjects.

Low fat meal: Mavorixafor C_max decreased by 55% and AUC decreased by 51% following single-dose administration of mavorixafor 400 mg with a low-fat meal (500 calories, 25% fat) to healthy subjects. In addition, a 14% higher mavorixafor C_max and 18% lower AUC was observed following single-dose administration of mavorixafor 400 mg with a low-fat meal to healthy subjects after an overnight fast compared to fasting for an additional 4 hours after the mavorixafor dose.

Distribution

Mavorixafor volume of distribution is 120 L/kg. Mavorixafor is > 93% bound to human plasma proteins in vitro.

Biotransformation

CYP3A4 and, to a lesser extent, CYP2D6 are primarily responsible for mavorixafor metabolism.

Elimination

Mavorixafor's terminal half-life was 82 h with an apparent clearance of 62 L/h following single-dose administration of mavorixafor 400 mg in healthy subjects. Mavorixafor exhibits at least partial nonlinear apparent clearance; however, this is not clinically significant at the approved recommended dose.

After a single oral dose of radiolabelled mavorixafor, 74.2% of the administered dose was recovered out of which 61.0% of administered radioactivity was recovered in faeces and 13.2% (3% unchanged) was recovered in the urine over the 240-hour collection period in healthy subjects.

Linearity/non-linearity

Mavorixafor demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in C_max and AUC_0-24h over a dose range of 50 mg (0.125 times the recommended dose) to 400 mg. Mavorixafor steady state is reached after approximately 9 to 12 days in healthy subjects at the highest approved recommended dose.

Pharmacokinetic/pharmacodynamic relationship(s)

In study 2, mean ANC levels for doses 50 to 200 mg generally remained below the clinical benefit threshold of 500 cells/μL during the 24-hour dosing interval. For 300 mg and 400 mg, mean ANC levels rose above the threshold by approximately 1 hour post-dose and remained above or at the threshold over the entire dosing interval. A mavorixafor dose of 300/400 mg QD was required to achieve AUC_ANC ≥600/μL and AUC_ALC ≥1 000/μL.

Drug interaction studies

For information regarding drug interactions with other medicinal products please refer to section 4.5.

Other medicinal products: No clinically significant differences in the pharmacokinetics of caffeine (CYP1A2 substrate), losartan (CYP2C9 substrate), omeprazole (CYP2C19 substrate), furosemide (OAT1 and OAT3 substrate) and oral contraceptives were observed following concomitant use with mavorixafor.

Special populations

Hepatic impairment

Mavorixafor is metabolised by the liver. The effect of moderate to severe hepatic impairment on the pharmacokinetics of mavorixafor has not been studied.

Renal impairment

Renal clearance is a minor excretion pathway for mavorixafor. No clinically significant differences in the pharmacokinetics of mavorixafor were observed in mild to moderate renal impairment (CLcr 30 to less than 90 mL/min). The pharmacokinetics of mavorixafor have not been studied in subjects with severe renal impairment or end-stage renal disease.

Elderly

In clinical studies of mavorixafor in patients with WHIM syndrome, 2 (5%) patients were aged 65 years and older, and no patients were aged 75 years and older. Clinical studies did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

Race/Ethnicity

The effect of race/ethnicity on mavorixafor systemic exposure is unknown.

Gender

The effect of gender on mavorixafor systemic exposure is unknown.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels comparable to clinical exposure levels and with possible relevance to clinical use were as follows: testicular toxicity, hepatotoxicity, retinal degeneration and atrophy.

Genotoxicity

Mavorixafor was not genotoxic in an in vitro bacterial reverse mutation assay (Ames test), in an in vitro human lymphocyte culture chromosome aberration assay, or in an in vivo rat bone marrow micronucleus assay.

Reproductive toxicity

Animal reproduction studies have not been conducted with mavorixafor to evaluate effects on reproduction and embryo-foetal development. CXCR4/SDF-1 signalling plays an important role in mammalian embryo-foetal and placental development. In mice, CXCR4-/- knockout is embryo lethal and causes multiple developmental toxicities, most notably in the hematopoietic, cardiovascular and nervous systems. CXCR4/SDF-1 levels also have a key role in stimulating trophoblast proliferation and differentiation necessary for appropriate placental growth and function in humans. Based on its mechanism of action, mavorixafor may cause foetal harm when administered to a pregnant woman.

The effect of mavorixafor on male or female fertility was not studied in designated reproductive toxicology studies.

In a 39-week study with initiation of treatment in young prepubertal dogs, testicular changes of seminiferous tubule degeneration/atrophy including spermatogonial stem cell depletion were observed at exposure levels equivalent to the human exposure at MRHD; similar changes were not observed in a 13-week dog study in sexually mature male dogs and in a 26-week dog study in juvenile dogs covering the period of puberty. The mechanism by which mavorixafor may exert this effect is unknown, but a relation to pharmacological action of mavorixafor cannot be excluded. There are no data on the recovery of this effect.