Plerixafor

Plerixafor is a bicyclam derivative, a selective reversible antagonist of the CXCR4 chemokine receptor and blocks binding of its cognate ligand, stromal cell-derived factor-1 (SDF-1), also known as CXCL12. Plerixafor-induced leukocytosis and elevations in circulating haematopoietic progenitor cell levels are thought to result from a disruption of CXCR4 binding to its cognate ligand, resulting in the appearance of both mature and pluripotent cells in the systemic circulation. CD34+ cells mobilised by plerixafor are functional and capable of engraftment with long-term repopulating capacity.

Pharmacodynamic effects

In pharmacodynamic studies in healthy volunteers of plerixafor alone, peak mobilisation of CD34+ cells was observed from 6 to 9 hours after administration. In pharmacodynamic studies in healthy volunteers of plerixafor in conjunction with G-CSF administered at identical dose regimen to that in studies in patients, a sustained elevation in the peripheral blood CD34+ count was observed from 4 to 18 hours after plerixafor administration with peak response between 10 and 14 hours.

In order to compare the pharmacokinetics and pharmacodynamics of plerixafor following 0.24 mg/kg based and fixed (20 mg) doses, a trial was conducted in adult 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 (median: 63.7 kg, min: 34.2 kg, max: 70 kg). The fixed 20 mg dose showed 1.43-fold higher exposure (AUC_0-10h) than the 0.24 mg/kg dose (Table). 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. 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. Body weight of 83 kg was selected as the cut-off point to transition patients from fixed to weight based dosing (83 kg x 0.24 mg = 19.92 mg/kg).

Systemic Exposure (AUC_0-10h) comparisons of fixed and weight based regimens:

The pharmacokinetics of plerixafor have been evaluated in lymphoma and multiple myeloma patients at the clinical dose level of 0.24 mg/kg following pre-treatment with G-CSF (10 μg/kg once daily for 4 consecutive days).

Absorption

Plerixafor is rapidly absorbed following subcutaneous injection, reaching peak concentrations in approximately 30-60 minutes (t_max). Following subcutaneous administration of a 0.24 mg/kg dose to patients after receiving 4-days of G-CSF pre-treatment, the maximal plasma concentration (C_max) and systemic exposure (AUC_0-24) of plerixafor were 887 ± 217 ng/ml and 4337 ± 922 ng·hr/ml, respectively.

Distribution

Plerixafor is moderately 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.

Biotransformation

Plerixafor is not metabolised in vitro using human liver microsomes or human primary hepatocytes and does not exhibit inhibitory activity in vitro towards the major drug-metabolising CYP450 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, and CYP3A4 enzymes. These findings suggest that plerixafor has a low potential for involvement in 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 unchanged in urine during the first 24 hours following administration. The elimination half-life (t_1/2) in plasma is 3-5 hours. 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 dose of 0.24 mg/kg plerixafor, clearance was reduced in subjects with varying degrees of renal impairment and was positively correlated with creatinine clearance (CrCl). Mean values of AUC_0-24 of plerixafor in subjects with mild (CrCl 51-80 ml/min), moderate (CrCl 31-50 ml/min) and severe (CrCl ≤ 30 ml/min) renal impairment were 5410, 6780, and 6990 ng.hr/ml, respectively, which were higher than the exposure observed in healthy subjects with normal renal function (5070 ng·hr/ml). Renal impairment had no effect on C_max.

Gender

A population pharmacokinetic analysis showed no effect of gender on pharmacokinetics of plerixafor.

Elderly

A population pharmacokinetic analysis showed no effect of age on pharmacokinetics of plerixafor.

Paediatric population

The pharmacokinetics of plerixafor were evaluated in 48 paediatric patients (1 to less than 18 years) with solid tumours at subcutaneous doses of 0.16, 0.24 and 0.32 mg/kg with standard mobilisation (GCSF plus or minus chemotherapy). Based on population pharmacokinetic modeling and similar to adults, µg/kg-based dosage results in increase in plerixafor exposure with increasing body weight in paediatric patients. At the same weight-based dosing regimen of 240 µg/kg, the plerixafor mean exposure (AUC_0-24h) is lower in paediatric patients aged 2 to <6 years (1410 ng.h/mL), 6 to <12 years (2318 ng.h/mL), and 12 to <18 years (2981 ng.h/mL) than in adults (4337 ng.h/mL). Based on population pharmacokinetic modeling, the plerixafor mean exposures (AUC_0-24h) in paediatric patients aged 2 to <6 years (1905 ng.h/mL), 6 to <12 years (3063 ng.h/mL), and 12 to <18 years (4015 ng.h/mL), at the dose of 320 µg/kg are closer to the exposure in adults receiving 240 µg/kg. However, mobilization of PB CD34+ count was observed in stage 2 of the trial.

The results from single dose subcutaneous studies in rats and mice showed plerixafor can induce transient but severe neuromuscular effects (uncoordinated movement), sedative-like effects (hypoactivity), dyspnoea, ventral or lateral recumbency, and/or muscle spasms. Additional effects of plerixafor consistently noted in repeated dose animal studies included increased levels of circulating white blood cells and increased urinary excretion of calcium and magnesium in rats and dogs, slightly higher spleen weights in rats, and diarrhoea and tachycardia in dogs. Histopathology findings of extramedullary haematopoiesis were observed in the liver and spleen of rats and/or dogs. One or more of these findings were usually observed at systemic exposures in the same order of magnitude or slightly higher than the human clinical exposure.

The results of the dose range-finding study in juvenile miniature pigs and the range-finding and definitive studies in juvenile rats were similar to those observed in adult mice, rats, and dogs. Exposure margins in the juvenile rat study at the maximum tolerated dose (MTD) were ≥18 fold when compared with the highest clinical paediatric dose in children up to 18 years of age.

An in vitro general receptor activity screen showed that plerixafor, at a concentration (5 µg/ml) several fold higher than the maximum human systemic level, has moderate or strong binding affinity for a number of different receptors predominantly located on pre-synaptic nerve endings in the central nervous system (CNS) and/or the peripheral nervous system (PNS) (N-type calcium channel, potassium channel SK_CA, histamine H₃, acetylcholine muscarinic M₁ and M₂, adrenergic α1_B and α2_C, neuropeptide Y/Y₁ and glutamate NMDA polyamine receptors). The clinical relevance of these findings is not known.

Safety pharmacology studies with intravenously administered plerixafor in rats showed respiratory and cardiac depressant effects at systemic exposure slightly above the human clinical exposure, whilst subcutaneous administration elicited respiratory and cardiovascular effects only at higher systemic levels.

SDF-1α and CXCR4 play major roles in embryo-foetal development. Plerixafor has been shown to cause increased resorptions, decreased foetal weights, retarded skeletal development and increased foetal abnormalities in rats and rabbits. Data from animal models also suggest modulation of foetal haematopoiesis, vascularisation, and cerebellar development by SDF-1α and CXCR4. Systemic exposure at No Observed Adverse Effect Level for teratogenic effects in rats and rabbits was of the same magnitude or lower as found at therapeutic doses in patients. This teratogenic potential is likely due to its pharmacodynamic mechanism of action. In rat distribution studies concentrations of radiolabelled plerixafor was detected in reproductive organs (testes, ovaria, uterus) two weeks after single or 7 daily repeated doses in males and after 7 daily repeated doses in females. The elimination rate from tissues was slow. The potential effects of plerixafor on male fertility and postnatal development have not been evaluated in non-clinical studies.

Carcinogenicity studies with plerixafor have not been conducted. Plerixafor was not genotoxic in an adequate battery of genotoxicity tests.

Plerixafor inhibited tumour growth in in vivo models of non-Hodgkin’s lymphoma, glioblastoma, medulloblastoma, and acute lymphoblastic leukaemia when dosed intermittently. An increase of nonHodgkin’s lymphoma growth was noted after a continuous administration of plerixafor for 28 days. The potential risk associated with this effect is expected to be low for the intended short term duration of dosing plerixafor in humans.