Plerixafor

Plerixafor is a bicyclam derivative and a selective, reversible antagonist of the CXCR4 chemokine receptor. By blocking CXCR4 it frees haematopoietic stem and progenitor cells (CD34+ cells) from the bone marrow, and together with G-CSF it raises their number in the peripheral blood so that they can be collected by apheresis.

Mechanism of Action

• CXCR4 blockade: CXCR4 and its ligand SDF-1α (CXCL12) take part in the homing of stem cells to the bone marrow, where CXCR4 helps anchor them to the marrow matrix. Plerixafor blocks the binding of SDF-1α to CXCR4, so mature and pluripotent cells appear in the circulation; the associated rise in white cells is thought to result from the same disruption.
• Functional cells: CD34+ cells mobilised by plerixafor are functional and capable of engraftment with long-term repopulating capacity.
• Timing: in healthy volunteers given plerixafor alone, CD34+ mobilisation peaked 6 to 9 hours after the dose. With G-CSF, the blood CD34+ count stayed raised from 4 to 18 hours after plerixafor, with a peak response at 10 to 14 hours.
• With G-CSF: adding G-CSF increases the stem-cell yield, an important determinant of whether the graft is adequate.
• Cardiac safety: plerixafor was not associated with QT/QTc prolongation at single doses up to 0.40 mg/kg.

Pharmacokinetics

• Absorption: rapid after subcutaneous injection, with peak concentrations (tmax) in about 30 to 60 minutes. At 0.24 mg/kg after 4 days of G-CSF, Cmax was 887 ± 217 ng/mL and AUC0–24 4,337 ± 922 ng·h/mL. In adults with non-Hodgkin lymphoma weighing 70 kg or less, a fixed 20 mg dose gave 1.43-fold higher exposure (AUC0–10h) than 0.24 mg/kg.
• Distribution: moderately bound to plasma proteins (up to 58 %); apparent volume of distribution 0.3 L/kg, so the drug is largely, but not only, confined to the extravascular fluid space.
• Metabolism: not metabolised by human liver microsomes or hepatocytes in vitro. It neither inhibits the major CYP450 enzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5) nor induces CYP1A2, CYP2B6 or CYP3A4, and is neither a substrate nor an inhibitor of P-glycoprotein in vitro, so P450-dependent interactions are unlikely.
• Elimination: mainly urinary; about 70 % of the dose was excreted unchanged in urine in the first 24 hours (healthy volunteers, normal renal function). Plasma half-life is 3 to 5 hours.
• Renal impairment: clearance falls with creatinine clearance. Mean AUC0–24 was 5,410 ng·h/mL in mild impairment (creatinine clearance 51–80 mL/min), 6,780 in moderate impairment (31–50 mL/min) and 6,990 in severe impairment, against 5,070 in subjects with normal renal function; Cmax was unaffected.

Plerixafor is always used in combination with granulocyte-colony stimulating factor (G-CSF).

• Adults: to enhance mobilisation of haematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in adult patients with lymphoma or multiple myeloma whose cells mobilise poorly.
• Children and adolescents (1 to under 18 years): with G-CSF, to enhance mobilisation of haematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in children with lymphoma or solid malignant tumours, either pre-emptively, when the circulating stem cell count on the predicted day of collection after adequate mobilisation with G-CSF (with or without chemotherapy) is expected to be insufficient for the desired stem cell yield, or in those who previously failed to collect sufficient haematopoietic stem cells.
• The SmPC names predictors of poor mobilisation: age over 60 years, prior myelosuppressive chemotherapy, extensive prior chemotherapy, and a peak circulating stem cell count below 20 cells per microlitre.

• Hypersensitivity to plerixafor or to any of the excipients (sodium chloride, hydrochloric acid, sodium hydroxide, water for injections).

Safety data come from two placebo-controlled phase III studies (301 patients given plerixafor with G-CSF, 292 given placebo with G-CSF) and 10 uncontrolled phase II studies (242 patients). Patients received mainly 0.24 mg/kg daily by subcutaneous injection for 1 to 7 consecutive days (median 2). The reactions below occurred more often with plerixafor plus G-CSF than with placebo plus G-CSF and were reported as related in at least 1 % of plerixafor patients during mobilisation and apheresis. From the start of chemotherapy before transplantation to 12 months afterwards, adverse reactions did not differ significantly between the groups.

Very common (≥1/10): diarrhoea, nausea; injection and infusion site reactions.

Common (≥1/100 to <1/10): insomnia; dizziness, headache; vomiting, abdominal pain, stomach discomfort, dyspepsia, abdominal distension, constipation, flatulence, oral hypoaesthesia, dry mouth; hyperhidrosis, erythema; arthralgia, musculoskeletal pain; fatigue, malaise.

Uncommon (≥1/1,000 to <1/100): allergic reactions (urticaria, periorbital swelling, dyspnoea or hypoxia; usually mild or moderate and starting within about 30 minutes of the injection); abnormal dreams, nightmares; anaphylactic reactions including anaphylactic shock (post-marketing experience).

Not known: splenomegaly and splenic rupture (post-marketing experience).

Other points from the SmPC: white blood cell counts of 100 × 10⁹/L or more occurred in 7 % of plerixafor patients and 1 % of placebo patients, without signs of leukostasis. Fewer than 1 % of subjects had vasovagal reactions (orthostatic hypotension and/or syncope) after injection, mostly within 1 hour. Severe gastrointestinal events were rarely reported. Myocardial infarction occurred in 7 of 679 oncology patients, all at least 14 days after the last dose, and the SmPC does not see an independent risk from plerixafor in patients who also receive G-CSF. Paraesthesia was equally frequent with plerixafor and placebo (about 21 %). Elderly patients and the 30 children studied had a safety profile consistent with that of younger adults.

• No interaction studies have been performed. In vitro, plerixafor is not metabolised by P450 CYP enzymes, does not inhibit or induce them, and is neither a substrate nor an inhibitor of P-glycoprotein.
• Rituximab: in clinical studies in non-Hodgkin lymphoma, adding rituximab to plerixafor and G-CSF did not change patient safety or CD34+ cell yield.
• G-CSF: plerixafor is always combined with G-CSF, which is given each morning for 4 days before the first plerixafor dose and on each morning before apheresis (see Administration and Dosage).

Plerixafor therapy should be initiated and supervised by a physician experienced in oncology and/or haematology. The mobilisation and apheresis procedures should be performed in collaboration with an oncology-haematology centre with acceptable experience in this field, where haematopoietic progenitor cells can be monitored correctly. Plerixafor is for subcutaneous injection only, and each vial is for single use.

Recommended Dose

• Adults weighing up to 83 kg: a fixed dose of 20 mg once daily, or 0.24 mg/kg of body weight.
• Adults weighing more than 83 kg: 0.24 mg/kg of body weight once daily.
• Children and adolescents (1 to under 18 years): 0.24 mg/kg of body weight once daily.
• The dose should not exceed 40 mg/day. The weight used for the calculation should be taken within 1 week before the first dose. Studies calculated the dose by body weight in patients up to 175 % of ideal body weight; dose and treatment above that have not been investigated. Ideal body weight: men 50 + 2.3 × ((height in cm × 0.394) − 60) kg; women 45.5 + 2.3 × ((height in cm × 0.394) − 60) kg.
• Timing: inject 6 to 11 hours before the start of each apheresis, after 4 days of G-CSF pre-treatment. In clinical trials plerixafor was commonly used for 2 to 4, and up to 7, consecutive days.
• G-CSF: in the pivotal studies all patients received G-CSF 0.01 mg/kg each morning for 4 consecutive days before the first plerixafor dose and on each morning before apheresis.

Preparing the Dose

Each vial is filled to deliver 1.2 mL of 20 mg/mL solution (24 mg). The syringe is chosen by patient weight: for patients up to 45 kg, a 1 mL infant syringe (major graduations 0.1 mL, minor 0.01 mL) can be used, suitable for children weighing at least 9 kg at 0.24 mg/kg; above 45 kg, a 1 mL or 2 mL syringe with 0.1 mL graduations. Inspect the vial and do not use it if there is particulate matter or discolouration. The product is sterile and preservative-free, so use aseptic technique when drawing it up.

Special Populations

• Renal impairment: with creatinine clearance 20–50 mL/min, reduce the dose by one-third to 0.16 mg/kg/day (clinical data with this adjustment are limited). The dose should not exceed 27 mg/day if creatinine clearance is below 50 mL/min. There is too little experience to recommend a dose for creatinine clearance below 20 mL/min or for patients on haemodialysis.
• Elderly (over 65 years): no dose change with normal renal function; with reduced creatinine clearance, adjust as for renal impairment. Take care in dose selection because renal function often declines with age.
• Children and adolescents: studied in an open-label, multicentre, controlled study; the dose is 0.24 mg/kg.

Tumour Cell Mobilisation

• In lymphoma or multiple myeloma, tumour cells may be released from the marrow and collected in the apheresis product. If tumour cells are mobilised, their number is not higher with plerixafor plus G-CSF than with G-CSF alone.
• In a compassionate use programme in acute myelogenous leukaemia and plasma cell leukaemia, some patients had more circulating leukaemia cells. Plerixafor may mobilise leukaemic cells and contaminate the product, so it is not recommended for stem cell mobilisation and harvest in patients with leukaemia.

Haematological Effects

• Hyperleukocytosis: plerixafor with G-CSF raises circulating white cells, so white blood cell counts should be monitored. Clinical judgement is needed when giving it to patients with peripheral blood neutrophil counts above 50 × 10⁹/L.
• Thrombocytopenia: a known complication of apheresis, also seen with plerixafor. Platelet counts should be monitored in all patients having apheresis.

Allergic and Vasovagal Reactions

• Plerixafor has uncommonly been associated with systemic reactions to the injection, such as urticaria, periorbital swelling, dyspnoea or hypoxia. They responded to antihistamines, corticosteroids, hydration or supplemental oxygen, or resolved on their own. Anaphylactic reactions, including anaphylactic shock, have been reported after marketing worldwide, so appropriate precautions are needed.
• Vasovagal reactions, orthostatic hypotension and/or syncope can occur after subcutaneous injection; precautions are advised.

Spleen

Splenic enlargement and/or rupture have been reported when plerixafor was given with G-CSF. Patients with left upper abdominal pain and/or scapular or shoulder pain should be evaluated for splenic integrity.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment.
• Pregnancy: no adequate data. Given its mechanism of action, plerixafor is suggested to cause congenital malformations, and animal studies showed teratogenicity. It should not be used in pregnancy unless the woman’s clinical condition requires it.
• Breastfeeding: it is unknown whether plerixafor passes into human milk and a risk to the suckling child cannot be excluded. Breastfeeding should be discontinued during treatment.
• Fertility: the effects on male and female fertility are not known.

Sodium

Mozobil contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially sodium-free.

Effect on Driving

Some patients have had dizziness, fatigue or vasovagal reactions, so caution is advised when driving or operating machines.

Mozobil does not require any special storage conditions. The solution is supplied in a clear type I glass 2 mL vial with a chlorobutyl/butyl rubber stopper and an aluminium seal with a plastic flip-off cap; each vial holds 1.2 mL, in packs of one vial.

Unopened vial: 3 years. After opening, the product should be used immediately from a microbiological point of view; if it is not, in-use storage times and conditions are the responsibility of the user.

Prescription only (Rx): a medicinal product subject to restricted medical prescription. Therapy is initiated and supervised by a physician experienced in oncology and/or haematology, and mobilisation and apheresis are carried out in collaboration with an oncology-haematology centre. Because the injection is given 6 to 11 hours before each apheresis, it is supplied to the hospital or clinic that administers it.