Plerixafor

Plerixafor is a symmetric bicyclam originally developed as an anti-HIV agent, because CXCR4 is a co-receptor for T-tropic HIV strains; the stem cell mobilisation was discovered as an unexpected finding when healthy volunteers developed marked leukocytosis. It binds the CXCR4 pocket reversibly, and unlike motixafortide it dissociates comparatively quickly, so mobilisation peaks 6 to 9 hours after dosing and repeat daily doses are needed for multi-day collections. The mobilised graft has a slightly different cellular composition than G-CSF-only grafts, with more primitive progenitors and more T cells, which has never translated into a clinically important difference in engraftment. It works in patients who have already failed G-CSF-only mobilisation, which is its main clinical role.

Targets: CXCR4 chemokine receptor, CXCL12 / SDF-1 signalling axis

• · 0.24 mg/kg subcutaneously, capped at 40 mg per day. In an 80 kg patient that is about 19 mg. Reduce to 0.16 mg/kg (max 27 mg) if creatinine clearance is 50 mL/min or less.

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• very commonDiarrhoea— The most common complaint, usually mild and short-lived.
• very commonNausea
• very commonInjection-site reactions— Notably milder than with motixafortide.
• very commonLeukocytosis— Expected pharmacology.
• commonFatigue and headache
• commonDizziness and vasovagal reactions— Can occur within an hour of dosing, sometimes with orthostatic hypotension.
• commonArthralgia and bone pain— Often hard to separate from G-CSF-induced bone pain.
• rareSplenic enlargement and rupture— Left upper quadrant or scapular pain after dosing must be taken seriously.

• Leukaemia — plerixafor mobilises leukaemic blasts along with stem cells, so it is not approved for mobilisation in leukaemia.
• Pregnancy — embryo-fetal toxicity in animals.
• Known hypersensitivity.

• synergyFilgrastim / G-CSF — The approved use is always in combination after four days of G-CSF priming.
• redundantmotixafortide — Same receptor and same indication; motixafortide achieves single-session collection more often but costs far more.
• cautionDrugs that lower the seizure threshold — Rare seizures have been reported, particularly in patients with prior neurologic disease.

• · Peripheral blood CD34 count before each apheresis.
• · Full blood count with attention to platelet count during repeated apheresis.
• · Renal function at baseline to set the dose.
• · Assessment for left upper quadrant pain after dosing, for splenic enlargement.

FDA and EMA approved, available generically. Transplant-centre use.

• DiPersio et al. 2009, phase 3 trial of plerixafor plus G-CSF in multiple myeloma, Blood (trial)
• DiPersio et al. 2009, phase 3 trial of plerixafor plus G-CSF in non-Hodgkin lymphoma, Journal of Clinical Oncology (trial)
• FDA prescribing information for Mozobil (label)

Plerixafor's history explains its pharmacology. Bicyclams were developed as anti-HIV agents because CXCR4 is the co-receptor for T-tropic HIV strains, and the mobilisation effect was discovered as an unexplained marked leukocytosis in healthy volunteers during those early studies — one of the more productive accidents in drug development. Mechanistically it is a reversible competitive antagonist that inserts its two protonated macrocycles into the CXCR4 binding pocket where they form salt bridges with acidic aspartate and glutamate residues in the transmembrane bundle. That is a shallower and more electrostatic interaction than the deep insertion the peptide antagonists achieve, and it dissociates comparatively fast. Fast dissociation is the whole clinical personality of the drug: mobilisation peaks 6 to 9 hours after a dose, the effect fades, and multi-day collections need daily redosing. It is why the drug is given roughly 11 hours before each apheresis session rather than once for a whole collection. Two further points are worth knowing. First, the composition of a plerixafor-mobilised graft differs from a G-CSF-only graft — more primitive CD34+CD38- progenitors, more T cells, more plasmacytoid dendritic cells — and despite two decades of looking, this has never translated into a clinically important difference in engraftment or outcome, which is a useful reminder that graft composition differences are easier to measure than to matter. Second, the drug works in patients who have already failed G-CSF-only mobilisation, and that rescue role rather than routine use is where most of its value sits. The rare seizures reported with it are thought to relate to CXCR4 expression in the central nervous system, though the drug does not meaningfully cross the blood-brain barrier and the mechanism is not established.

Very little, which is the point of including it as the comparator. Diarrhoea and nausea are the commonest complaints and are mild. Injection-site reactions are noticeably milder than with motixafortide. Vasovagal reactions and orthostatic hypotension occur within an hour of dosing and are worth warning about, especially in someone who then drives home. The two genuine hazards are splenic enlargement and rupture, which presents as left upper quadrant or left scapular pain and must not be dismissed, and rare seizures. The recurring practical error is forgetting the renal dose reduction — clearance tracks creatinine clearance closely, and a full dose in someone with a clearance of 40 mL/min is an unnecessary overexposure. The other error is timing: the 11-hour interval before apheresis exists because mobilisation peaks at 6 to 9 hours, and giving the dose too early or too late costs collection yield. Finally, the contraindication that matters is leukaemia, where mobilising blasts is an active harm.

1. —Days 1 to 4 — G-CSF priming at 10 micrograms per kg daily for four days before the first plerixafor dose. The approved use is always in combination.
2. 240 mcgEvening of day 4, about 11 hours before apheresis — 0.24 mg per kg subcutaneously, which is 240 micrograms per kg, capped at 40 mg per day. For an 80 kg patient that is about 19 mg.
3. 160 mcgBaseline, in renal impairment — 0.16 mg per kg, which is 160 micrograms per kg, capped at 27 mg per day, when creatinine clearance is at or below 50 mL/min. Roughly a one-third reduction.
4. 240 mcgRepeat daily for up to 4 consecutive days — Because dissociation is fast and the effect fades, each apheresis day needs its own dose the evening before. Four consecutive days is the ceiling.

• CXCR4 chemokine receptor — Reported affinity varies widely by assay — figures from the low nanomolar to the high hundreds of nanomolar appear in the literature depending on whether binding, calcium flux or HIV entry inhibition was measured. What is consistent is that it is a reversible antagonist with fast dissociation.

  Competitive blockade of CXCL12 binding, releasing haematopoietic stem and progenitor cells into the circulation with a peak at 6 to 9 hours.

• CXCL12 / SDF-1 signalling axis — Blocked indirectly

  Loss of marrow retention signalling. Also mobilises leukaemic blasts, which is why leukaemia is not an approved setting.

• CXCR7 / ACKR3 — Reported as a weak allosteric agonist at this second CXCL12 receptor in some studies

  Uncertain clinical relevance. Mentioned because it appears in the literature and is sometimes invoked to explain effects the CXCR4 story does not cover.

• Phase 3 plerixafor plus G-CSF in multiple myeloma Phase 3, randomised, double-blind, placebo-controlled · n=302 · 2009

  Proportion of patients collecting at least 6 million CD34+ cells per kg in two or fewer apheresis days. Substantially higher with plerixafor plus G-CSF than with placebo plus G-CSF, and more patients reached target in a single day.

• Phase 3 plerixafor plus G-CSF in non-Hodgkin lymphoma Phase 3, randomised, double-blind, placebo-controlled · n=298 · 2009

  Proportion of patients collecting at least 5 million CD34+ cells per kg in four or fewer apheresis days. 59 percent with plerixafor plus G-CSF versus 20 percent with placebo plus G-CSF.

Plasma concentration peaks 30 to 60 minutes after the subcutaneous injection. White cell count and peripheral CD34 counts rise over the following hours and peak at 6 to 9 hours, which is why the dose is given about 11 hours before a morning apheresis. The effect fades over the following day, hence daily redosing. Terminal half-life is 5.3 hours in normal renal function and longer in impairment. Adverse effects — diarrhoea, nausea, dizziness — occur within the first hours and are self-limiting. The whole clinical episode is a maximum of four days.

Always with G-CSF, never alone — four days of filgrastim priming, then plerixafor the evening before each apheresis day. There is essentially no metabolic interaction to manage: the drug is not metabolised by human liver microsomes or hepatocytes and is neither a CYP substrate nor an inhibitor, which makes it unusually safe to add to a complicated regimen. The one drug-class caution worth keeping is anything that lowers the seizure threshold, because rare seizures have been reported, particularly in patients with prior neurological disease. The relationship with motixafortide is substitution, not combination — same receptor, no reason to give both. Preemptive dosing strategies, where plerixafor is added only when the day-4 CD34 count predicts a poor collection, are widely used and save a great deal of money compared with giving it to everyone. In leukaemia the drug has been studied to evict blasts from the marrow niche before chemotherapy, but it is not approved for mobilisation in leukaemia because the same mechanism mobilises the malignant cells.

Against motixafortide, the same receptor and the same job, and the difference is entirely kinetic. Plerixafor dissociates fast, peaks at 6 to 9 hours and needs a dose per apheresis day; motixafortide dissociates slowly, peaks at 10 to 14 hours and can cover a whole collection with one injection, which translates into more single-session collections. Plerixafor's compensating advantages are real: fifteen-plus years of experience, generic pricing, a much gentler injection experience and no requirement for antihistamine and montelukast premedication. Against G-CSF alone it roughly doubles or triples the proportion of patients reaching target in the registration trials. Against chemomobilisation with cyclophosphamide plus G-CSF, plerixafor avoids the neutropenic fever and hospital admissions but costs more in drug. Against the peptide CXCR4 antagonists as a class, plerixafor is the small molecule that got there first and is included in this catalogue as the benchmark they are measured against, not as a peptide.

Not characterised, and monthly is the wrong unit for a drug given on up to four consecutive days once in a lifetime. Plerixafor is now generic in most markets and its acquisition cost has fallen substantially from the brand era, which is precisely why preemptive rather than universal dosing strategies matter less than they used to.

• ?Absolute subcutaneous bioavailability is not stated in the US label and is left null.
• ?The 21 L volume of distribution is derived from the label's 0.3 L/kg figure applied to a 70 kg reference person; the label reports the weight-normalised value, not an absolute litre figure.
• ?Numeric clearance is not published for normal renal function, only the statement that clearance correlates with creatinine clearance.
• ?Reported CXCR4 binding affinity varies by more than an order of magnitude across assay formats, so no single number is quoted.
• ?The reported weak agonism at CXCR7/ACKR3 appears in the literature but its clinical relevance is unestablished and I did not resolve a primary source in this session.
• ?The mechanism of the rare seizures is not established, and the drug is not thought to cross the blood-brain barrier meaningfully.
• ?Trial enrolment figures of 302 and 298 are as commonly cited for these two studies; I resolved both publication records but not participant-level detail.
• ?Sponsor study numbers commonly attached to the two registration trials were removed because I resolved the publications but not the study codes.

• Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma DiPersio JF, Stadtmauer EA, Nademanee A, et al., Blood, 2009 · PMID 19363221

  One of the two registration trials. The myeloma half of the approval package.

• Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma DiPersio JF, Micallef IN, Stiff PJ, et al., Journal of Clinical Oncology, 2009 · PMID 19720922

  The lymphoma registration trial and the source of the 59 versus 20 percent collection figure.

• MOZOBIL (plerixafor) injection — US prescribing information Genzyme / Sanofi, FDA prescribing information

  Source of the 0.3 L/kg apparent volume of distribution, 58 percent protein binding, 5.3-hour terminal half-life in normal renal function, absence of hepatic metabolism and the 70 percent urinary excretion of parent drug in 24 hours.