Please sign in so that we can notify you about a reply
Indications/Uses
Plerixafor is indicated in combination with G-CSF to enhance mobilisation of haematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma whose cells mobilise poorly.
Dosage/Direction for Use
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 and where the monitoring of haematopoietic progenitor cells can be correctly performed.
Posology: The recommended dose of plerixafor is 0.24 mg/kg body weight/day. It should be administered by subcutaneous injection 6 to 11 hours prior to initiation of apheresis following 4 day pre-treatment with granulocyte-colony stimulating factor (G-CSF). In clinical trials, Plerixafor has been commonly used for 2 to 4 (and up to 7) consecutive days.
The weight used to calculate the dose of plerixafor should be obtained within 1 week before the first dose of plerixafor. In clinical studies, the dose of plerixafor has been calculated based on body weight in patients up to 175% of ideal body weight. Plerixafor dose and treatment of patients weighing more than 175% of ideal body weight have not been investigated. Ideal body weight can be determined using the following equations: male (kg): 50 + 2.3 x ((Height (cm) x 0.394) - 60); female (kg): 45.5 + 2.3 x ((Height (cm) x 0.394) - 60).
Based on increasing exposure with increasing body weight, the plerixafor dose should not exceed 40 mg/day.
Recommended concomitant medicinal products: In pivotal clinical studies supporting the use of Plerixafor, all patients received daily morning doses of 10 μg/kg G-CSF for 4 consecutive days prior to the first dose of plerixafor and on each morning prior to apheresis.
Special populations: Renal impairment: Patients with creatinine clearance 20-50 ml/min should have their dose of plerixafor reduced by one-third to 0.16 mg/kg/day. Clinical data with this dose adjustment are limited. There is insufficient clinical experience to make alternative posology recommendations for patients with a creatinine clearance <20 ml/min, as well as to make posology recommendations for patients on haemodialysis.
Based on increasing exposure with increasing body weight the dose should not exceed 27 mg/day if the creatinine clearance is lower than 50 ml/min.
Paediatric population: The experience in paediatric patients is limited. The safety and efficacy of Plerixafor in paediatric patients have not been established in controlled clinical studies.
Elderly patients (> 65 years old): No dose modifications are necessary in elderly patients with normal renal function. Dose adjustment in elderly patients with creatinine clearance 50 ml/min is recommended (see Renal impairment as previously mentioned). In general, care should be taken in dose selection for elderly patients due to the greater frequency of decreased renal function with advanced age.
Method of administration: For subcutaneous injection.
Each vial of Plerixafor is intended for single use only. Vials should be inspected visually prior to administration and not used if there is particulate matter or discolouration. Since Plerixafor is supplied as a sterile, preservative-free formulation, aseptic technique should be followed when transferring the contents of the vial to a suitable syringe for subcutaneous administration.
Posology: The recommended dose of plerixafor is 0.24 mg/kg body weight/day. It should be administered by subcutaneous injection 6 to 11 hours prior to initiation of apheresis following 4 day pre-treatment with granulocyte-colony stimulating factor (G-CSF). In clinical trials, Plerixafor has been commonly used for 2 to 4 (and up to 7) consecutive days.
The weight used to calculate the dose of plerixafor should be obtained within 1 week before the first dose of plerixafor. In clinical studies, the dose of plerixafor has been calculated based on body weight in patients up to 175% of ideal body weight. Plerixafor dose and treatment of patients weighing more than 175% of ideal body weight have not been investigated. Ideal body weight can be determined using the following equations: male (kg): 50 + 2.3 x ((Height (cm) x 0.394) - 60); female (kg): 45.5 + 2.3 x ((Height (cm) x 0.394) - 60).
Based on increasing exposure with increasing body weight, the plerixafor dose should not exceed 40 mg/day.
Recommended concomitant medicinal products: In pivotal clinical studies supporting the use of Plerixafor, all patients received daily morning doses of 10 μg/kg G-CSF for 4 consecutive days prior to the first dose of plerixafor and on each morning prior to apheresis.
Special populations: Renal impairment: Patients with creatinine clearance 20-50 ml/min should have their dose of plerixafor reduced by one-third to 0.16 mg/kg/day. Clinical data with this dose adjustment are limited. There is insufficient clinical experience to make alternative posology recommendations for patients with a creatinine clearance <20 ml/min, as well as to make posology recommendations for patients on haemodialysis.
Based on increasing exposure with increasing body weight the dose should not exceed 27 mg/day if the creatinine clearance is lower than 50 ml/min.
Paediatric population: The experience in paediatric patients is limited. The safety and efficacy of Plerixafor in paediatric patients have not been established in controlled clinical studies.
Elderly patients (> 65 years old): No dose modifications are necessary in elderly patients with normal renal function. Dose adjustment in elderly patients with creatinine clearance 50 ml/min is recommended (see Renal impairment as previously mentioned). In general, care should be taken in dose selection for elderly patients due to the greater frequency of decreased renal function with advanced age.
Method of administration: For subcutaneous injection.
Each vial of Plerixafor is intended for single use only. Vials should be inspected visually prior to administration and not used if there is particulate matter or discolouration. Since Plerixafor is supplied as a sterile, preservative-free formulation, aseptic technique should be followed when transferring the contents of the vial to a suitable syringe for subcutaneous administration.
Overdosage
No case of overdose has been reported. Based on limited data at doses above the recommended dose and up to 0.48 mg/kg the frequency of gastrointestinal disorders, vasovagal reactions, orthostatic hypotension, and/or syncope may be higher.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Special Precautions
Potential for tumour cell mobilisation in patients with lymphoma and multiple myeloma: The effect of potential re-infusion of tumour cells has not been adequately studied. When Plerixafor is used in conjunction with G-CSF for haematopoietic stem cell mobilisation in patients with lymphoma or multiple myeloma, tumour cells may be released from the marrow and subsequently collected in the leukapheresis product. The clinical relevance of the theoretical risk of tumour cell mobilisation is not fully elucidated. In clinical studies of patients with non-Hodgkin's lymphoma and multiple myeloma, mobilisation of tumour cells has not been observed with plerixafor.
Tumour cell mobilisation in leukaemia patients: In a compassionate use programme, Plerixafor and G-CSF have been administered to patients with acute myelogenous leukaemia and plasma cell leukaemia. In some instances, these patients experienced an increase in the number of circulating leukaemia cells. For the purpose of haematopoietic stem cell mobilisation, plerixafor may cause mobilisation of leukaemic cells and subsequent contamination of the apheresis product. Therefore, plerixafor is not recommended for haematopoietic stem cell mobilisation and harvest in patients with leukaemia.
Haematological effects: Hyperleukocytosis: Administration of Plerixafor in conjunction with G-CSF increases circulating leukocytes as well as haematopoietic stem cell populations. White blood cell counts should be monitored during Plerixafor therapy. Clinical judgment should be exercised when administering Plerixafor to patients with peripheral blood neutrophil counts above 50,000 cells/μl.
Thrombocytopenia: Thrombocytopenia is a known complication of apheresis and has been observed in patients receiving Plerixafor. Platelet counts should be monitored in all patients receiving Plerixafor and undergoing apheresis.
Laboratory monitoring: White blood cell and platelet counts should be monitored during Plerixafor use and apheresis.
Allergic reactions: Plerixafor has been uncommonly associated with potential systemic reactions related to subcutaneous injection such as urticaria, periorbital swelling, dyspnoea, or hypoxia. Symptoms responded to treatments (e.g., antihistamines, corticosteroids, hydration or supplemental oxygen) or resolved spontaneously. Appropriate precautions should be taken because of the potential for these reactions.
Vasovagal reactions: Vasovagal reactions, orthostatic hypotension, and/or syncope can occur following subcutaneous injections. Appropriate precautions should be taken because of the potential for these reactions.
Splenomegaly: In preclinical studies, higher absolute and relative spleen weights associated with extramedullary haematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor subcutaneous administration in rats at doses approximately 4 fold higher than the recommended human dose.
The effect of plerixafor on spleen size in patients has not been specifically evaluated in clinical studies. The possibility that plerixafor in conjunction with G-CSF can cause splenic enlargement cannot be excluded. Due to the very rare occurrence of splenic rupture following G-CSF administration, individuals receiving Plerixafor in conjunction with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain should be evaluated for splenic integrity.
Sodium: Plerixafor contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free'.
Plerixafor may influence the ability to drive and use machines. Some patients have experienced dizziness, fatigue or vasovagal reactions; therefore caution is advised when driving or operating machinery.
Tumour cell mobilisation in leukaemia patients: In a compassionate use programme, Plerixafor and G-CSF have been administered to patients with acute myelogenous leukaemia and plasma cell leukaemia. In some instances, these patients experienced an increase in the number of circulating leukaemia cells. For the purpose of haematopoietic stem cell mobilisation, plerixafor may cause mobilisation of leukaemic cells and subsequent contamination of the apheresis product. Therefore, plerixafor is not recommended for haematopoietic stem cell mobilisation and harvest in patients with leukaemia.
Haematological effects: Hyperleukocytosis: Administration of Plerixafor in conjunction with G-CSF increases circulating leukocytes as well as haematopoietic stem cell populations. White blood cell counts should be monitored during Plerixafor therapy. Clinical judgment should be exercised when administering Plerixafor to patients with peripheral blood neutrophil counts above 50,000 cells/μl.
Thrombocytopenia: Thrombocytopenia is a known complication of apheresis and has been observed in patients receiving Plerixafor. Platelet counts should be monitored in all patients receiving Plerixafor and undergoing apheresis.
Laboratory monitoring: White blood cell and platelet counts should be monitored during Plerixafor use and apheresis.
Allergic reactions: Plerixafor has been uncommonly associated with potential systemic reactions related to subcutaneous injection such as urticaria, periorbital swelling, dyspnoea, or hypoxia. Symptoms responded to treatments (e.g., antihistamines, corticosteroids, hydration or supplemental oxygen) or resolved spontaneously. Appropriate precautions should be taken because of the potential for these reactions.
Vasovagal reactions: Vasovagal reactions, orthostatic hypotension, and/or syncope can occur following subcutaneous injections. Appropriate precautions should be taken because of the potential for these reactions.
Splenomegaly: In preclinical studies, higher absolute and relative spleen weights associated with extramedullary haematopoiesis were observed following prolonged (2 to 4 weeks) daily plerixafor subcutaneous administration in rats at doses approximately 4 fold higher than the recommended human dose.
The effect of plerixafor on spleen size in patients has not been specifically evaluated in clinical studies. The possibility that plerixafor in conjunction with G-CSF can cause splenic enlargement cannot be excluded. Due to the very rare occurrence of splenic rupture following G-CSF administration, individuals receiving Plerixafor in conjunction with G-CSF who report left upper abdominal pain and/or scapular or shoulder pain should be evaluated for splenic integrity.
Sodium: Plerixafor contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium- free'.
Plerixafor may influence the ability to drive and use machines. Some patients have experienced dizziness, fatigue or vasovagal reactions; therefore caution is advised when driving or operating machinery.
Use In Pregnancy & Lactation
Pregnancy: There are no adequate data on the use of plerixafor in pregnant women.
Based on the pharmacodynamic mechanism of action, plerixafor is suggested to cause congenital malformations when administered during pregnancy. Studies in animals have shown teratogenicity. Plerixafor should not be used during pregnancy unless the clinical condition of the woman requires treatment with plerixafor.
Women of childbearing potential: Women of childbearing potential have to use effective contraception during treatment.
Breastfeeding: It is not known whether plerixafor is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with Plerixafor.
Based on the pharmacodynamic mechanism of action, plerixafor is suggested to cause congenital malformations when administered during pregnancy. Studies in animals have shown teratogenicity. Plerixafor should not be used during pregnancy unless the clinical condition of the woman requires treatment with plerixafor.
Women of childbearing potential: Women of childbearing potential have to use effective contraception during treatment.
Breastfeeding: It is not known whether plerixafor is excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with Plerixafor.
Adverse Reactions
Safety data for Plerixafor in conjunction with G-CSF in oncology patients with lymphoma and multiple myeloma were obtained from 2 placebo-controlled Phase III studies and 10 uncontrolled Phase II studies in 543 patients. Patients were primarily treated with daily doses of 0.24 mg/kg plerixafor by subcutaneous injection. The exposure to plerixafor in these studies ranged from 1 to 7 consecutive days (median= 2 days).
In the two Phase III studies in non-Hodgkin's lymphoma and multiple myeloma patients (AMD3100-3101 and AMD3100-3102, respectively), a total of 301 patients were treated in the Plerixafor and G-CSF group and 292 patients were treated in the placebo and G-CSF group. Patients received daily morning doses of G-CSF 10 μg/kg for 4 days prior to the first dose of plerixafor or placebo and on each morning prior to apheresis. Adverse reactions that occurred more frequently with Plerixafor and G-CSF than placebo and G-CSF and were reported as related in ≥ 1% of the patients who received Plerixafor, during haematopoietic stem cell mobilisation and apheresis and prior to chemotherapy/ablative treatment in preparation for transplantation are shown in Table 6. Adverse reactions are listed by System Organ Class and frequency. Frequencies are defined according to the following convention; very common ≥ 1/10); common ≥ 1/100 to < 1/10); uncommon (≥ 1 /1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
From chemotherapy/ablative treatment in preparation of transplantation through 12 months post-transplantation, no significant differences in the incidence of adverse reactions were observed across treatment groups. (See Table 6.)
The adverse reactions reported in patients with lymphoma and multiple myeloma who received Plerixafor in the controlled Phase III studies and uncontrolled studies, including a Phase II study of Plerixafor as monotherapy for haematopoietic stem cell mobilisation, are similar. No significant differences in the incidence of adverse reactions were observed for oncology patients by disease, age, or gender.
Myocardial infarction: In clinical studies, 7 of 679 oncology patients experienced myocardial infarctions after haematopoietic stem cell mobilisation with plerixafor and G-CSF. All events occurred at least 14 days after last Plerixafor administration. Additionally, two female oncology patients in the compassionate use programme experienced myocardial infarction following haematopoietic stem cell mobilisation with plerixafor and G-CSF. One of these events occurred 4 days after last Plerixafor administration. Lack of temporal relationship in 8 of 9 patients coupled with the risk profile of patients with myocardial infarction does not suggest Plerixafor confers an independent risk for myocardial infarction in patients who also receive G-CSF.
Hyperleukocytosis: White blood cell counts of 100 x 109/l or greater were observed, on the day prior to or any day of apheresis, in 7% patients receiving Plerixafor and in 1 % patients receiving placebo in the Phase 111 studies. No complications or clinical symptoms of leukostasis were observed.
Vasovagal reactions: In Plerixafor oncology and healthy volunteer clinical studies, less than 1% of subjects experienced vasovagal reactions (orthostatic hypotension and/or syncope) following subcutaneous administration of plerixafor doses ≥ 0.24 mg/kg. The majority of these events occurred within 1 hour of Plerixafor administration.
Gastrointestinal disorders: In Plerixafor clinical studies of oncology patients, there have been rare rep orts of severe gastrointestinal events, including diarrhoea, nausea, vomiting, and abdominal pain.
Paresthesiae: Paresthesiae are commonly observed in oncology patients undergoing autologous transplantation following multiple disease interventions. In the placebo-controlled Phase Ill studies, the incidence of paresthesiae was 20.6% and 21.2% in the plerixafor and placebo groups, respectively.
Elderly patients: In the two placebo-controlled clinical studies of plerixafor, 24% of patients were ≥ 65 years old. No notable differences in the incidence of adverse reactions were observed in these elderly patients when compared with younger ones.
In the two Phase III studies in non-Hodgkin's lymphoma and multiple myeloma patients (AMD3100-3101 and AMD3100-3102, respectively), a total of 301 patients were treated in the Plerixafor and G-CSF group and 292 patients were treated in the placebo and G-CSF group. Patients received daily morning doses of G-CSF 10 μg/kg for 4 days prior to the first dose of plerixafor or placebo and on each morning prior to apheresis. Adverse reactions that occurred more frequently with Plerixafor and G-CSF than placebo and G-CSF and were reported as related in ≥ 1% of the patients who received Plerixafor, during haematopoietic stem cell mobilisation and apheresis and prior to chemotherapy/ablative treatment in preparation for transplantation are shown in Table 6. Adverse reactions are listed by System Organ Class and frequency. Frequencies are defined according to the following convention; very common ≥ 1/10); common ≥ 1/100 to < 1/10); uncommon (≥ 1 /1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
From chemotherapy/ablative treatment in preparation of transplantation through 12 months post-transplantation, no significant differences in the incidence of adverse reactions were observed across treatment groups. (See Table 6.)
The adverse reactions reported in patients with lymphoma and multiple myeloma who received Plerixafor in the controlled Phase III studies and uncontrolled studies, including a Phase II study of Plerixafor as monotherapy for haematopoietic stem cell mobilisation, are similar. No significant differences in the incidence of adverse reactions were observed for oncology patients by disease, age, or gender.
Myocardial infarction: In clinical studies, 7 of 679 oncology patients experienced myocardial infarctions after haematopoietic stem cell mobilisation with plerixafor and G-CSF. All events occurred at least 14 days after last Plerixafor administration. Additionally, two female oncology patients in the compassionate use programme experienced myocardial infarction following haematopoietic stem cell mobilisation with plerixafor and G-CSF. One of these events occurred 4 days after last Plerixafor administration. Lack of temporal relationship in 8 of 9 patients coupled with the risk profile of patients with myocardial infarction does not suggest Plerixafor confers an independent risk for myocardial infarction in patients who also receive G-CSF.
Hyperleukocytosis: White blood cell counts of 100 x 109/l or greater were observed, on the day prior to or any day of apheresis, in 7% patients receiving Plerixafor and in 1 % patients receiving placebo in the Phase 111 studies. No complications or clinical symptoms of leukostasis were observed.
Vasovagal reactions: In Plerixafor oncology and healthy volunteer clinical studies, less than 1% of subjects experienced vasovagal reactions (orthostatic hypotension and/or syncope) following subcutaneous administration of plerixafor doses ≥ 0.24 mg/kg. The majority of these events occurred within 1 hour of Plerixafor administration.
Gastrointestinal disorders: In Plerixafor clinical studies of oncology patients, there have been rare rep orts of severe gastrointestinal events, including diarrhoea, nausea, vomiting, and abdominal pain.
Paresthesiae: Paresthesiae are commonly observed in oncology patients undergoing autologous transplantation following multiple disease interventions. In the placebo-controlled Phase Ill studies, the incidence of paresthesiae was 20.6% and 21.2% in the plerixafor and placebo groups, respectively.
Elderly patients: In the two placebo-controlled clinical studies of plerixafor, 24% of patients were ≥ 65 years old. No notable differences in the incidence of adverse reactions were observed in these elderly patients when compared with younger ones.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacotherapeutic group: Other immunostimulants. ATC code: L03AX16.
Pharmacology: Pharmacodynamics: Mechanism of action: 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-1α (SDF-1α), also known as CXCL 12.
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.
Clinical efficacy and safety: In two Phase III randomised-controlled studies patients with non-Hodgkin's lymphoma or multiple myeloma received Plerixafor 0.24 mg/kg or placebo on each evening prior to apheresis. Patients received daily morning doses of G-CSF 10 μg/kg for 4 days prior to the first dose of plerixafor or placebo and on each morning prior to apheresis. Optimal (5 or 6 x 106 cells/kg) and minimal (2 x 106 cells/kg) numbers of CD34+ cells/kg within a given number of days, as well as the primary composite endpoints which incorporated successful engraftment are presented in Tables 1 and 3; the proportion of patients reaching optimal numbers of CD34+ cells/kg by apheresis day are presented in Tables 2 and 4. (See Tables 1, 2, 3, and 4.)
Rescue patients: In study AMD3100-3101, 62 patients (10 in the Plerixafor + G-CSF group and 52 in the placebo + G-CSF group), who could not mobilise sufficient numbers of CD34+ cells and thus not could not proceed to transplantation, entered into an open-label Rescue procedure with Plerixafor and G-CSF. Of these patients, 55 % (34 out of 62) mobilised ≥ 2 x106/kg CD34+ cells and had successful engraftment. In study AMD3100-3102, 7 patients (all from the placebo + G-CSF group) entered the Rescue procedure. Of these patients, 100% (7 out of 7) mobilised ≥ 2 x106/kg CD34+ cells and had successful engraftment.
The dose of haematopoietic stem cells used for each transplant was determined by the investigator and all haematopoietic stem cells that were collected were not necessarily transplanted. For transplanted patients in the Phase III studies, median time to neutrophil engraftment (10-11 days), median time to platelet engraftment (18-20 days) and graft durability up to 12 months post-transplantation were similar across the Plerixafor and placebo groups.
Mobilisation and engraftment data from supportive Phase II studies (plerixafor 0.24 mg/kg dosed on the evening or morning prior to apheresis) in patients with non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma were similar to those data for the Phase III studies.
In the placebo-controlled studies, fold increase in peripheral blood CD34+ cell count (cells/μl) over the 24-hour period from the day prior to the first apheresis to just before the first apheresis was evaluated (Table 5). During that 24-hour period, the first dose of plerixafor 0.24 mg/kg or placebo was administered 10-11 hours prior to apheresis. (See Table 5.)
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.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Plerixafor in children aged 0 to 1 year in myelosuppression caused by chemotherapy to treat malignant disorders, which requires an autologous hematopoietic stem cell transplant.
The European Medicines Agency has deferred the obligation to submit the results of studies with Plerixafor in children aged 1 to 18 years in myelosuppression caused by chemotherapy to treat malignant disorders, which requires an autologous hematopoietic stem cell transplant.
Pharmacokinetics: 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 (tmax). 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 (Cmax) and systemic exposure (AUC0-24) 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.
Metabolism: Plerixafor is not metabolized 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 (t1/2) 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 AUC0-24 of plerixafor in subjects with mild (CrCl 51-80 ml/min), moderate (CrCl 31-50 ml/min) and severe (CrCI ≤ 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 Cmax.
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: There are limited pharmacokinetic data in paediatric patients.
Pharmacology: Pharmacodynamics: Mechanism of action: 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-1α (SDF-1α), also known as CXCL 12.
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.
Clinical efficacy and safety: In two Phase III randomised-controlled studies patients with non-Hodgkin's lymphoma or multiple myeloma received Plerixafor 0.24 mg/kg or placebo on each evening prior to apheresis. Patients received daily morning doses of G-CSF 10 μg/kg for 4 days prior to the first dose of plerixafor or placebo and on each morning prior to apheresis. Optimal (5 or 6 x 106 cells/kg) and minimal (2 x 106 cells/kg) numbers of CD34+ cells/kg within a given number of days, as well as the primary composite endpoints which incorporated successful engraftment are presented in Tables 1 and 3; the proportion of patients reaching optimal numbers of CD34+ cells/kg by apheresis day are presented in Tables 2 and 4. (See Tables 1, 2, 3, and 4.)
Rescue patients: In study AMD3100-3101, 62 patients (10 in the Plerixafor + G-CSF group and 52 in the placebo + G-CSF group), who could not mobilise sufficient numbers of CD34+ cells and thus not could not proceed to transplantation, entered into an open-label Rescue procedure with Plerixafor and G-CSF. Of these patients, 55 % (34 out of 62) mobilised ≥ 2 x106/kg CD34+ cells and had successful engraftment. In study AMD3100-3102, 7 patients (all from the placebo + G-CSF group) entered the Rescue procedure. Of these patients, 100% (7 out of 7) mobilised ≥ 2 x106/kg CD34+ cells and had successful engraftment.
The dose of haematopoietic stem cells used for each transplant was determined by the investigator and all haematopoietic stem cells that were collected were not necessarily transplanted. For transplanted patients in the Phase III studies, median time to neutrophil engraftment (10-11 days), median time to platelet engraftment (18-20 days) and graft durability up to 12 months post-transplantation were similar across the Plerixafor and placebo groups.
Mobilisation and engraftment data from supportive Phase II studies (plerixafor 0.24 mg/kg dosed on the evening or morning prior to apheresis) in patients with non-Hodgkin's lymphoma, Hodgkin's disease, or multiple myeloma were similar to those data for the Phase III studies.
In the placebo-controlled studies, fold increase in peripheral blood CD34+ cell count (cells/μl) over the 24-hour period from the day prior to the first apheresis to just before the first apheresis was evaluated (Table 5). During that 24-hour period, the first dose of plerixafor 0.24 mg/kg or placebo was administered 10-11 hours prior to apheresis. (See Table 5.)
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.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Plerixafor in children aged 0 to 1 year in myelosuppression caused by chemotherapy to treat malignant disorders, which requires an autologous hematopoietic stem cell transplant.
The European Medicines Agency has deferred the obligation to submit the results of studies with Plerixafor in children aged 1 to 18 years in myelosuppression caused by chemotherapy to treat malignant disorders, which requires an autologous hematopoietic stem cell transplant.
Pharmacokinetics: 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 (tmax). 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 (Cmax) and systemic exposure (AUC0-24) 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.
Metabolism: Plerixafor is not metabolized 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 (t1/2) 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 AUC0-24 of plerixafor in subjects with mild (CrCl 51-80 ml/min), moderate (CrCl 31-50 ml/min) and severe (CrCI ≤ 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 Cmax.
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: There are limited pharmacokinetic data in paediatric patients.
MedsGo Class
Features
Dosage
20 mg / ml (24 mg / 1.2 ml)
Ingredients
- Plerixafor
Packaging
Solution for Injection (S.C.) 1.2ml x 1's
Generic Name
Plerixafor
Registration Number
DR-XY 47388
Classification
Prescription Drug (RX)
Product Questions
Questions
