Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1.   PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Cytotoxic agents (alkylating agents). ATC Code: L01AB01 
Mechanism of action

Busulfan is a potent cytotoxic agent and a bifunctional alkylating agent. In aqueous media, release of the methanesulphonate groups produces carbonium ions which can alkylate DNA, thought to be an important biological mechanism for its cytotoxic effect.

Clinical trials

Clinical trials in adults
Documentation of the safety and efficacy of BUSULFAN 6 MG/ML in combination with cyclophosphamide in myeloablation prior to autologous or allogeneic haematopoietic stem cell transplantation (HSCT) in adults is derived from two uncontrolled clinical trials (trials OMC-BUS 3 and 4 respectively).

The trials were conducted in patients with haematological disease, the majority of whom had advanced disease. Diseases included were acute leukaemia past first remission, in first or subsequent relapse, in first remission (high risk), or induction failures; chronic myelogenous leukaemia in chronic or advanced phase; primary refractory or resistant relapsed Hodgkin’s disease or non-Hodgkin’s lymphoma, and myelodysplastic syndrome. The age of patients was 18-63 years and 60% were male. Patients received 0.8 mg/kg BUSULFAN 6 MG/ML every 6 hours by intravenous (IV) infusion for 4 days from day 7 to day 4 before HSCT. Cyclophosphamide 60 mg/kg/day once daily IV was given for 2 days from day 3 to 2 before HSCT (BuCy2 regimen).

The primary efficacy parameters in these studies were myeloablation, engraftment, relapse, and survival. BUSULFAN 6 MG/ML with cyclophosphamide was effective in inducing myeloablation and engraftment. Relapse-free and overall survival were similar in the two trials (Table 2).

Table 2. BUSULFAN 6 MG/ML qid/Cyclophosphamide – HSCT Conditioning Efficacy in Adults

OMC-BUS 3 (n=42)              OMC-BUS-4 (n=61)
Myeloablation1 %                              100                            100 Median time to neutropenia                      4                              4 (range) days                                 (-7, 6)                        (-7, 5) Median duration of                              6                              9 neutropenia (range) days                    (2, 13)                         (1, 28) Engraftment2 %                                100                             983 Median time to engraftment                     10                             13 (range) days                                (8, 19)                         (9, 29) Relapse-free Kaplan-Meier                      56                             51 estimate % at 1 yr [95% CI]                [40, 72]                        [35, 67] Survival Kaplan-Meier                          70                             67 estimate % at 1 yr [95% CI]                [52, 88]                        [54, 80] 1
Absolute neutrophil count (ANC) < 0.5 x 109/L, absolute lymphocyte count <0.1 x 109/L or platelet count <20 x 109/L or bleeding requiring platelet transfusion.
2
ANC >0.5 x 109/L within 100 days of HSCT.
3
One patient died before engraftment could be determined.

Uncontrolled (Fernandez) and non-randomised controlled trials (Mamlouk) in adults with haematological malignancies showed comparable incidences of engraftment for once daily and twice daily BUSULFAN RAZ 6 MG/ML 3.2 mg/kg/day regimens in combination with cyclophosphamide 60 mg/kg/day compared with the four times daily regimen.
Short-term survival was above 80% (Table 3). Reproducible busulfan pharmacokinetic parameters were demonstrated for once daily BUSULFAN 6 MG/ML.


Table 3. BUSULFAN 6 MG/ML od or bd/Cyclophosphamide – HSCT Conditioning Efficacy in Adults

Fernandez                        Mamlouk
(n=12)
BUSULFAN 6 MG/ML        od (n=6) or bd     od IV 4d        qid IV 4d       qid po 4d /oral busulfan              (n=6),          (n=20)          (n=11)          (n=25) schedule                days -7 to -41
Cyclophosphamide             daily,      2 days, start    2 days, start   2 days, start schedule                 days -3 to -2    27 h after       18 h after      18 h after BUSULFAN         BUSULFAN          busulfan
6 MG/ML          6 MG/ML
Engraftment2%                923             100              100             100 Median time to                11              12              14               13 engraftment3 (range)       (10, 20)        (11, 17)         (12, 18)        (10, 26) days
Relapse-free at 100          67               90              100              88 days post-HSCT %
Survival at 100 days         83               95               82              84 post-HSCT %
1
Before HSCT.
2
ANC > 0.5 x 109/L.
3
One patient died before engraftment could be determined.

Two uncontrolled trials in adults with haematological malignancies (Russell, de Lima) showed comparable incidences of engraftment for once daily BUSULFAN 6 MG/ML 3.2- 3.3 mg/kg in combination with fludarabine compared with the four times daily BUSULFAN 6 MG/ML with cyclophosphamide regimen. Twoyear survival was 37-88% depending on risk (Table 4). Reproducible busulfan pharmacokinetic parameters were demonstrated for BUSULFAN 6 MG/ML.

Table 4. BUSULFAN 6 MG/ML od or bd/Fludarabine – HSCT Conditioning Efficacy in Adults

Russell (n=70)               de Lima (n=96)
BUSULFAN 6 MG/ML                       3.2 mg/kg od,                130 mg/m2 od schedule                               days -5 to -21                ≡ 3.3 mg/kg, days -6 to -31
Fludarabine schedule                    50 mg/m2/d                   40 mg/m2/d days -6 to -21               days -6 to -31
Engraftment2 %                              943                           99 Medium time to engraftment2                 18                            12 (range) days                              (12, 42)                      (9, 25) Relapse-free %                   26-74 (depending on risk)                66 (2 yr est)
Survival %                       37-88 (depending on risk)               65 (2 yr est)                   (1 yr est)
1
Before HSCT.
2
ANC > 0.5 x 109/L.
3
Two patients failed engraftment because of persistent leukaemia and two died before engraftment could be determined. In unrelated or mismatched donor, anti- thymocyte globulin (ATG) was used.

In a retrospective analysis (Alyea) comparing the outcomes of allogeneic transplant in patients aged >50 years with haematological malignancies, who received either a non- myeloablative conditioning regimen of once-daily BUSULFAN 6 MG/ML 0.8 mg/kg for 4 days in combination with fludarabine 30 mg/m2 for 4 days or a myeloablative conditioning regimen of total body irradiation (TBI)/cyclophosphamide or oral busulfan/cyclophosphamide, improved 100-day treatmentrelated mortality rates and non- relapse mortality rates were noted in patients receiving the nonmyeloablative BUSULFAN 6 MG/ML-fludarabine conditioning regimen (Table 5). Although the cumulative incidence of disease relapse was higher in patients receiving the non- myeloablative conditioning regimen, overall survival and progression-free survival were not adversely affected by the reduction in intensity of the conditioning regimen.

Table 5. BUSULFAN 6 MG/ML /Fludarabine – Comparison of Myeloablative and Non-Myeloablative HSCT Conditioning Efficacy in Adults – Alyea 
Non-Myeloablative (n=71)         Myeloablative (n=81)
Myeloablative/non-             BUSULFAN RAZ 6 MG/ML              Cyclophosphamine/ myeloablative schedule                0.8 mg/kg/d,                   TBI or oral fludarabine 30 mg/m2/d                busulfan/ days -6 to -31              cyclophosphamine2
Treatment related mortality               6%                            30% (100 day)
Non-relapse mortality                     32%                          50% Non-Myeloablative (n=71)         Myeloablative (n=81)
Cumulative relapse rate                 46%                            30% Kaplan-Meier overall                39% (2 yr est)                 29% (2 yr est) survival
Kaplan-Meier progression-            27% (2 yr est)                25% (2yr est) free survival
1
Before HSCT.
2
94% received Cytarabine 1800 mg/m2/d for 2 days and TBI (total body irradiation) 1400cGy in 7 fractions over 4 days. 6% received oral busulfan 16 mg/kg divided over 4 days and cyclophosphamide.

Clinical trials in Children

Documentation of the safety and efficacy of BUSULFAN 6 MG/ML in combination with cyclophosphamide or melphalan in myeloablation prior to autologous or allogeneic HSCT in children is derived from one uncontrolled clinical trial (trial F60002 IN 1 01 G0).
The age of patients was 0.3-17.2 years and 53% were male. The dose of BUSULFAN 6 MG/ML ranged from 3.2-4.8 mg/kg/day depending on weight group. The BUSULFAN 6 MG/ML dose was based on body weight as detailed in Section 4.2 DOSE AND METHOD OF ADMINISTRATION and given in four divided doses daily for 4 days.

In autologous HSCT, BUSULFAN 6 MG/ML was given from day 6 to day 3 before HSCT and melphalan 140 mg/m2 IV on the day before HSCT (BuMel regimen). In allogeneic HSCT, BUSULFAN 6 MG/ML was given from day 9 to day 6 before HSCT and cyclophosphamide 50 mg/kg IV for 4 days from day 5 to 2 before HSCT (BuCy4 regimen). All patients achieved myeloablation and engraftment. The estimated 2-year survival was almost 80% (Table 6).


Table 6. BUSULFAN 6 MG/ML qid/Melphalan (Bu/Mel) or Cyclophosphamide (Bu/Cy) – HSCT Conditioning Efficacy in Children – Trial F60002 IN 1 01 
Bu/Mel (n=27)                   Bu/Cy (n=28)
Myeloablation1 %                              100                             100 Median time to neutropenia                     5                               5 (range) days                                 (3, 8)                          (3, 8) Median duration of                             5                               5 neutropenia (range) days                    (3, 10)                         (3, 10) Engraftment2 %                                100                             100 Median time to engraftment                     11                              21 (range) days                               (10, 15)                        (12, 47) Median follow-up (range)                      16.9                            13.5 mths                                      (5.4, 26.9)                    (3.4, 23.5) Relapse-free Kaplan-Meier                      72                              88 estimate % at 2 yrs [95% CI]               [66, 73]                        [84, 91] Survival Kaplan-Meier                          77                              79 estimate % at 2 yrs [95% CI]               [73, 82]                        [73, 85] 1
Absolute neutrophil count (ANC) < 0.5 x 109/L, absolute lymphocyte count <0.1 x 109/L or platelet count <20 x 109/L or bleeding requiring platelet transfusion.
2
ANC >0.5 x 109/L within 100 days of HSCT.

Four uncontrolled trials in children (Table 7) with malignant and non-malignant conditions showed comparable incidences of engraftment for once daily BUSULFAN 6 MG/ML 4 mg/kg/day for 4 days (Grigull) or with BUSULFAN 6 MG/ML targeted to a steady-state concentration of 900 ng/mL four times daily (approx 3.2 mg/kg/day) for 4 days (Horn) in combination with fludarabine 30- 40 mg/m2/day, compared with four times daily BUSULFAN 6 MG/ML with cyclophosphamide or melphalan. Lower incidences of engraftment were obtained for reduced intensity conditioning regimens using a reduced dose or reduced duration of BUSULFAN 6 MG/ML (Kletzel, Horn, Jacobsohn). The reduced intensity conditioning was associated with lower incidences of treatment related toxicity.

Table 7. BUSULFAN 6 MG/ML od or bd/Fludarabine – HSCT Conditioning Efficacy in Children

Grigull (n=5)      Horn (n=19)        Kletzel (n=30)     Jacobsohn (n=13)
BUSULFAN         4 mg/kg/d od,     Target Css 600      3.2 mg/kg/d od,   0.8 mg/kg qid, 6 MG/ML          days -8 to -5      ng/mL (n=16),        target 3200-     target 3800- schedule†                         900 ng/mL (n=3)      4800 μmol.min     4200 μmol.min qid, days -9 to -6    days -5 to -41    days -5 to -4
Fludarabine       30 mg/m2/d      40 mg/m2/d days         30 mg/m2/d       30 mg/m2/d schedule         days -10 to -5        -5 to -2         days -5 to -2    days -10 to -5 Engraftment2 %       100                75%                   87               72 (Css 600 mg/mL)
100%
(Css 900 mg/mL)
Med time to            16            20 (16, 28)         not stated       18 (14, 25) engraft
(range) days
Relapse-free %       100                74                    63               23 Survival %           100                89                    60               69 (med 32 mth      (med 2 yr KM)          (2 yr KM)        (2 yr KM) F/U)
1
Before HSCT.
2
ANC >0.5 x 109/L within 100 days of HSCT. KM – Kaplan-Meier.
†
Rabbit or equine ATG was also used.

Pharmacokinetic Properties

5.2.   PHARMACOKINETIC PROPERTIES

Absorption and distribution pharmacokinetics of IV busulfan has been investigated. The information presented on metabolism and elimination is based on oral busulfan.

Absorption

The pharmacokinetics of IV busulfan was studied in 124 evaluable patients following a 2- hour intravenous infusion for a total of 16 doses over four days. Immediate and complete availability of the dose is obtained after intravenous infusion of busulfan.
Similar blood exposure was observed when comparing plasma concentrations in patients receiving 1 mg/kg oral and 0.8 mg/kg IV busulfan. Low inter (CV=21%) and intra (CV=12%) patient variability on drug exposure was demonstrated through a population pharmacokinetic analysis with IV busulfan, performed on 102 patients.

Distribution

Terminal volume of distribution Vz ranged between 0.62 and 0.85 L/kg. Busulfan concentrations in the cerebrospinal fluid are comparable to those in plasma although these concentrations are probably insufficient for anti-neoplastic activity. Reversible binding to plasma proteins was around 7% while irreversible binding, primarily to albumin, was about 32%.

Metabolism

Busulfan is metabolised mainly through conjugation with glutathione (spontaneous and glutathione-S-transferase mediated). The glutathione conjugate is then further metabolised in the liver by oxidation. None of the metabolites is thought to contribute significantly to either efficacy or toxicity.

Excretion

Total clearance in plasma ranged 2.25 - 2.74 mL/minute/kg. The terminal half-life ranged from 2.8 to 3.9 hours. Approximately 30% of the administered dose is excreted into the urine over 48 hours with 1% as unchanged drug. Elimination in faeces is negligible. Irreversible protein binding may explain the incomplete recovery.
Contribution of long- lasting metabolites is not excluded.

Pharmacokinetic linearity

The dose proportional increase of drug exposure was demonstrated following intravenous busulfan up to 1 mg/kg.

Pharmacokinetic/ pharmacodynamics Relationships

The literature on oral busulfan when used in myeloablative conditioning regimens every six hours for four days suggests a therapeutic window between 900 and 1500 μMol- minute for AUC. During clinical trials with IV busulfan administered in this way, 90% of patients AUCs were below the upper AUC limit (1500 μMol-minute) and at least 80 % were within the targeted therapeutic window (900 - 1500 μMol-minute).

Special populations

The effects of renal dysfunction on IV busulfan disposition have not been thoroughly assessed. However, BUSULFAN 6 MG/ML was not well tolerated in a Phase I study conducted in patients with metastatic renal carcinoma where all patients had only one functioning kidney.

The effects of hepatic dysfunction on IV busulfan disposition have not been assessed.
Nevertheless, the risk of liver toxicity may be increased in this population.

No age effect on busulfan clearance was evidenced from available IV busulfan data in patients over 60 years.

Pharmacokinetics in children

A continuous variation of clearance ranging from 2.49 to 3.92 mL/minute/kg was established in children from < 6 months up to 17 years old. The terminal half life ranged from 2.26 to 2.52 h. The described dosing based on body weight allows achievement of a similar targeted AUC whatever the child’s age, comparable with adult plasma exposure. Inter and intra patient variabilities in plasma exposure were lower than 20% and lower than 10%, respectively.
The successful engraftment achieved in all paediatric patients during the phase II clinical trial suggests the appropriateness of the targeted AUCs of 900 to 1500 μMol- minute. Occurrence of hepatic veno-occlusive disease (HVOD) was not related to overexposure. A pharmacokinetic/pharmacodynamic relationship was observed between stomatitis and AUCs in autologous patients and between bilirubin increase and AUCs in a combined autologous and allogeneic patient analysis.