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 Busulfex 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 Busulfex 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. Busulfex with cyclophosphamide was effective in inducing myeloablation and engraftment. Relapse-free and overall survival were similar in the two trials (Table 2).

Table 2. Busulfex qid/Cyclophosphamide – HSCT Conditioning Efficacy in Adults 
OMC-BUS 3 (n=42)                  OMC-BUS-4 (n=61)
Myeloablation1 %                                 100                               100 
Median time to neutropenia (range)                     4                                   4 days                                                (-7, 6)                             (-7, 5) Median duration of neutropenia                         6                                   9 (range) days                                        (2, 13)                             (1, 28) Engraftment2 %                                        100                                 983 Median time to engraftment (range)                     10                                  13 days                                                 (8, 19)                             (9, 29) Relapse-free Kaplan-Meier                              56                                  51 estimate % at 1 yr [95% CI]                         [40, 72]                            [35, 67] Survival Kaplan-Meier estimate %                       70                                  67 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 Busulfex 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 Busulfex.

Table 3. Busulfex od or bd/Cyclophosphamide – HSCT Conditioning Efficacy in Adults 
Fernandez                             Mamlouk
(n=12)
Busulfex/oral busulfan        od (n=6) or bd       od IV 4d           qid IV 4d             qid po 4d schedule                           (n=6),           (n=20)             (n=11)                (n=25) 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 Busulfex           Busulfex              busulfan
Engraftment2%                      923                100                100                  100 Median time to                     11                  12                 14                   13 engraftment3 (range) days        (10, 20)           (11, 17)           (12, 18)             (10, 26) Relapse-free at 100 days           67                  90                100                   88 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 Busulfex 3.2-3.3 mg/kg in combination with fludarabine compared with the four times daily Busulfex with cyclophosphamide regimen. Two- year survival was 37-88% depending on risk (Table 4). Reproducible busulfan pharmacokinetic parameters were demonstrated for Busulfex.

Table 4. Busulfex od or bd/Fludarabine – HSCT Conditioning Efficacy in Adults 
Russell (n=70)                   de Lima (n=96)
Busulfex schedule                               3.2 mg/kg od,                     130 mg/m2 od 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 Busulfex 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 treatment- related mortality rates and non- relapse mortality rates were noted in patients receiving the non- myeloablative Busulfex-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. Busulfex/Fludarabine – Comparison of Myeloablative and Non-Myeloablative HSCT Conditioning Efficacy in Adults – Alyea

Non-Myeloablative (n=71)            Myeloablative (n=81)
Myeloablative/non-myeloablative                     Busulfex 0.8 mg/kg/d,              Cyclophosphamine/ schedule                                           fludarabine 30 mg/m2/d                  TBI or oral days -6 to -31                      busulfan/ cyclophosphamine2
Treatment related mortality (100 day)                         6%                              30% Non-relapse mortality                                        32%                              50% Cumulative relapse rate                                      46%                              30% Kaplan-Meier overall survival                            39% (2 yr est)                   29% (2 yr est) Kaplan-Meier progression-free survival                   27% (2 yr est)                   25% (2yr est) 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 Busulfex 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 Busulfex ranged from 3.2-4.8 mg/kg/day depending on weight group. The Busulfex 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, Busulfex 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, Busulfex 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. Busulfex 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)
1
Myeloablation %                                     100                             100 Median time to neutropenia (range)                   5                               5 days                                               (3, 8)                          (3, 8) Median duration of neutropenia                       5                               5 (range) days                                      (3, 10)                         (3, 10) Engraftment2 %                                      100                             100 Median time to engraftment (range)                   11                              21 days                                             (10, 15)                        (12, 47) Median follow-up (range) mths                       16.9                            13.5 (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 estimate %                     77                              79 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 Busulfex 4 mg/kg/day for 4 days (Grigull) or with Busulfex 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 Busulfex with cyclophosphamide or melphalan. Lower incidences of engraftment were obtained for reduced intensity conditioning regimens using a reduced dose or reduced duration of Busulfex (Kletzel, Horn, Jacobsohn). The reduced intensity conditioning was associated with lower incidences of treatment related toxicity.

Table 7. Busulfex od or bd/Fludarabine – HSCT Conditioning Efficacy in Children Grigull (n=5)         Horn (n=19)      Kletzel (n=30) Jacobsohn (n=13) †
Busulfex schedule        4 mg/kg/d od,        Target Css 600 3.2 mg/kg/d od,     0.8 mg/kg qid, days -8 to -5      ng/mL (n=16), target 3200-4800 target 3800-4200
900 ng/mL (n=3)      μmol.min        μmol.min
1 qid, days -9 to -6 days -5 to -4     days -5 to -4


Fludarabine schedule     30 mg/m2/d         40 mg/m2/d        30 mg/m2/d           30 mg/m2/d days -10 to -5      days -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 engraft           16              20 (16, 28)       not stated         18 (14, 25) (range) days

Relapse-free %               100             74                     63                  23 Survival %                   100              89                    60                  69 (med 32 mth F/U) (med 2 yr KM)           (2 yr KM)           (2 yr KM) 
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, Busulfex 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.