Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties


Pharmacotherapeutic group: Antineoplastic agents, Alkylating Agents, ATC code: L01AC01 
Mechanism of action
Thiotepa is a polyfunctional cytotoxic agent related chemically and pharmacologically to the nitrogen mustard. The radiomimetic action of thiotepa is believed to occur through the release of ethylene imine radicals that, as in the case of irradiation therapy, disrupt the bonds of DNA, e.g. by alkylation of guanine at the N-7, breaking the linkage between the purine base and the sugar and liberating alkylated guanine.

Clinical safety and efficacy
The conditioning treatment must provide cytoreduction and ideally disease eradication. Thiotepa has marrow ablation as its dose-limiting toxicity, allowing significant dose escalation with the infusion of autologous HPCT. In allogeneic HPCT, the conditioning treatment must be sufficiently immunosuppressive and myeloablative to overcome host rejection of the graft. Due to its highly myeloablative characteristics, thiotepa enhances recipient immunosuppression and myeloablation, thus strengthening engraftment; this compensates for the loss of the GvHD-related GvL effects. As alkylating agent, thiotepa produces the most profound inhibition of tumour cell growth in vitro with the smallest increase in medicinal product concentration. Due to its lack of extramedullary toxicity despite dose escalation beyond myelotoxic doses, thiotepa has been used for decades in combination with other chemotherapy medicinal products prior to autologous and allogeneic HPCT.
The results of published clinical studies supporting the efficacy of thiotepa are summarised: 
Autologous HPCT
Haematological diseases
Engraftment: Conditioning treatments including thiotepa have proved to be myeloablative.
Disease Free Survival (DFS): An estimated 43% at five years has been reported, confirming that conditioning treatments containing thiotepa following autologous HPCT are effective therapeutic strategies for treating patients with haematological diseases.
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been reported as being 60% or lower, which was considered by the physicians as the threshold to prove efficacy. In some of the conditioning treatments evaluated, relapse rates lower than 60% have also been reported at 5 years.
Overall Survival (OS): OS ranged from 29% to 87% with a follow-up ranging from 22 up to 63 months.
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging from 2.5% to 29% have been reported. TRM values ranged from 0% to 21% at 1 year, confirming the safety of the conditioning treatment including thiotepa for autologous HPCT in adult patients with haematological diseases.
Solid tumours
Engraftment: Conditioning treatments including thiotepa have proved to be myeloablative.
Disease Free Survival (DFS): Percentages reported with follow-up periods of more than 1 year confirm that conditioning treatments containing thiotepa following autologous HPCT are effective choices for treating patients with solid tumours.
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have been reported as being lower than 60%, which was considered by the physicians as the threshold to prove efficacy. In some cases, relapse rates of 35% and of 45% have been reported at 5 years and 6 years respectively.
Overall Survival: OS ranged from 30% to 87% with a follow-up ranging from 11.7 up to 87 months.


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Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging from0% to 2% have been reported. TRM values ranged from 0% to 7.4% confirming the safety of the conditioning treatment including thiotepa for autologous HPCT in adult patients with solid tumours.

Allogeneic HPCT
Haematological diseases
Engraftment: Engraftment has been achieved (92%-100%) in all reported conditioning treatments and itwas considered to occur at the expected time. Therefore it can be concluded that conditioning treatmentsincluding thiotepa are myeloablative.
GvHD (graft versus host disease): all conditioning treatments evaluated assured a low incidence of acuteGvHD grade III-IV (from 4% to 24%).
Disease Free Survival (DFS): Percentages reported with follow-up periods of more than 1 year and up to5 years confirm that conditioning treatments containing thiotepa following allogeneic HPCT are effective choices for treating patients with haematological diseases.
Relapse: In all conditioning treatments containing thiotepa, relapse rates at more than 1 year have beenreported as being lower than 40% (which was considered by the physicians as the threshold to prove efficacy). In some cases, relapse rates lower than 40% have also been reported at 5 years and 10 years.
Overall Survival: OS ranged from 31% to 81% with a follow-up ranging from 7.3 up to 120 months.
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): low values have been reported, confirming the safety of the conditioning treatments including thiotepa for allogeneic HPCT inadults patients with haematological diseases.

Paediatric population

Autologous HPCT
Solid tumours
Engraftment: It has been achieved with all reported conditioning regimens including thiotepa.
Disease Free Survival (DFS): With a follow-up of 36 to 57 months, DFS ranged from 46% to 70% inthe reported studies. Considering that all patients were treated for high risk solid tumours, DFS resultsconfirm that conditioning treatments containing thiotepa following autologous HPCT are effective therapeutic strategies for treating paediatric patients with solid tumours.
Relapse: In all the reported conditioning regimens containing thiotepa, relapse rates at 12 to 57 monthsranged from 33% to 57%. Considering that all patients suffer of recurrence or poor prognosis solid tumours, these rates support the efficacy of conditioning regimens based on thiotepa.
Overall Survival (OS): OS ranged from 17% to 84% with a follow-up ranging from 12.3 up to 99.6months.
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging from0% to 26.7% have been reported. TRM values ranged from 0% to 18% confirming the safety of the conditioning treatments including thiotepa for autologous HPCT in paediatric patients with solid tumours.

Allogeneic HPCT
Haematological diseases
Engraftment: It has been achieved with all evaluated conditioning regimens including thiotepa with a success rate of 96% - 100%. The haematological recovery is in the expected time.
Disease Free Survival (DFS): Percentages of 40% - 75% with follow-up of more than 1 year have beenreported. DFS results confirm that conditioning treatment containing thiotepa following allogeneic HPCT are effective therapeutic strategies for treating paediatric patients with haematological diseases.



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Relapse: In all the reported conditioning regimens containing thiotepa, the relapse rate was in the rangeof 15% - 44%. These data support the efficacy of conditioning regimens based on thiotepa in all haematological diseases.
Overall Survival (OS): OS ranged from 50% to 100% with a follow-up ranging from 9.4 up to 121months.
Regimen Related Mortality (RRM) and Transplant Related Mortality (TRM): RRM values ranging from0% to 2.5% have been reported. TRM values ranged from 0% to 30% confirming the safety of the conditioning treatment including thiotepa for allogeneic HPCT in paediatric patients with haematological diseases.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Thiotepa is unreliably absorbed from the gastrointestinal tract: acid instability prevents thiotepa frombeing administered orally.

Distribution
Thiotepa is a highly lipophilic compound. After intravenous administration, plasma concentrations of the active substance fit a two compartment model with a rapid distribution phase. The volume of distribution of thiotepa is large and it has been reported as ranging from 40.8 l/m2 to 75 l/m2, indicatingdistribution to total body water. The apparent volume of distribution of thiotepa appears independent ofthe administered dose. The fraction unbound to proteins in plasma is 70-90%; insignificant binding of thiotepa to gamma globulin and minimal albumin binding (10-30%) has been reported.
After intravenous administration, CSF medicinal product exposure is nearly equivalent to that achieved in plasma; the mean ratio of AUC in CSF to plasma for thiotepa is 0.93. CSF and plasma concentrationsof TEPA, the first reported active metabolite of thiotepa, exceed the concentrations of the parent compound.

Biotransformation
Thiotepa undergoes rapid and extensive hepatic metabolism and metabolites could be detected in urine within 1 hour after infusion. The metabolites are active alkylating agents but the role they play in the antitumor activity of thiotepa remains to be elucidated. Thiotepa undergoes oxidative desulphuration viathe cytochrome P450 CYP2B and CYP3A isoenzyme families to the major and active metabolite TEPA(triethylenephosphoramide). The total excreted amount of thiotepa and its identified metabolites accounts for 54-100% of the total alkylating activity, indicating the presence of other alkylating metabolites. During conversion of GSH conjugates to N-acetylcysteine conjugates, GSH, cysteinylglycine, and cysteine conjugates are formed. These metabolites are not found in urine, and, if formed, are probably excreted in bile or as intermediate metabolites rapidly converted into thiotepa- mercapturate.

Elimination
The total clearance of thiotepa ranged from 11.4 to 23.2 l/h/m2. The elimination half-life varied from 1.5 to 4.1 hours. The identified metabolites TEPA, monochlorotepa and thiotepa-mercapturate are allexcreted in the urine. Urinary excretion of thiotepa and TEPA is nearly complete after 6 and 8 hours respectively. The mean urinary recovery of thiotepa and its metabolites is 0.5% for the unchanged medicinal product and monochlorotepa, and 11% for TEPA and thiotepa- mercapturate.

Linearity/non-linearity
There is no clear evidence of saturation of metabolic clearance mechanisms at high doses of thiotepa.

Special populations
Paediatric population


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Thiotepa Medomie-SPC-0322-V1
The pharmacokinetics of high dose thiotepa in children between 2 and 12 years of age do not appear to vary from those reported in children receiving 75 mg/m2 or adults receiving similar doses.

Renal impairment
The effects of renal impairment on thiotepa elimination have not been assessed.

Hepatic impairment
The effects of hepatic impairment on thiotepa metabolism and elimination have not been assessed.