Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors; ATC code: L01E G01 
Mechanism of action

Temsirolimus is a selective inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein/temsirolimus complex binds and inhibits the activity of mTOR that controls cell division. In vitro, at high concentrations (10-20 µM), temsirolimus can bind and inhibit mTOR in the absence of FKBP-12. Biphasic dose response of cell growth inhibition was observed. High concentrations resulted in complete cell growth inhibition in vitro, whereas inhibition mediated by FKBP-12/temsirolimus complex alone resulted in approximately 50% decrease in cell proliferation. Inhibition of mTOR activity results in a G1 growth delay at nanomolar concentrations and growth arrest at micromolar concentrations in treated tumour cells resulting from selective disruption of translation of cell cycle regulatory proteins, such as D-type cyclins, c-myc, and ornithine decarboxylase. When mTOR activity is inhibited, its ability to phosphorylate, and thereby control the activity of protein translation factors (4E-BP1 and S6K, both downstream of mTOR in the P13 kinase/AKT pathway) that control cell division, is blocked.

In addition to regulating cell cycle proteins, mTOR can regulate translation of the hypoxia-inducible factors, HIF-1 and HIF-2 alpha. These transcription factors regulate the ability of tumours to adapt to hypoxic microenvironments and to produce the angiogenic factor vascular endothelial growth factor (VEGF). The anti-tumour effect of temsirolimus, therefore, may also in part stem from its ability to depress levels of HIF and VEGF in the tumour or tumour microenvironment, thereby impairing vessel development.

Clinical efficacy and safety

Renal cell carcinoma
The safety and efficacy of temsirolimus in the treatment of advanced RCC were studied in the following two randomised clinical trials:


RCC clinical trial 1
RCC clinical trial 1 was a Phase 3, multi-centre, 3-arm, randomised, open-label study in previously untreated patients with advanced RCC and with 3 or more of 6 pre-selected prognostic risk factors (less than 1 year from time of initial renal cell carcinoma diagnosis to randomisation, Karnofsky performance status of 60 or 70, haemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dl, lactate dehydrogenase>1.5 times the upper limit of normal, more than 1 metastatic organ site). The primary study endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate, time to treatment failure (TTF), and quality adjusted survival measurement. Patients were stratified for prior nephrectomy status within 3 geographic regions and were randomly assigned (1:1:1) to receive IFN-α alone (n = 207), temsirolimus alone (25 mg weekly; n = 209), or the combination of IFN-α and temsirolimus (n = 210).

In RCC clinical trial 1, temsirolimus 25 mg was associated with a statistically significant advantage over IFN-α in the primary endpoint of OS at the 2nd pre-specified interim analysis (n = 446 events, p = 0.0078). The temsirolimus arm showed a 49% increase in median OS compared with the IFN-α arm. Temsirolimus also was associated with statistically significant advantages over IFN-α in the secondary endpoints of PFS, TTF, and clinical benefit rate.

The combination of temsirolimus 15 mg and IFN-α did not result in a significant increase in overall survival when compared to IFN-α alone at either the interim analysis (median 8.4 vs. 7.3 months, hazard ratio = 0.96, p = 0.6965) or final analysis (median 8.4 vs. 7.3 months, hazard ratio = 0.93, p = 0.4902). Treatment with the combination of temsirolimus and IFN-α resulted in a statistically significant increase in the incidence of certain Grade 3-4 adverse events (weight loss, anaemia, neutropenia, thrombocytopenia and mucosal inflammation) when compared to the adverse events observed in the IFN-α or temsirolimus-alone arms.




Summary of efficacy results in temsirolimus RCC clinical trial 1
Parameter                      Temsirolimus          IFN-α    P-value a
Hazard ratio n = 209          n = 207                 (95% CI) b

Pre-specified interim analysis
Median overall survival,                                       7.3 (6.1, 10.9 (8.6, 12.7)                0.0078 0.73 (0.58, 0.92)
Months (95% CI)                                                  8.8) Final analysis
Median overall survival,                                       7.3 (6.1, 10.9 (8.6, 12.7)                0.0252 0.78 (0.63, 0.97)
Months (95% CI)                                                  8.8) Median progression-free survival by independent                                        3.2 (2.2, 5.6 (3.9, 7.2)                 0.0042 0.74 (0.60, 0.91) assessment                                                       4.0) Months (95% CI)
Median progression-free survival by investigator                                       1.9 (1.9, 3.8 (3.6, 5.2)                 0.0028 0.74 (0.60, 0.90) assessment                                                       2.2) Months (95% CI)
Overall response rate by
5.3 (2.3,        c independent assessment                     9.1 (5.2, 13.0)               0.1361           NA 8.4)
% (95% CI)
CI = confidence interval; NA = not applicable.
a
Based on log-rank test stratified by prior nephrectomy and region.
b
Based on Cox proportional hazard model stratified by prior nephrectomy and region (95% CI are descriptive only).
c
Based on Cochran-Mantel-Hansel test stratified by prior nephrectomy and region.

In RCC clinical trial 1, 31% of patients treated with temsirolimus were 65 or older. In patients younger than 65, median overall survival was 12 months (95% CI: 9.9, 14.2) with a hazard ratio of 0.67 (95% CI: 0.52, 0.87) compared with those treated with IFN-α. In patients 65 or older, median overall survival was 8.6 months (95% CI: 6.4, 11.5) with a hazard ratio of 1.15 (95% CI: 0.78, 1.68) compared with those treated with IFN-α.

RCC clinical trial 2
RCC clinical trial 2 was a randomised, double-blind, multi-centre, outpatient trial to evaluate the efficacy, safety, and pharmacokinetics of three dose levels of temsirolimus when administered to previously treated patients with advanced RCC. The primary efficacy endpoint was ORR, and OS was also evaluated. One hundred eleven (111) patients were randomly assigned in a 1:1:1 ratio to receive 25 mg, 75 mg, or 250 mg intravenous temsirolimus weekly. In the 25 mg arm (n = 36), all patients had metastatic disease; 4 (11%) had no prior chemo- or immunotherapy; 17 (47%) had one prior treatment, and 15 (42%) had 2 or more prior treatments for RCC. Twenty-seven (27, 75%) had undergone a nephrectomy. Twenty-four (24, 67%) were Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 1, and 12 (33%) were ECOG PS = 0.

For patients treated weekly with 25 mg temsirolimus OS was 13.8 months (95% CI: 9.0, 18.7 months); ORR was 5.6% (95% CI: 0.7, 18.7%).

Mantle cell lymphoma

The safety and efficacy of intravenous temsirolimus for the treatment of relapsed and/or refractory MCL were studied in the following Phase 3 clinical study.



MCL clinical trial
MCL clinical trial is a controlled, randomised, open-label, multicentre, outpatient study comparing 2 different dosing regimens of temsirolimus with an investigator's choice of therapy in patients with relapsed and/or refractory MCL. Subjects with MCL (that was confirmed by histology, immunophenotype, and cyclin D1 analysis) who had received 2 to 7 prior therapies that included anthracyclines and alkylating agents, and rituximab (and could include haematopoietic stem cell transplant) and whose disease was relapsed and/or refractory were eligible for the study. Subjects were randomly assigned in a 1:1:1 ratio to receive intravenous temsirolimus 175 mg (3 successive weekly doses) followed by 75 mg weekly (n = 54), intravenous temsirolimus 175 mg (3 successive weekly doses) followed by 25 mg weekly (n = 54), or the investigator’s choice of single-agent treatment (as specified in the protocol; n = 54). Investigator's choice therapies included: gemcitabine (intravenous: 22 [41.5%]), fludarabine (intravenous: 12 [22.6%] or oral: 2 [3.8%]), chlorambucil (oral: 3 [5.7%]),
cladribine (intravenous: 3 [5.7%]), etoposide (intravenous: 3 [5.7%]), cyclophosphamide (oral: 2 [3.8%]), thalidomide (oral: 2 [3.8%]), vinblastine (intravenous: 2 [3.8%]), alemtuzumab (intravenous: 1 [1.9%]), and lenalidomide (oral: 1 [1.9%]). The primary endpoint of the study was PFS, as assessed by an independent radiologist and oncology review. Secondary efficacy endpoints included OS and ORR.

The results for the MCL clinical trial are summarized in the following table. Temsirolimus 175/75 (temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly) led to an improvement in PFS compared with investigator's choice in patients with relapsed and/or refractory MCL that was statistically significant (hazard ratio = 0.44; p-value = 0.0009). Median PFS of the temsirolimus 175/75 mg group (4.8 months) was prolonged by 2.9 months compared to the investigator's choice group (1.9 months). OS was similar.

Temsirolimus also was associated with statistically significant advantages over investigator’s choice in the secondary endpoint of ORR. The evaluations of PFS and ORR were based on blinded independent radiologic assessment of tumour response using the International Workshop Criteria.
Summary of efficacy results in temsirolimus MCL clinical trial temsirolimus       Investigator’s
Parameter                   175/75 mg            Choice                            Hazard ratio P-value n = 54          (inv choice)                         (97.5% CI)a n = 54
Median progression-free          4.8 (3.1, 8.1)      1.9 (1.6, 2.5)       0.0009c        0.44 (0.25, 0.78) survivalb
Months (97.5% CI)
Objective response rateb           22.2 (11.1, 33.3)    1.9 (0.0, 5.4)       0.0019d              NA % (95% CI)
Overall survival
Months (95% CI)          12.8 (8.6, 22.3)    10.3 (5.8, 15.8)      0.2970c        0.78 (0.49, 1.24) 
One-year survival rate                  0.47 (0.31, 0.61) 0.46 (0.30, 0.60)
% (97.5% CI) a
Compared with inv choice based on Cox proportional hazard model.
b
Disease assessment is based on radiographic review by independent radiologists and review of clinical data by independent oncologists.
c
Compared with inv choice based on log-rank test.
d
Compared with inv choice alone based on Fisher's exact test.
Abbreviations: CI = confidence interval; NA = not applicable.


The temsirolimus 175 mg (3 successive weekly doses) followed by 25 mg weekly treatment arm did not result in a significant increase in PFS when compared with investigator’s choice (median 3.4 vs. 1.9 months, hazard ratio = 0.65, CI = 0.39, 1.10, p = 0.0618).

In the MCL clinical trial, there was no difference in efficacy in patients with respect to age, sex, race, geographic region, or baseline disease characteristics.

Paediatric population

In a Phase 1/2 safety and exploratory efficacy study, 71 patients (59 patients, aged from 1 to 17 years, and 12 patients, aged from 18 to 21 years) received temsirolimus as a 60-minute intravenous infusion once weekly in three-week cycles. In Part 1, 14 patients aged from 1 to 17 years with advanced recurrent/refractory solid tumours received temsirolimus at doses ranging from 10 mg/m2 to 150 mg/m2. In Part 2, 45 patients aged from 1 to 17 years with recurrent/relapsed rhabdomyosarcoma, neuroblastoma, or high- grade glioma were administered temsirolimus at a weekly dose of 75 mg/m2.
Adverse events were generally similar to those observed in adults (see section 4.8).

Temsirolimus was found to be ineffective in paediatric patients with neuroblastoma, rhabdomyosarcoma, and high-grade glioma (n = 52). For subjects with neuroblastoma, the objective response rate was 5.3% (95% CI: 0.1%, 26.0%). After 12 weeks of treatment, no response was observed in subjects with rhabdomyosarcoma or high-grade glioma. None of the 3 cohorts met the criterion for advancing to the second stage of the Simon 2-stage design.

The European Medicines Agency has waived the obligation to submit the results of studies with Torisel in all subsets of the paediatric population in MCL (see section 4.2 on paediatric use).

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption
Following administration of a single 25 mg intravenous dose of temsirolimus in patients with cancer, mean Cmax in whole blood was 585 ng/ml (coefficient of variation [CV] = 14%), and mean AUC in blood was 1627 ng•h/ml (CV = 26%). For patients receiving 175 mg weekly for 3 weeks followed by 75 mg weekly, estimated Cmax in whole blood at end of infusion was 2457 ng/ml during Week 1, and 2574 ng/ml during Week 3.

Distribution

Temsirolimus exhibits a polyexponential decline in whole blood concentrations, and distribution is attributable to preferential binding to FKBP-12 in blood cells. The mean ±standard deviation (SD) dissociation constant (Kd) of binding was 5.1 ± 3.0 ng/ml, denoting the concentration at which 50% of binding sites in blood cells were occupied. Temsirolimus distribution is dose-dependent with mean (10th, 90th percentiles) maximal specific binding in blood cells of 1.4 mg (0.47 to 2.5 mg). Following a single 25 mg temsirolimus intravenous dose, mean steady-state volume of distribution in whole blood of patients with cancer was 172 liters.



Biotransformation

Sirolimus, an equally potent metabolite to temsirolimus, was observed as the principal metabolite in humans following intravenous treatment. During in vitro temsirolimus metabolism studies, sirolimus, seco-temsirolimus and seco-sirolimus were observed; additional metabolic pathways were hydroxylation, reduction and demethylation. Following a single 25 mg intravenous dose in patients with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer half-life of sirolimus.

Elimination

Following a single 25 mg intravenous dose of temsirolimus, temsirolimus mean ± SD systemic clearance from whole blood was 11.4 ± 2.4 l/h. Mean half-lives of temsirolimus and sirolimus were 17.7 hours and 73.3 hours, respectively. Following administration of [14C] temsirolimus, excretion was predominantly via the faeces (78%), with renal elimination of active substance and metabolites accounting for 4.6% of the administered dose. Sulfate or glucuronide conjugates were not detected in the human faecal samples, suggesting that sulfation and glucuronidation do not appear to be major pathways involved in the excretion of temsirolimus. Therefore, inhibitors of these metabolic pathways are not expected to affect the elimination of temsirolimus.

Model-predicted values for clearance from plasma, after applying a 175 mg dose for 3 weeks, and subsequently 75 mg for 3 weeks, indicate temsirolimus and sirolimus metabolite trough concentrations of approximately 1.2 ng/ml and 10.7 ng/ml, respectively.

Temsirolimus and sirolimus were demonstrated to be substrates for P-gp in vitro.

Pharmacokinetic/pharmacodynamic relationship(s)
Inhibition of CYP isoforms

In in vitro studies in human liver microsomes, temsirolimus inhibited CYP3A4/5, CYP2D6, CYP2C9 and CYP2C8 catalytic activity with Ki values of 3.1, 1.5, 14 and 27 μM, respectively.

IC50 values for inhibition of CYP2B6 and CYP2E1 by temsirolimus were 48 and 100 μM, respectively. Based on a whole blood mean Cmax concentration of 2.6 μM for temsirolimus in MCL patients receiving the 175 mg dose there is a potential for interactions with concomitantly administered medicinal products that are substrates of CYP3A4/5 in patients treated with the 175 mg dose of temsirolimus (see section 4.5). Physiologically-based pharmacokinetic modelling has shown that after four weeks treatment with temsirolimus, the AUC of midazolam can be increased 3-to 4-fold and Cmax around 1.5-fold when midazolam is taken within a few hours after the start of the temsirolimus infusion. However, it is unlikely that whole blood concentrations of temsirolimus after intravenous administration of temsirolimus will inhibit the metabolic clearance of concomitant medicinal products that are substrates of CYP2C9, CYP2C8, CYP2B6 or CYP2E1.

Special populations

Hepatic impairment
Temsirolimus should be used with caution when treating patients with hepatic impairment.
Temsirolimus is cleared predominantly by the liver.

Temsirolimus and sirolimus pharmacokinetics have been investigated in an open-label, dose-escalation study in 110 patients with advanced malignancies and either normal or impaired hepatic function. For 7 patients with severe hepatic impairment (ODWG, group D) receiving the 10 mg dose of temsirolimus, the mean AUC of temsirolimus was ~1.7-fold higher compared to 7 patients with mild hepatic impairment (ODWG, group B). For patients with severe hepatic impairment, a reduction of the temsirolimus dose to 10 mg is recommended to provide temsirolimus plus sirolimus exposures in blood (mean AUCsum approximately 6510 ng·h/ml; n=7), which approximate to those following the 25 mg dose (mean AUCsum approximately 6580 ng·h/ml; n=6) in patients with normal liver function
(see sections 4.2 and 4.4).

The AUCsum of temsirolimus and sirolimus on day 8 in patients with mild and moderate hepatic impairment receiving 25 mg temsirolimus was similar to that observed in patients without hepatic impairment receiving 75 mg (mean AUCsum mild: approximately 9770 ng*h/ml, n=13; moderate: approximately 12380 ng*h/ml, n=6; normal approximately 10580 ng*h/ml, n=4).

Gender, weight, race, age
Temsirolimus and sirolimus pharmacokinetics are not significantly affected by gender. No relevant differences in exposure were apparent when data from the Caucasian population was compared with either the Japanese or Black population.

In population pharmacokinetic-based data analysis, increased body weight (between 38.6 and 158.9 kg) was associated with a two-fold range of trough concentration of sirolimus in whole blood.

Pharmacokinetic data on temsirolimus and sirolimus are available in patients up to age 79 years. Age does not appear to affect temsirolimus and sirolimus pharmacokinetics significantly.

Paediatric population
In the paediatric population, clearance of temsirolimus was lower and exposure (AUC) was higher than in adults. In contrast, exposure to sirolimus was commensurately reduced in paediatric patients, such that the net exposure as measured by the sum of temsirolimus and sirolimus AUCs (AUCsum) was comparable to that for adults.