What Is Temsirolimus (Torisel)? FDA Approval, Licensing in Türkiye and Reimbursement Status
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Temsirolimus (Torisel)
- FDA Approval: Yes (First approval: May 30, 2007)
- Brand Name: Torisel
- Active Ingredient: Temsirolimus
- Administration: Intravenous infusion (usually 1 time per week, 30–60 min)
- Class: mTOR inhibitor (rapamycin derivative)
- Category: Antineoplastic / Targeted therapy
- Manufacturer: Wyeth (acquired by Pfizer)
- Distribution / License in Türkiye: Licensed in Türkiye as Torisel; used for specific indications according to SGK conditions.
- Approved Cancer Indication: Metastatic renal cell carcinoma (mRCC)
What Is Temsirolimus?
Temsirolimusbelongs to the mTOR (mammalian target of rapamycin) inhibitor class and is used particularly for advanced renal cell carcinoma treatment as an IV targeted agent. It is an ester derivative of Sirolimus (rapamycin) and, after metabolism, continues to act through its active metabolite, sirolimus .
Mechanism of Action
Temsirolimus’ antitumor effect is based primarily on inhibition of the mTORC1 pathway:
- mTORC1 inhibition: Forms a complex with FKBP-12 to suppress mTORC1.
- Downstream targets: p70 S6 kinase (S6K1) and 4E-BP1 → reduced protein synthesis and cell growth.
- Cell cycle: G1 phase arrest → slower proliferation.
- Angiogenesis: HIF-1α reduction → lower VEGF and proangiogenic factors.
- Apoptosis / autophagy: May increase in some tumor cell lines.
FDA Approval History
- May 31, 2007: Torisel approval for advanced RCC
- December 19, 2006: Priority review status for the NDA
- October 6, 2006: NDA and European MAA submissions
🇹🇷 Licensing in Türkiye & SGK Reimbursement
Licensed in Türkiye as Torisel. SGK reimbursement for metastatic RCC is possible for patients considered to have a poor prognosis (meeting, out of the following 6 criteria, at least 3) under specific medical report conditions:
| Poor-prognosis criteria (≥3) |
|---|
| LDH > 1.5 times the upper limit |
| Hemoglobin < lower limit |
| Corrected calcium > 10 mg/dL |
| Time from diagnosis to systemic treatment < 1 year |
| ECOG performance status ≥ 2 |
| Metastases in two or more organs |
Note: Temsirolimus is assessed within restrictions on sequential/combined use with sunitinib, sorafenib and pazopanib in RCC, and under medical report requirements.
Price & Cost per Cycle
Diagnosis / Indication: Metastatic renal cell carcinoma (mRCC) — use in the “poor prognosis” group (≥3 criteria) according to SGK conditions.
| Cost Item | Value |
|---|---|
| Dose | 25 mg IV, 1 time per week (30–60 min) |
| Unit price | Temsirolimus 25 mg vial = 19,898.39 TL |
| Cost of 1 administration | 19,898.39 TL (assuming 1 vial/administration) |
| 1 cycle (4 weeks / 4 doses) | 79,593.56 TL (4 × 19,898.39 TL) |
| 1 month (approximately) | 79,593.56 TL (with weekly administration) |
Resistance Mechanisms
- mTORC2 activation & AKT reactivation: Feedback is disrupted after mTORC1 suppression → PI3K/AKT may reactivate.
- Upstream activation (PI3K/PTEN): PI3K mutation / PTEN loss → mTOR suppression may be insufficient.
- Bypassing 4E-BP1 inhibition: Protein synthesis may not be fully suppressed.
- Adaptation through autophagy: Autophagy may become a “survival” mechanism in some tumors.
- mTOR mutations: Drug binding may decrease.
- Alternative pathways: Growth may continue through activation of MAPK/ERK, JAK/STAT and RAS.
Pharmacokinetics
Absorption
- IV administration; no oral bioavailability.
- Cmax usually within ~30 min after infusion.
Distribution
- Plasma protein binding: 87–91%
- Vd ~172 L (extensive tissue distribution)
- Limited BBB penetration
Metabolism
- Primarily metabolized by CYP3A4 enzymatic activity
- Active metabolite: sirolimus
- High interaction risk with strong CYP3A4 inhibitors/inducers
Elimination
- Predominantly hepatobiliary (bile–feces); minimal urinary elimination (<5%)
- Temsirolimus t1/2 ~17 hours
Dosing Interval
- Recommended starting dose: 25 mg IV, 1 time per week
- Infusion duration: 30–60 min
- Premedication: Antihistamine ~30 min before administration (e.g., diphenhydramine 25–50 mg IV) to reduce infusion reaction risk.
- Dose reduction (example): 15 mg/week in moderate hepatic impairment; clinical judgment is needed according to interactions/toxicity.
Drug Interactions
CYP3A4 inhibitors → levels ↑ / toxicity ↑ (dose reduction may be needed):
- Ketoconazole, itraconazole, clarithromycin, verapamil, diltiazem, ritonavir, etc.
- Grapefruit juice
CYP3A4 inducers → levels ↓ / efficacy ↓:
- Rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort
Other precautions: Additive infection risk with immunosuppressants; arrhythmia risk with QT-prolonging drugs; live vaccines are not recommended.
Situations Requiring Caution
- Infusion reaction: H1 antihistamine premedication before each administration.
- Hepatic impairment: Hepatic metabolism → toxicity may increase; reduce the dose in Child-Pugh B and avoid in Child-Pugh C.
- Infection: Immunosuppressive effect → monitor for opportunistic infections.
- Metabolic effects: Monitor for hyperglycemia/hyperlipidemia.
- Pulmonary toxicity: Evaluate new cough/dyspnea/fever.
- Hematological toxicity: Monitor with a complete blood count (anemia, leukopenia, thrombocytopenia).
- Pregnancy/breastfeeding: Fetotoxicity risk; contraindicated/not recommended.
Side Effects (Example Frequencies)
| Side effect | Frequency (approximately) |
|---|---|
| Rash | 42–47% |
| Fatigue / asthenia | ~40% |
| Anemia | 34–45% |
| Nausea | 33–37% |
| Diarrhea | ~31% |
| Dyspnea | ~29% |
| Infections | ~27% |
| Hyperglycemia | ~26% |
| Thrombocytopenia | ~14% |
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