Lutetium (177Lu) Vipivotide Tetraxetan

Absorption

The blood area under the curve (AUC) (geometric mean coefficient of variation or %CV) of lutetium Lu 177 vipivotide tetraxetan is 52.3 ng x h/mL (31.4%) and the maximum blood concentration (%CV) is 6.58 ng/mL (43.5%) at the recommended dosage.

Toxicity

The LD50 of lutetium Lu 177 vipivotide tetraxetan is unknown. The oral and intraperitoneal LD50 lutetium Lu-177 chloride in mice was 315 mg/kg and 7100 mg/kg, respectively.
There is limited clinical experience of overdose from lutetium Lu 177 vipivotide tetraxetan. In the event of administration of a radiation overdosage with lutetium Lu 177 vipivotide tetraxetan, reduce the radiation absorbed dose to the patient by increasing the elimination of the radionuclide from the body by frequent micturition or by forced diuresis and frequent bladder voiding. Estimate the effective radiation dose that was applied and treat with additional supportive care measures as clinically indicated.

Description

Lutetium-177 vipivotide tetraxetan1 is a widely approved breakthrough drug for metastatic prostate cancer. It is manufactured and distributed by Novartis (Basel, Switzerland) under the trade name Pluvicto. According to a recent Novartis press release, “Pluvicto shows statistically significant and clinically meaningful radiographic progression-free survival benefit in patients with PSMA-positive metastatic castration-resistant prostate cancer.”
PSMA, or prostate-specific membrane antigen, is the target of the radioactive 177Lu atom in the molecule, which is surrounded by the complex vipivotide tetraxetan2 ligand that binds to the PSMA-expressing tumor cells. The drug, in solution form, is administered intravenously.
Pluvicto was approved first by the US Food and Drug Administration in March 2022. Approvals by the United Kingdom, Canada, and the European Medicines Agency followed later in 2022.
Pluvicto is considered to be a safe drug, although Novartis advises that to minimize radiation exposure, patients should avoid close contact with others for at least 2 days after injection and with children and pregnant women for 7 days. Patients should also urinate as often as possible to reduce the risk of bladder irradiation. The drug’s most common side effects include fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation.
Safety data sheets for Pluvicto are not available, but Novartis published detailed safety information for the drug earlier this year.
1. SciFinder: Lutetate(3–)-177Lu, [N2-[[[(1S)-1,3-dicarboxypropyl]amino]carbonyl]-N6-[3-(2-naphthalenyl)-N-[[trans-4-[[[2-[4,7,10-tris[(carboxy-κO)methyl]-1,4,7,10-tetraazacyclododec-1-yl-κN1,κN4,κN7,κN10]acetyl-κO]amino]methyl]cyclohexyl]carbonyl]-L-alanyl]-L-lysinato(6–)]-, hydrogen (1:3). 2. CAS Reg. No. 1702967-37-0.

Background

Lutetium Lu-177 vipivotide tetraxetan is a radioligand therapeutic agent. It consists of a radionuclide, lutetium Lu-177, linked to a moiety that binds to PSMA, a transmembrane protein that is expressed in prostate cancer.
Lutetium Lu-177 vipivotide tetraxetan was first approved by the FDA on March 23, 2022 as a treatment for prostate-specific membrane antigen–positive metastatic castration-resistant prostate cancer. In October 2022, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended lutetium Lu-177 vipivotide tetraxetan be granted marketing authorization for the treatment of prostate cancer. In December 2022, lutetium Lu-177 vipivotide tetraxetan was approved by the EMA.

Indications

Lutetium Lu 177 vipivotide tetraxetan is a radioligand therapeutic agent indicated for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy.

Pharmacokinetics

Lutetium Lu 177 vipivotide tetraxetan is a radioligand that exerts cytotoxic effects on cancer cells. Tumor uptake value is 11.2%ID/g.
In clinical trials of patients with metastatic castration-resistant prostate cancer, treatment with lutetium Lu 177 vipivotide tetraxetan was associated with an 80.4% decline of serum PSA levels and median progression-free survival of 13.7 months.

Metabolism

Once dissociated from the parent compound, lutetium-177 decays to a stable hafnium-177.