Identification

Summary

Lutetium Lu-177 vipivotide tetraxetan is a radioligand therapeutic agent used to treat prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer in adults.

Brand Names
Pluvicto
Generic Name
Lutetium Lu-177 vipivotide tetraxetan
DrugBank Accession Number
DB16778
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.3

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.4 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.6

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 1216.074
Monoisotopic: 1215.422157133
Chemical Formula
C49H68LuN9O16
Synonyms
  • 177Lu-PSMA-617

Pharmacology

Indication

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.3

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Lutetium Lu 177 vipivotide tetraxetan is a radioligand that exerts cytotoxic effects on cancer cells.3 Tumor uptake value is 11.2%ID/g.2

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. 2

Mechanism of action

Prostate‐specific membrane antigen (PSMA) is a transmembrane glycoprotein involved in various cellular functions, such as cellular uptake of folate, cell migration, and cell survival. Due to its overexpression on the surface of prostate cancer cells, PMSA remains a useful protein target for targeted diagnostic processes and radionuclide therapy in prostate cancer.1

Lutetium Lu 177 vipivotide tetraxetan consists of lutetium Lu-177, a radionuclide and an active moiety of the drug, linked to a moiety that binds to PSMA. Once administered, lutetium Lu 177 vipivotide tetraxetan binds to PSMA-expressing cells. The beta-minus emission from lutetium Lu-177 delivers radiation to PSMA-expressing cells, as well as to surrounding cells, and induces DNA damage which can lead to cell death.3

TargetActionsOrganism
AProstate-specific antigen
binder
Humans
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.3

Volume of distribution

The mean volume of distribution (%CV) is 123 L (78.1%). Within 2.5 hours of administration, lutetium Lu 177 vipivotide tetraxetan distributes to gastrointestinal tract, liver, lungs, kidneys, heart wall, bone marrow, and salivary glands.3

Protein binding

Vipivotide tetraxetan and non-radioactive lutetium vipivotide tetraxetan are 60% to 70% bound to human plasma proteins.3

Metabolism

Once dissociated from the parent compound, lutetium-177 decays to a stable hafnium-177.3

Route of elimination

Lutetium Lu 177 vipivotide tetraxetan is primarily eliminated renally.3 It is renally-excreted in the first 48 h following injection.1

Half-life

The terminal elimination half-life (%CV) of lutetium Lu 177 vipivotide tetraxetan is 41.6 hours (68.8%)3

Clearance

The mean clearance (CL) (%CV) is 2.04 L/h (31.5%).3

Adverse Effects
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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.5

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.3

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
No interactions found.

Products

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Active Moieties
NameKindUNIICASInChI Key
Lutetium Lu-177complexBRH40Y9V1Q14265-75-9OHSVLFRHMCKCQY-NJFSPNSNSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PluvictoInjection, solution27 mCi/1mLIntravenousAdvanced Accelerator Applications Usa, Inc2022-03-23Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
G6UF363ECX
CAS number
1703749-62-5
InChI Key
RSTDSVVLNYFDHY-BGOLSCJMSA-K
InChI
InChI=1S/C49H71N9O16.Lu/c59-40(28-55-17-19-56(29-42(62)63)21-23-58(31-44(66)67)24-22-57(20-18-55)30-43(64)65)51-27-32-8-12-35(13-9-32)45(68)52-39(26-33-10-11-34-5-1-2-6-36(34)25-33)46(69)50-16-4-3-7-37(47(70)71)53-49(74)54-38(48(72)73)14-15-41(60)61;/h1-2,5-6,10-11,25,32,35,37-39H,3-4,7-9,12-24,26-31H2,(H,50,69)(H,51,59)(H,52,68)(H,60,61)(H,62,63)(H,64,65)(H,66,67)(H,70,71)(H,72,73)(H2,53,54,74);/q;+3/p-3/t32-,35-,37-,38-,39-;/m0./s1/i;1+2
IUPAC Name
(177Lu)lutetium(3+) 2-[4,7-bis(carboxylatomethyl)-10-[({[(1r,4r)-4-{[(1S)-1-{[(5S)-5-carboxy-5-({[(1S)-1,3-dicarboxypropyl]carbamoyl}amino)pentyl]carbamoyl}-2-(naphthalen-2-yl)ethyl]carbamoyl}cyclohexyl]methyl}carbamoyl)methyl]-1,4,7,10-tetraazacyclododecan-1-yl]acetate
SMILES
[177Lu+3].OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CC1=CC2=CC=CC=C2C=C1)NC(=O)[C@H]1CC[C@H](CNC(=O)CN2CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC2)CC1)C(O)=O)C(O)=O

References

General References
  1. Emmett L, Willowson K, Violet J, Shin J, Blanksby A, Lee J: Lutetium (177) PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy. J Med Radiat Sci. 2017 Mar;64(1):52-60. doi: 10.1002/jmrs.227. [Article]
  2. Tateishi U: Prostate-specific membrane antigen (PSMA)-ligand positron emission tomography and radioligand therapy (RLT) of prostate cancer. Jpn J Clin Oncol. 2020 Apr 7;50(4):349-356. doi: 10.1093/jjco/hyaa004. [Article]
  3. FDA Approved Drug Products: PLUVICTO (lutetium Lu 177 vipivotide tetraxetan) injection, for intravenous use [Link]
  4. Novartis News: Novartis Pluvicto™ approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer [Link]
  5. EMA Assessment Report: EndolucinBeta, INN-Lutetium (177 Lu) chloride [Link]
  6. EMA Summary of Opinion: Pluvicto (lutetium Lu 177 vipivotide tetraxetan) [Link]
ChemSpider
58828499
RxNav
2597053

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentProstate Cancer1
3Active Not RecruitingTreatmentProstatic Neoplasms1
3RecruitingTreatmentProstatic Neoplasms1
2RecruitingTreatmentGenital Neoplasms, Male / Genitourinary tract neoplasm / Neoplasms by Site / Neoplastic Disease / Prostate Cancer / Prostatic Diseases / Prostatic Neoplasms1
2RecruitingTreatmentMetastatic Hormone Naive Prostate Cancer1
2RecruitingTreatmentProstate Cancer2
2TerminatedTreatmentMetastatic Castration Resistant Prostate Cancer (CRPC)1
1Active Not RecruitingTreatmentAdenocarcinoma, Prostate / Castration Levels of Testosterone / Castration-Resistant Prostate Carcinoma / Refractory, metastatic hormone-refractory Prostate cancer / Stage IV Prostate Cancer / Stage IVA Prostate Cancer / Stage IVB Prostate Cancer1
1Not Yet RecruitingTreatmentMetastatic Castration Resistant Prostate Cancer (CRPC)1
1RecruitingTreatmentProstate Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous27 mCi/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10406240No2019-09-102028-08-15US flag
US10398791No2019-09-032034-10-17US flag
US11318121No2008-08-152028-08-15US flag

Properties

State
Liquid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.064 mg/mLALOGPS
logP1.52ALOGPS
logP-3.5Chemaxon
logS-4.3ALOGPS
pKa (Strongest Acidic)0.45Chemaxon
pKa (Strongest Basic)7.01Chemaxon
Physiological Charge-5Chemaxon
Hydrogen Acceptor Count20Chemaxon
Hydrogen Donor Count8Chemaxon
Polar Surface Area373.68 Å2Chemaxon
Rotatable Bond Count27Chemaxon
Refractivity294.99 m3·mol-1Chemaxon
Polarizability107.26 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Binder
General Function
Hydrolyzes semenogelin-1 thus leading to the liquefaction of the seminal coagulum.
Specific Function
Endopeptidase activity
Gene Name
KLK3
Uniprot ID
P07288
Uniprot Name
Prostate-specific antigen
Molecular Weight
28741.1 Da
References
  1. FDA Approved Drug Products: PLUVICTO (lutetium Lu 177 vipivotide tetraxetan) injection, for intravenous use [Link]

Drug created at March 24, 2022 15:52 / Updated at November 02, 2022 16:59