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Details

Stereochemistry ACHIRAL
Molecular Formula C27H21ClFN3O2
Molecular Weight 473.926
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LIXIVAPTAN

SMILES

CC1=C(C=C(F)C=C1)C(=O)NC2=CC(Cl)=C(C=C2)C(=O)N3CC4=CC=CN4CC5=C3C=CC=C5

InChI

InChIKey=PPHTXRNHTVLQED-UHFFFAOYSA-N
InChI=1S/C27H21ClFN3O2/c1-17-8-9-19(29)13-23(17)26(33)30-20-10-11-22(24(28)14-20)27(34)32-16-21-6-4-12-31(21)15-18-5-2-3-7-25(18)32/h2-14H,15-16H2,1H3,(H,30,33)

HIDE SMILES / InChI

Description

Lixivaptan is an orally-active, vasopressin 2 receptor antagonist. It is indicated for the treatment of symptomatic hypervolemic and euvolemic hyponatremia, associated with heart failure (HF) and syndrome of inappropriate antidiuretic hormone (SIADH). Adverse events likely to be result of the pharmacologic action of lixivaptan are: constipation, dry mouth, dizziness, insomnia. Grapefruit juice significantly increased the extent of lixivaptan absorption as compared to lixivaptan administered under fasted conditions but not under fed conditions. Lixivaptan Cmax and AUC∞ increased by 2.4-fold and 3.2-fold, respectively, when lixivaptan was administered with ketoconazole (the same in case of Simvastatin).

Originator

Approval Year

Targets

Primary TargetPharmacologyConditionPotency
0.48 nM [Ki]
4.4 µM [IC50]
0.57 µM [IC50]
0.79 µM [IC50]
55.0 nM [Ki]

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Cmax

ValueDoseCo-administeredAnalytePopulation
1877 ng/mL
300 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
719 ng/mL
100 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
183 ng/mL
25 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
1208 ng/mL
200 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
210 ng/mL
50 mg single, oral
LIXIVAPTAN plasma
Homo sapiens

AUC

ValueDoseCo-administeredAnalytePopulation
14884 ng × h/mL
300 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
4391 ng × h/mL
100 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
499 ng × h/mL
25 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
8775 ng × h/mL
200 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
953 ng × h/mL
50 mg single, oral
LIXIVAPTAN plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
21.62 h
300 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
9.05 h
100 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
14.61 h
25 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
22.56 h
200 mg single, oral
LIXIVAPTAN plasma
Homo sapiens
12.49 h
50 mg single, oral
LIXIVAPTAN plasma
Homo sapiens

Doses

AEs

PubMed

Sample Use Guides

In Vivo Use Guide
The starting dose for hospitalized patients with hyponatremia is 50 mg once daily (25 mg for outpatients) without regard to meals. The dose may be doubled every 24 hours depending on individual patient response to a maximum of 100 mg once daily (total daily dose 100 mg) in syndrome of inappropriate antidiuretic hormone patients and to a maximum of 100 mg BID (total daily dose 200 mg) in heart failure patients, as needed, to achieve the desired sodium concentration.
Route of Administration: Oral
In Vitro Use Guide
Scatchard analysis of binding to cloned human V2-receptors showed that the dissociation constant (Kd) of [3H]-AVP increased from 0.79 nM in the vehicle-control to 1.04 nM in the presence of 0.5 nM VPA-985, while the maximum binding (B max) remained unchanged (1.14 vs. 1.02 fmole/ug protein, respectively).