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The SARfaris: GPCR, Kinase, ADME

Friday, 9 March 2012

New Drug Approvals 2012 - Pt. VII - Lucinactant (SurfaxinTM)

ATC code: R07AA30

On March 6, the FDA approved Lucinactant (previously known as KL4-surfactant and ATI 02) for the prevention of infant respiratory distress syndrome (IRDS), which occurs in premature infants with an incidence of 1%. The onset of IRDS is shortly after birth and it typically lasts 2-3 days. Symptoms include shortness of breath, increased heart rate and bluish discoloration of the skin (cyanosis). IRDS can lead to serious complications such as chronic changes of the lung structure, acidosis, intracranial hemorrhage and an incomplete closure of the vascular connection between the aorta and the pulmonary artery (patent ductus arteriosus). In developed countries, IRDS is one of the leading causes of death in the first month after birth.

IRDS is caused by insufficient production of surfactant, a substance that is secreted into the air-filled alveoli of the lung by specialized cells called type II pneumocytes. The lack of surfactant causes an increased surface tension on the interface between the capillary blood vessels (and embedding alveolar tissue) and the air-filled lumen of the alveolus. This results in a contraction of the air-space and obstructs normal breathing.

Lucinactant is a substitute for endogenuous surfactant that is administered via a intratracheal tube. Unlike other formulations on the market such as beractant, poractant and calfactant - which are animal derived - Lucinactant is a synthetic formulation consisting of a mixture of phospholipids, fatty acids and a synthetic peptide called sinapultide. Sinapultide is a hydrophobic peptide composed of 17 leucine residues and 5 lysine residues. The peptide is designed to mimick the properties of apolipoprotein SP-B (Uniprot P07988). The remaining components of Lucinactant are palmitic acid and the phospholipids DPPC and POPG.

palmitic acid



Palmitic acid (CHEMBL82293) is a fatty acid with molecular weight 256.42 Da.
IUPAC name: Hexadecanoic acid

DPPC  (CHEMBL1200737) is a phospholipid with molecular weight 734.06Da.
IUPAC name: 1,2-dipalmitoyl-sn-glycero-3-phosphocholine

DOPG is a phospholipid with molecular weight 747.50 Da.
IUPAC name: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol

Sinapultide is a synthetic peptide of 21 amino acids with molecular weight 2469.46 Da.
CAS: 138531-07-4

It is of note that Lucinactant is a USAN which is a mixture of four distinct components (without a defined composition in the USAN document). This creates a surprising number of issues in the storage and retrieval of drug information (sigh), and this sort of thing is dragging us towards defining a ChEMBL USAN-like data object for use in our systems (double sigh). Sinapultide has its own distinct assigned USAN, but DPPC, Palmitic acid and DOPG do not (or not that I can find).

Lucinactent is an off-white gel at the recommended storage temperature of 2-8 C  but becomes a liquid when warmed before use. Each mL of SURFAXIN contains 22.50 mg DPPC and 7.50 mg POPG, Na, 4.05 mg palmitic acid, and 0.862 mg sinapultide in tromethamine and sodium chloride. It is recommended that a maximum of 4 doses at 5.8 mL/kg is administered within 48 h after onset of IRDS, within intervals of at least 6h.

Pharmakokinetics of Lucinactent were not studied in humans. A study into the treatment of adult respiratory distress syndrome (ARDS) resulted in increased mortality rate of treated patients. Lucinactent is not indicated for the treatment of ARDS.

Lucinactent is marketed by Discovery Labs Inc. under the name Surfaxin. Full prescribing information can be found here.

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