ChEMBL Resources

The SARfaris: GPCR, Kinase, ADME

Thursday, 20 March 2014

New Drug Approvals 2014 - Pt. III - Droxidopa (Northera ™)

ATC Code: Unavailable
Wikipedia: Droxidopa

On February 18th the FDA approved Droxidopa (tarde name Northera™) for the treatment of neurogenic orthostatic hypotension (NOH). NOH is a rare, chronic and often debilitating drop in blood pressure upon standing, and is associated with Parkinson's disease, multiple-system atrophy, and pure autonomic failure. Symptoms of NOH include dizziness, light-headedness, blurred vision, fatigue and fainting when a person stands. 

Droxidopa (also known as L-DOPS, L-threo-dihydroxyphenylserine, and SM-5688) is a prodrug which can be converted to norepinephrine (noradrenaline) by Aromatic L-amino acid decarboxylase (Uniprot P20711 ; EC Norepinephrine in turn can be converted to epinephrine by Phenylethanolamine N-methyltransferase ( Uniprot P11086 ). Droxidopa can cross the blood brain barrier, contrary to epinephrine and norepinephrine.  Patients with NOH suffer from depleted levels of epinephrine and norepinephrine. Droxidopa increases the levels of both in the peripheral nervous system and leads to an increased heart rate and blood pressure.

Droxidopa (CHEMBL2103827Pubchem : 92974 ) is a small molecule drug with a molecular weight of 213.2 Da, an AlogP of -2.92, 3 rotatable bonds, and no rule of 5 violations.

Canonical SMILES : N[C@@H]([C@H](O)c1ccc(O)c(O)c1)C(=O)O
InChi: InChI=1S/C9H11NO5/c10-7(9(14)15)8(13)4-1-2-5(11)6(12)3-4/h1-3,7-8,11-13H,10H2,(H,14,15)/t7-,8+/m0/s1

Droxidopa starting dose is 100mg three times daily (which can be titrated to a maximum of 600 mg three times daily). One dose should be taken in late afternoon at least 3 hours prior to bedtime to reduce the potential for supine hypertension during sleep.

Neuroleptic malignant syndrome (NMS) has been reported with Droxidopa use during post-marketing surveillance in Japan. NMS is an uncommon but life-threatening syndrome characterized by fever or hyperthermia, muscle rigidity, involuntary movements, altered consciousness, and mental status changes.

Ischemic Heart Disease, Arrhythmias, and Congestive Heart Failure
Droxidopa may exacerbate existing ischemic heart disease, arrhythmias and congestive heart failure.

Cmax of droxidopa were reached by 1 - 4 hours post-dose in healthy volunteers. High-fat meals have a moderate impact on droxidopa exposure with Cmax and AUC decreasing by 35% and 20% respectively, and delaying Cmax by approximately 2 hours.

Droxidopa exhibits plasma protein binding of 75% at 100 ng/mL and 26% at 10,000 ng/mL with an apparent volume of distribution of about 200 L.

The metabolism of droxidopa is mediated by catecholamine pathway and not through the cytochrome P450 system. Plasma norepinephrine levels peak within 3 to 4 hours (generally < 1 ng/mL) and variable with no consistent relationship with dose. The contribution of the metabolites of droxidopa other than norepinephrine to its pharmacological effects is not well understood.

The mean elimination half-life of droxidopa is 2.5 hours. The major route of elimination of droxidopa and its metabolites is via the kidneys.

Drug Interactions 
No dedicated drug-drug interaction studies were performed for droxidopa. Carbidopa, a peripheral dopa-decarboxylase inhibitor, could prevent the conversion of droxidopa to norepinephrine outside of the central nervous system (CNS).

L-DOPA/dopa-decarboxylase inhibitor combination drugs decreased clearance of droxidopa, increased AUC to droxidopa approximately 100%, and increased exposure to 3-OM-DOPS of approximately 50%. However, it was found that the decreased clearance was not associated with a significant need for a different treatment dose or increases in associated adverse events.

Dopamine agonists, amantadine derivatives, and MAO-B inhibitors do not appear to effect droxidopa clearance, no dose adjustments are required. 

Droxidopa is classified as pregnancy category C. There are no adequate and well controlled trials in pregnant women.

The license holder is Chelsea Therapeutics, the prescribing information can be found here.

No comments: