Adverse effects
The most common adverse reactions experienced by patients who received ivacaftor in the pooled placebo-controlled Phase III studies were abdominal pain (15.6% versus 12.5% on placebo), diarrhoea (12.8% versus 9.6% on placebo), dizziness (9.2% versus 1.0% on placebo), rash (12.8% versus 6.7% on placebo), upper respiratory tract reactions (including upper respiratory tract infection, nasal congestion, pharyngeal erythema, oropharyngeal pain, rhinitis, sinus congestion, and nasopharyngitis) (63.3% versus 50.0% on placebo), headache (23.9% versus 16.3% on placebo) and bacteria in sputum (7.3% versus 3.8% on placebo). One patient in the ivacaftor group reported a serious adverse reaction: abdominal pain. Pharmacology
Pharmacodynamics
Ivacaftor is a "potentiator" of CFTR, meaning it increases the probability that the defective channel will be open and allow chloride ions pass through the channel pore. Pharmacokinetics
Distribution
Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells. Biotransformation
Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active. Elimination
Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the faeces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of total dose eliminated with 22% as M1 and 43% as M6.
Common associated injuries include head injury, injuries to the aorta, fractures of the pelvis and long bones, and lacerations of the liver and spleen. Associated injuries occur in over three quarters of cases. History
In 1579, Ambroise Paré made the first description of diaphragmatic rupture in a French artillery captain who had been shot eight months before his death. He died from complications of the rupture. Using autopsies, Paré also described diaphragmatic rupture in people who had suffered blunt and penetrating trauma. Reports of diaphragmatic herniation due to injury date back at least as far as the 17th century. Petit was the first to establish the difference between acquired and congenital diaphragmatic hernia, which results from a congenital malformation of the diaphragm. In 1888, Naumann repaired a hernia of the stomach into the left chest that was caused by trauma. Other animals
Diaphragmatic rupture is a common and well-known complication of blunt abdominal trauma in cats and dogs. The organs that herniate into the pleural cavity are determined by the location of the rupture. They are most commonly circumferential tears that occur at the attachment of the diaphragm and rib. Is these cases, the organs that herniate may include the liver, small intestine, stomach, spleen, omentum, and/or uterus. Dorsal tears are uncommon, and may cause a kidney to herniate into the thorax. Symptoms include difficulty breathing, vomiting, collapse, and an absence of palpable organs in the abdomen. Symptoms can worsen quickly and be lethal, especially in the case of severe bleeding, bruised heart, or strangulation of herniated intestine.