Lorlatinib is also a (moderate) CYP3A4/5 inducer, so that  drugs that are metabolized by these enzymes are broken down more quickly when combined with lorlatinib. Examples include midazolam and ciclosporin.Interactions via other enzymes have only been studied in vitro. According to these findings, lorlatinib may inhibit CYP2C9, UGT1A1 and several transport proteins, induce CYP2B6, and has probably no relevant effect on CYP1A2. Pharmacology
Mechanism of action
Lorlatinib is a small molecule kinase inhibitor of ALK and ROS1 as well as a number of other kinases. It is active in vitro against many mutated forms of ALK. Pharmacokinetics
The drug is swallowed in the form of tablets. It reaches highest blood plasma concentrations 1.2 hours after a single dose, or 2 hours after ingestion when taken regularly. Its absolute bioavailability is 80.8%. Intake with fatty food increases its availability by 5%, which is not considered clinically significant. When in the bloodstream, 66% of the substance are bound to plasma proteins. Lorlatinib is able to cross the blood-brain barrier.Lorlatinib is inactivated by oxidation, mainly through CYP3A4, and by glucuronidation, mainly through UGT1A4. Other CYPs and UGTs play a minor role. Lorlatinib and its metabolites are excreted with a half-life of 23.6 hours after a single dose; 47.7% into the urine (of which less than 1% in unchanged form), and 40.9% into the faeces (9.1% unchanged). Chemistry
Lorlatinib is a white to off-white powder. It has high solubility in 0.1 M hydrochloric acid and very low solubility at a pH over 4.5. History
Clinical studies
Several clinical trials were orchestrated.
About 20 percent of dofetilide is metabolized in the liver via the CYP3A4 isoenzyme of the cytochrome P450 enzyme system. Drugs that interfere with the activity of the CYP3A4 isoenzyme can increase serum dofetilide levels. If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via the CYP3A4 isoenzyme system. History
After its initial US FDA approval, due to the pro-arrhythmic potential it was only made available to hospitals and prescribers that had received education and undergone specific training in the risks of treatment with dofetilide; however, this restriction was subsequently removed in 2016. See also
Antiarrhythmic agents
Cardiac action potential
Electrocardiogram


== References ==