Crofelemer is an inhibitor of both the cyclic adenosine monophosphate (cAMP)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion (Cl¯) channel, and the calcium-activated Cl¯ channels (CaCC) at the luminal membrane of enterocytes. The CFTR Cl¯ channel and CaCC regulate Cl¯ and fluid secretion by intestinal epithelial cells. Crofelemer acts by blocking Cl¯ secretion and accompanying high volume water loss in diarrhea, normalizing the flow of Cl¯ and water in the gastrointestinal tract.
Consistent with the mechanism of action of crofelemer (i.e., inhibition of CFTR and CaCC in the gastrointestinal lumen), data suggest stool chloride concentrations decreased in patients treated with crofelemer 500 mg four times daily (8-times the recommended daily dosage) (n=25) for four days relative to placebo (n=24); stool chloride concentrations decreased in both African American patients treated with crofelemer (n=3) relative to placebo (n=5) and non-African American patients treated with Mytesi (n=22) relative to placebo (n=19).
At a dose 10 times the maximum recommended dose, crofelemer does not prolong the QTc interval to any clinically relevant extent.
The absorption of crofelemer is minimal following oral dosing in healthy adults and HIV-positive patients and concentrations of crofelemer in plasma are below the level of quantitation (50 ng/mL). Therefore, standard pharmacokinetic parameters such as area under the curve, maximum concentration, and half-life cannot be estimated.
Administration of crofelemer with a high-fat meal was not associated with an increase in systemic exposure of crofelemer in healthy subjects. In the clinical trial, a single 500 mg dose of crofelemer (4-times the recommended dose) was administered one-half hour before the morning and evening meals.
In vitro studies have shown that crofelemer has the potential to inhibit cytochrome P450 isoenzyme 3A and transporters MRP2 and OATP1A2 at concentrations expected in the gut. Due to the minimal absorption of crofelemer, crofelemer is unlikely to inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 systemically.
Results of a crossover study in healthy subjects showed crofelemer 500 mg administered four times daily (8-times the recommended dosage) for five days had no effect on the exposure of zidovudine and nelfinavir when administered as a single dose. A 20% decrease in lamivudine exposure was also observed in the same study but was not considered to be clinically important.
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