al 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.
Distribution
The distribution of crofelemer has not been determined.
Metabolism
No metabolites of crofelemer have been identified in healthy subjects or patients in clinical trials.
Elimination
The elimination route has not been identified in humans.
Food Effect
Administration of crofelemer with a high-fat meal was not associated with an increase in systemic exposure of crofelemer in healthy volunteers. In the clinical trial, a single 500 mg dose of crofelemer was administered one-half hour before the morning and evening meals. Therefore, crofelemer may be administered with or without a meal.
Drug‑Drug Interactions
Results of a crossover study in healthy volunteers showed crofelemer 500 mg administered four times daily 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.
Nonclinical Toxicology
Carcinogenesis and Mutagenesis and Impairment of Fertility
Carcinogenesis
Long-term studies in animals have not been performed to eva luate the carcinogenic potential of crofelemer.
Mutagenesis
Crofelemer was negative in the bacterial reverse mutation assay, chromosomal aberration assay, and rat bone marrow micronucleus assay.
Impairment of Fertility
Crofelemer, at oral doses of up to 738 mg/kg/day (177 times the recommended human daily dose of 4.2 mg/kg), had no effects on fertility or reproductive performance of male and female rats.
Clinical Studies
The efficacy of FULYZAQ 125 mg delayed-release tablets twice daily was eva luated in a randomized, double-blind, placebo-controlled (one month) and placebo-free (five month), multi-center study. The study enrolled 374 HIV-positive patients on stable anti-retroviral therapy (ART) with a history of diarrhea for one month or more. Diarrhea was defined as either persistently loose stools despite regular use of anti-diarrheal medication (ADM) (e.g., loperamide, diphenoxylate, and bismuth subsalicylate) or one or more watery bowel movements per day without regular ADM use.
Patients were excluded if they had a positive gastrointestinal (GI) biopsy, GI culture, or stool test for multiple bacteria (Salmonella, Shigella, Campylobacter, Yersinia, Mycobacterium), bacterial toxin (Clostridium difficile), ova and parasites (Giardia, Entamoeba, Isospora, Cyclospora, Cryptosporidium, Microsporidium), or viruses (Cytomegalovirus). Patients were also excluded if they had a history of ulcerative colitis, Crohn’s disease, celiac sprue (gluten-enteropathy), chronic pancreatitis, malabsorption, or any other GI disease associated with diarrhea.
The study had a two-stage adaptive design. In both stages, patients received placebo for 10 days (screening period) followed by randomization to crofelemer or placebo for 31 days of treatment (double-blind period). Only patients with 1 or more watery bowel movements per day on at least 5 of the last 7 days in the screening period were randomized |
