Mechanism Of Action
Crofelemer is an inhibitor of
both the cyclic adenosine monophosphate (cAMP)-stimulated cystic fibrosis
transmembrane conductance regulator (CFTR) chloride ion (ClÂ¯) channel, and the
calcium-activated ClÂ¯ channels (CaCC) at the luminal membrane of enterocytes.
The CFTR ClÂ¯ channel and CaCC regulate ClÂ¯ and fluid secretion by intestinal
epithelial cells. Crofelemer acts by blocking ClÂ¯ secretion and accompanying
high volume water loss in diarrhea, normalizing the flow of ClÂ¯ 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.
Effect Of Food
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 [see DOSAGE AND ADMINISTRATION].
Drug Interaction Studies
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.
Nelfinavir, Zidovudine, Lamivudine
Results of a crossover study in healthy subjects showed
crofelemer 500 mg administered four times daily (8times 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.
The efficacy of MYTESI was evaluated 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 antiretroviral
therapy 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 (e.g., loperamide, diphenoxylate, and bismuth subsalicylate) or one
or more watery bowel movements per day without regular anti-diarrheal medicine
Patients were excluded if they had a positive
gastrointestinal biopsy, gastrointestinal 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 gastrointestinal disease associated
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 to the
double-blind period. Each stage enrolled patients separately; the dose for the
second stage was selected based on an interim analysis of data from the first
stage. In the first stage, patients were randomized 1:1:1:1 to one of three
crofelemer dosage regimens (125 mg twice daily, or one of two higher dosage
regimens) or placebo. In the second stage, patients were randomized 1:1 to
MYTESI 125 mg twice daily or placebo. The efficacy analysis was based on
results from the double-blind portion of both stages.
Each study stage also had a five month period
(placebo-free period) that followed the double-blind period. Patients treated
with MYTESI continued the same dose in the placebo-free period. In the first
stage, patients that received placebo were re-randomized 1:1:1 to one of the
three crofelemer dosage regimens (125 mg twice daily, or one of the two higher
dosage regimens) in the placebo-free period. In the second stage, patients that
received placebo were treated with MYTESI 125 mg twice daily in the
The median time since diagnosis of HIV was 12 years. The
percentage of patients with a CD4 cell count of less than 404 was 39%. The
percentage of patients with a HIV viral load greater than or equal to 1000, 400
to 999, and less than 400 HIV copies/mL was 7%, 3%, and 9%, respectively; the
remainder had a viral load that was not detectable. The median time since
diarrhea started was 4 years. The median number of daily watery bowel movements
was 2.5 per day.
Most patients were male (85%). The percentage of patients
that were Caucasian was 46%; the percentage of patients that were
African-American was 32%. The median age was 45 years with a range of 21 to 68
In the double-blind period of the study, 136 patients
received MYTESI 125 mg twice daily, 101 patients received one of the two higher
dosage regimens and 138 patients received placebo. The percentages of patients
that completed the double-blind period were 92% in the MYTESI 125 mg group and
94% in the placebo arm.
Most patients received concomitant protease inhibitors
during the double-blind period (Table 2). The most frequently used
anti-retroviral therapies in the MYTESI 125 mg and placebo groups were
tenofovir/emtricitabine, ritonavir, and lopinavir/ritonavir.
Table 2: Concomitant Anti-Retroviral Therapy Used in
the Double-Blind Period in Patients with HIV
||MYTESI 125 mg twice daily
(N = 136)
N = 138
|Any antiretroviral therapy
|Any protease inhibitor
|Tenofovir disoproxil fumarate
|Abacavir w/ lamivudine
The primary efficacy endpoint
was the proportion of patients with a clinical response, defined as less than
or equal to 2 watery bowel movements per week during at least 2 of the 4 weeks
of the placebo-controlled phase. Patients who received concomitant
anti-diarrheal medications or opiates were counted as clinical non-responders.
A significantly larger
proportion of patients in the MYTESI 125 mg twice daily group experienced
clinical response compared with patients in the placebo group (18% vs. 8%,
1–sided p < 0.01). In the randomized clinical study, examination of duration
of diarrhea, baseline number of daily watery bowel movements, use of protease
inhibitors, CD4 cell count and age subgroups did not identify differences in
the consistency of the crofelemer treatment effect among these subgroups. There
were too few female patients and patients with an HIV viral load > 400
copies/mL to adequately assess differences in effects in these populations.
Among race subgroups, there were no differences in the consistency of the
crofelemer treatment effect except for the subgroup of African-Americans;
crofelemer was less effective in African-Americans than non-African-Americans.
Although the CD4 cell count and
HIV viral load did not appear to change over the one month placebo-controlled
period, the clinical significance of this finding is unknown because of the
short duration of the placebo-controlled period.
Of the 24 clinical responders
to MYTESI 125 mg twice daily, 22 entered the placebo-free period; 16 were
responding at the end of month 3, and 14 were responding at the end of month 5.