Crofelemer for the treatment of chronic diarrhea in patients living with HIV/AIDS

Figures & data

Table 1 Pharmacologic agents available for the treatment of noninfectious diarrhea

Antidiarrheal class	Mechanism of action	Examples
Adsorbents	Bulk forming agents that lead to the formation of more viscous stools by absorbing water and binding to other intraluminal contents	Bismuth subsalicylate
		Kaolin
		Pectin
		Psyllium
Antimotility agents	Inhibit peristalsis or propulsive movements in the intestines, thereby reducing fluid and electrolyte loss	Diphenoxylate-atropine
		Loperamide
		Octreotide (unlabeled use)
		Paregoric
Antisecretory agents	Inhibit the secretion of water and electrolytes into the intestines	Bismuth subsalicylate
		Crofelemer
		Octreotide (unlabeled use)
		Zinc
		Racecadotril (under development)

Table 2 Summary of clinical trials investigating the use of crofelemer for secretory diarrhea

Study	Indication	Trial design	Sample size	Intervention	Primary outcomes	Results
Holodniy et al^Citation14	AIDS-associated diarrhea	MC, DB, P, PC, RCT	51	Crofelemer 500 mg, placebo every 6 hours for 96 hours	Stool weight reduction from baseline versus placebo	Crofelemer 451.3 g/24 hour reduction versus placebo 150.7 g/24 hour reduction (P = 0.14)
					Stool frequency reduction from baseline versus placebo	Crofelemer three stool reduction/24 hours versus placebo two stool reduction/24 hours (P = 0.3)
DiCesare et al^Citation15	Travelers’ diarrhea	MC, DB, P, PC, RCT	184	Crofelemer 125 mg, 250 mg, 500 mg, placebo four times a day for 2 days	Decreased TLUS48 versus placebo	Crofelemer 125 mg 8.1 hour decrease (P = 0.005) versus crofelemer 250 mg 8.4-hour decrease (P = 0.0004) versus crofelemer 500 mg 6.1 -hour decrease (P = 0.01) versus placebo mean TLUS48 38.7 hours
					Complete or partial responder at day 1 versus placebo	Placebo 65.9% versus crofelemer 125 mg 85.4% (P = 0.04) versus crofelemer 250 mg 91.3% (P = 0.003) versus crofelemer 500 mg 68.3% (P = NS)
					Treatment failures versus placebo	Placebo 29.3% versus crofelemer 125 mg 7.3% (P = 0.01) versus crofelemer 250 mg 4.3% (P = 0.002) versus crofelemer 500 mg 9.8% (P = 0.026)
Mangel and Chaturved^Citation16	IBS-D	MC, DB, P, PC, RCT	241	Crofelemer 125 mg, 250 mg, 500 mg, placebo twice a day for 12 weeks	Stool consistency daily change from baseline	Placebo: −0.67 ± 0.62 versus crofelemer 125 mg −0.65 ± 0.64 (P = 0.81) versus crofelemer 250 mg −0.47 ± 0.639 (P = 0.14) versus crofelemer 500 mg −0.48 ± 0.56 (P = 0.I7)
Bardhan et al^Citation17	Acute infectious diarrhea	NR	100	Single-dose crofelemer 125 mg, 250 mg, placebo	Watery stool output reduction within 24 hours versus placebo	Crofelemer 125 mg, 250 mg 25%–30% reduction versus placebo
Bardhan et al^Citation17	Cholera	NR	98	Crofelemer 250 mg, placebo four times a day for 2 days	Resolution of watery diarrhea within 48 hours	Crofelemer 250 mg 75% reduction versus placebo 37% reduction

Abbreviations: AIDS, acquired immunodeficiency syndrome; MC, multicentered; DB, double blind; P, parallel; PC, placebo controlled; RCT, randomized controlled trial; TLUS₄₈, time from taking the first dose of study medication to time of passage of the last unformed stool during the 48 hours of treatment; NS, not significant; IBS-D, diarrhea-predominant irritable bowel syndrome; NR, not reported.

Figure 1 Chemical structure of crofelemer.³⁶

Note: Range n = 3.0 to 5.5.Abbreviation: n, number.

Figure 2 Mechanisms involved in the development of secretory diarrhea.

Notes: The CFTR and CaCC are responsible for the secretion of chloride ions into the intestinal lumen. Secretory diarrhea develops due to hyperactivity of these channels. Crofelemer binds to the CFTR and CaCC and inhibits chloride secretion, thus halting secretory diarrhea.
Abbreviations: Ca²⁺, calcium; CaCC, calcium-activated chloride channels; cAMP, cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; Cl⁻, chloride; H₂O, water; K⁺, potassium; Na⁺, sodium; NKCC, sodium potassium chloride cotransporter.

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