Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21st century

Table 1 Reasons for a poor response to supplemental enzyme therapy

Inactivation of the enzymes in the stomach by acid and/or proteases

Inadequate mixing of the enzymes and nutrients during delivery to the small intestine such that a proportion of the meal is not exposed to appropriate concentrations of enzymes

Separation of enteric-coated microspheres from meal contents in the stomach

Low duodenal and small bowel pH fail to provide optimal conditions for lipase and bile salts to provide optimal digestion of the ingested nutrients

Delayed dissolution of enteric-coated enzyme microspheres in the small intestine

Incorrect or incomplete diagnosis

Table 2 Myths regarding modern microbead enzyme therapy

Currently available formulations will reliably correct steatorrhea

Increasing the dose of microbeads increases the effectiveness

Choice of dose depends on fat content of the diet

Proton pump therapy generally improves success with microbead therapy

Microbeads are fully protected in applesauce

Uncoated enzymes have no place in modern pancreatic enzyme therapy

Table 3 Currently available United States Food and Drug Administration approved pancreatic enzyme preparations¹

DRUG	Stregth
	Lipase USP	Preparation	Diagmeter\e	pH1	Cost per tablet (United States)	Cost per 1000 units
CREON®
Creon 3000	3000	Capsule with enteric coated minimicrospheres	0.71-1.6 mm	5.5	$1.18	$0.39
Creon 6000	6000	Capsule with enteric coated minimicrospheres	0.71-1.6 mm	5.5	$1.30	$0.22
Creon 12000	12000	Capsule with enteric coated minimicrospheres	0.71-1.6 mm	5.5	$2.32	$0.19
Creon 24000	24000	Capsule with enteric coated minimicrospheres	0.71-1.6 mm	5.5	$4.56	$0.19
Creon 36000	36000	Capsule with enteric coated minimicrospheres	0.71-1.6 mm	5.5	$7.90	$0.22
Pancreaze®
Pancreaze 4200	4200	Capsule with enteric coated microtablets	2 mm	5.5	$0.92	$0.22
Pancreaze 10500	10500	Capsule with enteric coated microtablets	2 mm	5.5	$2.29	$0.22
Pancreaze 16800	16800	Capsule with enteric coated microtablets	2 mm	5.5	$3.68	$0.22
Pancreaze 21000	21000	Capsule with enteric coated microtablets	2 mm	5.5	$4.58	$0.22
Zenpep®
Zenpep 3000	3000	Capsule with enteric coated beads	1.8-1.9 mm	5.5	$1.27	$0.42
Zenpep 5000	5000	Capsule with enteric coated beads	1.8-1.9 mm	5.5	$1.21	$0.24
Zenpep 10000	10000	Capsule with enteric coated beads	2.2-2.5 mm	5.5	$2.39	$0.24
Zenpep 15000	15000	Capsule with enteric coated beads	2.2-2.5 mm	5.5	$3.47	$0.23
Zenpep 20000	20000	Capsule with enteric coated beads	2.2-2.5 mm	5.5	$4.71	$0.24
Zenpep 25000	25000	Capsule with enteric coated beads	2.2-2.5 mm	5.5	$5.83	$0.23
Ultresa®
Ultresa 13800	13800	Capsule with enteric coated minitablet	2 mm	5.5	$3.01	$0.22
Ultresa 20700	20700	Capsule with enteric coated minitablet	2 mm	5.5	$4.46	$0.22
Ultresa 23000	23000	Capsule with enteric coated minitablet	2 mm	5.5	$5.47	$0.24
Pertyze®
Pertyze 8000	8000	Capsule with bicarbonate buffered enteric coated microsphere	0.8-2.2 mm	5.5	$1.99	$0.25
Pertyze 16000	16000	Capsule with bicarbonate buffered enteric coated microsphere	0.8-2.2 mm	5.5	$3.99	$0.25
Viokase®
Viokase 10440	10440	Non-enteric coated			$2.92	$0.28
Viokase 20800	20880	Non-enteric coated			$5.76	$0.28

¹pH at or above which enzyme is designed to release most of the enzyme based on the package insert.

Table 4 Dissolution time for pancreatic enzyme in ileal fluid

Pancreatic enzyme	Initial pH	Start to dissolve (min)	Completely dissolved (min)
Creon® 24000	7.73 pH	9.0	45.8	7.28 pH
Ultresa® 23000	7.52 pH	10.5	30.0	7.48 pH
Zenpep® 25000	7.60 pH	15.0	33.0	7.59 pH

Table 5 Data needed to understand how to use new enzyme formulations

Results of all studies should not be withheld but should be published and/or placed on Clintrials.gov within 1 yr of completion

Trial data should provide the primary efficacy endpoint (e.g., coefficient of fat absorption) as mean, standard deviation, median, range, and proportion with coefficient of fat absorption > 90% as well as proportion with coefficient of fat absorption < 85%

Gastric emptying of enteric coated pellets studied for all products are needed and the data should be published and/or placed on Clintrials.gov within 1 yr of completion

Kinetics of dissolution of enteric-coated microbeads in intestinal fluid or simulated intestinal fluid are needed and should include data pH's starting at approximately pH 5 through 7 at increments (e.g., approximately 0.2 pH units)

Table 6 Recommended clinical trials

Head to head comparisons of different formulations within a product line as well as between commercial products

Comparative trials using different patterns of administration in relation to meals of enteric coated products (e.g., before and during)

Studies combining unprotected and enteric coated preparations

Studies of unprotected preparations combined with maintenance of the intragastric pH constantly above 4

Initial pilot studies using 13C-mixed triglyceride breath testing to test proof of concept may be the most efficient means of identifying which studies to test in human clinical trials