**5. Standard approaches for the treatment of fat malabsorption due to exocrine pancreatic insufficiency**

The main focus in the management of EPI is to prevent weight loss, EPI related symptoms, vitamin deficiencies, and to improve the patient's nutritional status. Whatever the aetiology, oral pancreatic enzyme supplements are widely used as the first-line approach to treat malabsorption secondary to exocrine pancreatic insufficiency (Breithaupt & al., 2007).

#### **5.1 Formulations and galenic properties**

Pancreatic enzyme preparations (PEPs) are typically a mixture of porcine-derived pancreatic enzymes. These preparations, also called pancreatin, contain a variable mixture of protease, lipase and amylase depending on the brand. Various preparations are commercially available. The main formulations are immediate-release, enteric-coated microspheres and minimicrospheres, enteric-coated microtablets and enteric-coated microspheres with a bicarbonate buffer (Table 4). A Comprehensive table of these preparations has been summarized in other reviews (Krishnamurty & al., 2009, Ferrone & al., 2007).

Emerging Approaches for the Treatment of

pancreatic insufficiency.

meal (Fieker et al., 2011).

al., 1991).

or after meals (Dominguez-Munoz & al., 2005).

Fat Malabsorption due to Exocrine Pancreatic Insufficiency 281

been standardized, marked variability in particle size, enzyme release, and for some, acid stability has been noted and may result in differences in clinical effect (Walters & Littlewood, 1996; Aloulou & al., 2008; Löhr & al., 2009). In the United States, marked variation in the enzyme content of the various formulations especially with generic products

Some general guidelines are given in spite of the absence of an easy applicable and objective method to establish the adequate dose of oral pancreatic enzymes to treat exocrine

In general, the recommended dosage of Pancreatic enzyme supplements (PES) for a main meal (breakfast, lunch, or dinner) ranges from 25,000 to 75,000 units of lipase and from 10,000 to 25,000 units of lipase for snacks, depending on the fat content of the meal (Sikkens et al., 2010). Initial dose must ensure supplementation of 60 UI/min of lipase activity in postparandial chyme throughout the digestive period; hence, dosing is adjusted considering this recommendation and the amount of lipase in the supplement (Krishnamurty et al., 2009) but it is not recommended to exceed 10,000 units of lipase per kg of body weight per

The timing of ingestion of the capsules is important to optimize therapeutic efficacy. A recent study compared three different administration schedules using enzyme replacement before, during or after meals. Better lipid digestion was found when giving enzymes during

Numerous randomized placebo controlled trials have shown that treatment with pancreatic enzyme supplements improves steatorrhea, as measured by increased fat absorption, reduced fecal fat excretion, decreased stool weight and frequency, improved stool consistency and improved symptom scores (Guarner et al., 1993; O'keefe et al., 2001; Dominguez-Munoz et al., 2005; Safdi et al., 2006, Trapnell et al., 2009; Wooldridge et al., 2009; Whitcomb et al., 2010). Enzyme supplements have been found to improve lipid malabsorption in children even those who are younger than 7 years old (Graff et al., 2010a, 2010b). In yet other studies, increased cholesterol absorption and improved enterohepatic cycling of bile salts have been reported (Dutta et al., 1986; Vuoristo et al., 1992). Moreover, it has been demonstrated that improvement of lipid digestion contributes to effective correction of motility disorders (Mizushima et al., 2004). Altered levels of gastro-intestinal hormones were normalized (Nustede et al., 1991); accelerated gastric emptying and

Even though, randomized controlled trials have suggested, years ago, that non-enteric coated pancreatic enzyme supplements reduce pain in chronic pancreatitis (Isaksson et al., 1983; Slaff et al., 1984), a more recent study did not support the use of these preparations for the relief of pain in all patients (Brown et al., 1997). Unfortunately, pancreatic enzyme supplements were reported to be not sufficient for correcting fat soluble vitamin deficiencies or B12 deficiency without simultaneous vitamin supplementation (Dutta et al., 1982; Bang et

**5.3 Efficacy assessment of the treatment with pancreatic enzyme supplements** 

abnormal antroduodenal motility were corrected (Layer et al., 1997).

has been attributed to a lack of stringent regulation (Fieker & al., 2011).

**5.2 Dosage recommendation and schedule of administration** 


Table 4. Commercially available pancreatic enzyme formulations (adapted from Krishnamurty et al., 2009)

The uncoated formulations are susceptible to acidic inactivation in the stomach and are currently used largely in clinical practice to treat the pain of chronic pancreatitis and not malabsorption (Chauhan & Forsmark, 2010). The enteric-coated pancreatic enzyme formulations have been developed to solve problems associated with acid-mediated inactivation of pancreatic lipase, especially in patients with EPI who also show low pH values in the small intestine. First generation of these preparations was the enteric coated tablet with diameter of 11-20 mm. Due to their large size, these formulations did not empty into the duodenum as quickly as smaller food particles and did not show any additional benefits over conventional preparations (Meyer & al., 1988; Meyer & Lake, 1997). Next generation of enteric-coated preparations consist of capsules (over 2 mm in size) coated with acid resistant agents designed to release the enzyme between pH 5.0-5.5. No therapeutic benefit of these preparations was seen. Studies of labeled capsules suggest that even with varying sizes of microspheres, the ingested lipid may enter the duodenum in advance of the pancreatic enzyme (Meyer & Lake, 1997). Hence, newer formulations consisting of capsules containing mini-microspheres, pellets or micro-tablets of less than 2 mm in size were designed to promote an adequate intragastric mixture of exogenous enzymes with chyme. Whether the use of these enteric coated mini-microsphere preparations adds any special advantage over the existing treatment options remains, however, subject to great discussion (Halm & al., 1999; Stern & al, 2000).

The most recent innovation in the formulation of pancreatic enzymes supplements has been the development of enteric-coated "buffered" micro-sphere preparations which have 1.5-2.5 mEq of bicarbonate per capsule. Clinical trials conducted to compare these formulations to standard enteric coated microspheres showed controversy results (Brady & al., 2006; Kalnins & al., 2006).

In Europe, availability of preparations varies by country and they are regulated nationally and not by the European Medicines Agency. In products in which the enzyme content has

**Product example (manufacturer)** 

Pancrelipase capsules (various manufacturers)

6 Pancrelipase tablets (various manufacturers) Vikokase powder (Axcan Scandipharm)

24 Lipram capsules (Global Pharmaceuticals)

Ultrase (Axcan Scandipharm)

3 Creon capsules (Solvay Pharmaceuticals)

Pangestym (Ethex)

3 Pancrecarb (Digestive Care)

7 Pancrease (McNeil)

The uncoated formulations are susceptible to acidic inactivation in the stomach and are currently used largely in clinical practice to treat the pain of chronic pancreatitis and not malabsorption (Chauhan & Forsmark, 2010). The enteric-coated pancreatic enzyme formulations have been developed to solve problems associated with acid-mediated inactivation of pancreatic lipase, especially in patients with EPI who also show low pH values in the small intestine. First generation of these preparations was the enteric coated tablet with diameter of 11-20 mm. Due to their large size, these formulations did not empty into the duodenum as quickly as smaller food particles and did not show any additional benefits over conventional preparations (Meyer & al., 1988; Meyer & Lake, 1997). Next generation of enteric-coated preparations consist of capsules (over 2 mm in size) coated with acid resistant agents designed to release the enzyme between pH 5.0-5.5. No therapeutic benefit of these preparations was seen. Studies of labeled capsules suggest that even with varying sizes of microspheres, the ingested lipid may enter the duodenum in advance of the pancreatic enzyme (Meyer & Lake, 1997). Hence, newer formulations consisting of capsules containing mini-microspheres, pellets or micro-tablets of less than 2 mm in size were designed to promote an adequate intragastric mixture of exogenous enzymes with chyme. Whether the use of these enteric coated mini-microsphere preparations adds any special advantage over the existing treatment options remains, however, subject to great discussion

The most recent innovation in the formulation of pancreatic enzymes supplements has been the development of enteric-coated "buffered" micro-sphere preparations which have 1.5-2.5 mEq of bicarbonate per capsule. Clinical trials conducted to compare these formulations to standard enteric coated microspheres showed controversy results (Brady & al., 2006; Kalnins

In Europe, availability of preparations varies by country and they are regulated nationally and not by the European Medicines Agency. In products in which the enzyme content has

Table 4. Commercially available pancreatic enzyme formulations (adapted from

**Formulation Number of** 

Immediate–release formulations

Enteric-coated microspheres

Enteric-coated microtablets

Enteric-coated minimicrospheres

Enteric-coated microsphere with bicarbonate buffer

Krishnamurty et al., 2009)

(Halm & al., 1999; Stern & al, 2000).

& al., 2006).

**available products** 

been standardized, marked variability in particle size, enzyme release, and for some, acid stability has been noted and may result in differences in clinical effect (Walters & Littlewood, 1996; Aloulou & al., 2008; Löhr & al., 2009). In the United States, marked variation in the enzyme content of the various formulations especially with generic products has been attributed to a lack of stringent regulation (Fieker & al., 2011).

#### **5.2 Dosage recommendation and schedule of administration**

Some general guidelines are given in spite of the absence of an easy applicable and objective method to establish the adequate dose of oral pancreatic enzymes to treat exocrine pancreatic insufficiency.

In general, the recommended dosage of Pancreatic enzyme supplements (PES) for a main meal (breakfast, lunch, or dinner) ranges from 25,000 to 75,000 units of lipase and from 10,000 to 25,000 units of lipase for snacks, depending on the fat content of the meal (Sikkens et al., 2010). Initial dose must ensure supplementation of 60 UI/min of lipase activity in postparandial chyme throughout the digestive period; hence, dosing is adjusted considering this recommendation and the amount of lipase in the supplement (Krishnamurty et al., 2009) but it is not recommended to exceed 10,000 units of lipase per kg of body weight per meal (Fieker et al., 2011).

The timing of ingestion of the capsules is important to optimize therapeutic efficacy. A recent study compared three different administration schedules using enzyme replacement before, during or after meals. Better lipid digestion was found when giving enzymes during or after meals (Dominguez-Munoz & al., 2005).

### **5.3 Efficacy assessment of the treatment with pancreatic enzyme supplements**

Numerous randomized placebo controlled trials have shown that treatment with pancreatic enzyme supplements improves steatorrhea, as measured by increased fat absorption, reduced fecal fat excretion, decreased stool weight and frequency, improved stool consistency and improved symptom scores (Guarner et al., 1993; O'keefe et al., 2001; Dominguez-Munoz et al., 2005; Safdi et al., 2006, Trapnell et al., 2009; Wooldridge et al., 2009; Whitcomb et al., 2010). Enzyme supplements have been found to improve lipid malabsorption in children even those who are younger than 7 years old (Graff et al., 2010a, 2010b). In yet other studies, increased cholesterol absorption and improved enterohepatic cycling of bile salts have been reported (Dutta et al., 1986; Vuoristo et al., 1992). Moreover, it has been demonstrated that improvement of lipid digestion contributes to effective correction of motility disorders (Mizushima et al., 2004). Altered levels of gastro-intestinal hormones were normalized (Nustede et al., 1991); accelerated gastric emptying and abnormal antroduodenal motility were corrected (Layer et al., 1997).

Even though, randomized controlled trials have suggested, years ago, that non-enteric coated pancreatic enzyme supplements reduce pain in chronic pancreatitis (Isaksson et al., 1983; Slaff et al., 1984), a more recent study did not support the use of these preparations for the relief of pain in all patients (Brown et al., 1997). Unfortunately, pancreatic enzyme supplements were reported to be not sufficient for correcting fat soluble vitamin deficiencies or B12 deficiency without simultaneous vitamin supplementation (Dutta et al., 1982; Bang et al., 1991).

Emerging Approaches for the Treatment of

Fat Malabsorption due to Exocrine Pancreatic Insufficiency 283

Table 5. Adverse Events (Preferred Term) Recorded for Pancreatic Enzyme Preparations in the Axcan Pharma Safety Database Classified by System Organ Class from November 1, 2008, to May 31, 2009 (Reproduced from Page 8 of the Safety Update for NDA 22-222 dated

August 4, 2009).

The most surprising fact regarding efficacy assessment of this therapy is that few investigations are made considering nutritional status and quality of life improvements as well as weight gain (Czako et al., 2003; Trolli et al., 2001; Dominguez-Munoz, 2007). Reduction in stool fat achieved by pancreatic enzyme replacement therapy has not been proven by robust research to be correlated with a complete correction of nutritional deficiency in patients with pancreatic insufficiency. Accordingly, an overall assessment of this therapy efficacy is yet dependent on future demonstration of long-term interesting outcomes.
