12.3 Pharmacokinetics The pancreatic enzymes in ULTRESA are enteric-coated to minimize destruction or inactivation in gastric acid. ULTRESA is designed to release most of the enzymes in vivo at pH greater than 5.5. Pancreatic enzymes are not absorbed from the gastrointestinal tract in appreciable amounts.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicity, genetic toxicology, and animal fertility studies have not been performed with pancrelipase.

14 CLINICAL STUDIESThe short-term efficacy and safety of ULTRESA were eva luated in 2 studies conducted in 40 patients, ages 7 to 37 years, with exocrine pancreatic insufficiency associated with cystic fibrosis.

Study 1 was a randomized, double-blind, placebo-controlled, crossover study of 31 patients, ages 8 to 37 years, with exocrine pancreatic insufficiency due to cystic fibrosis. The final analysis population was limited to 24 patients, who completed both treatment periods and had stool results available for each treatment period. Patients were randomized to receive ULTRESA (at a dose not to exceed 2,500 lipase units per kilogram per meal or snack) or matching placebo for 6 to 7 days of treatment followed by crossover to the alternate treatment for an additional 6 to 7 days. The mean dose during the controlled treatment periods was 6,270 lipase units per kilogram per day. All patients consumed a high-fat diet (2 grams of fat per kilogram of body weight per day) during the treatment periods.

The coefficient of fat absorption (CFA) was determined by a 72-hour stool collection during both treatments, when both fat excretion and fat ingestion were measured. Each patient’s CFA during placebo treatment was used as their no-treatment CFA value.

Mean CFA was 89% with ULTRESA treatment compared to 56% with placebo treatment. The mean difference in CFA was 35 percentage points in favor of ULTRESA treatment with 95% CI: (25, 45) and p<0.0001.

Subgroup analyses of the CFA results showed that mean change in CFA was greater in patients with lower no-treatment (placebo) CFA values than in patients with higher no-treatment (placebo) CFA values. There were similar responses to ULTRESA by age and gender.

The coefficient of nitrogen absorption (CNA) was determined by a 72 hour stool collection during both treatments, when nitrogen excretion was measured and nitrogen ingestion from a controlled diet was estimated (based on the assumption that proteins contain 16% nitrogen). Each patient’s CNA during placebo treatment was used as their no treatment CNA value.

In Study 1, mean CNA was 84% with ULTRESA treatment compared to 59% with placebo treatment. The mean difference in CNA was 26 percentage points in favor of ULTRESA treatment with 95% CI: (18, 33) and p<0.0001.

Study 2 was an open-label study of 9 patients, ages 7 years to 11 years (mean 10 years), with exocrine pancreatic insufficiency due to cystic fibrosis. The final analysis population was limited to 7 patients who completed both the washout and treatment phases of the study. After a 15 day screening period on individually-titrated doses of ULTRESA not to exceed 2,500 lipase units per kilogram per meal, patients in Study 2 entered a 7-day washout phase (no treatment) before returning to a