Exocrine Pancreatic Insufficiency Induced by Immune Checkpoint Inhibitors.

BACKGROUND: Scant data describe exocrine pancreatic insufficiency (EPI) secondary to immune checkpoint inhibitor (ICI) use. The goal of this study is to describe the incidence, risk factors, and clinical characteristics of patients with ICI-related EPI. PATIENTS AND METHODS: A single center, retrospective case-control study was performed of all ICI-treated patients at Memorial Sloan Kettering Cancer Center between January 2011 and July 2020. ICI-related EPI patients had steatorrhea with or without abdominal discomfort or weight loss, started pancrelipase after initiation of ICI, and demonstrated symptomatic improvement with pancrelipase. Controls were matched 2:1 by age, race, sex, cancer type, and year of ICI start. RESULTS: Of 12 905 ICI-treated patients, 23 patients developed ICI-related EPI and were matched to 46 controls. The incidence rate of EPI was 1.18 cases per 1000 person-years and the median onset of EPI was 390 days after the first dose of ICI. All 23 (100%) EPI cases had steatorrhea that improved with pancrelipase, 12 (52.2%) had weight loss, and 9 (39.1%) had abdominal discomfort; none had changes of chronic pancreatitis on imaging. Nine (39%) EPI patients had episodes of clinical acute pancreatitis preceding the onset of EPI, compared to 1 (2%) control (OR 18.0 (2.5-789.0), P < .001). Finally, the EPI group exhibited higher proportions of new or worsening hyperglycemia after ICI exposure compared with the control group (9 (39.1%) vs. 3 (6.5%), P < .01). CONCLUSION: ICI-related EPI is a rare but clinically significant event that should be considered in patients with late onset diarrhea after ICI treatment and often is associated with development of hyperglycemia and diabetes.

Effect of Pancrelipase Therapy on Exocrine Pancreatic Insufficiency Symptoms and Coefficient of Fat Absorption Associated With Chronic Pancreatitis.

OBJECTIVE: The aim of this study was to evaluate whether improvement in coefficient of fat absorption (CFA) with pancreatic enzyme replacement therapy correlates with clinical symptoms in patients with chronic pancreatitis with moderate to severe exocrine pancreatic insufficiency. METHODS: Data were pooled from 2 randomized double-blind trials of the effects of 1 week of pancrelipase (n = 59) versus placebo (n = 57) on CFA and stool frequency, stool consistency, abdominal pain, and flatulence; 1 trial included a 51-week open-label pancrelipase treatment period (n = 34). RESULTS: Compared with placebo, significantly more patients receiving pancrelipase reported decreased stool frequency at week 1 (72% vs 38%; P < 0.001). Although 30% of patients receiving pancrelipase and 20% receiving placebo reported improved stool consistency, changes in stool consistency, abdominal pain, and flatulence were not different between groups. Mean CFA absolute change from baseline was significantly greater with pancrelipase versus placebo (24.7% vs 6.4%; P < 0.001). Improvements in stool consistency and frequency correlated with CFA improvement. Symptom improvements persisted or further improved through 52 weeks of treatment. CONCLUSIONS: Pancrelipase significantly improved exocrine pancreatic insufficiency maldigestive symptoms. Improvements in objective stool symptoms with pancreatic enzyme replacement therapy correlated with CFA improvement at 1 week.

Pancreas exocrine replacement therapy is associated with increased survival following pancreatoduodenectomy for periampullary malignancy.

BACKGROUND: Although many patients undergoing pancreatoduodenectomy (PD) for cancer have pancreatic exocrine insufficiency, pancreatic enzyme replacement therapy (PERT) is not routinely used, and effects upon post-operative survival are unclear. METHODS: This review of patients undergoing PD for periampullary malignancy sought to test for an association between PERT and overall survival, with post-hoc subgroup analysis performed after stratifying patients by the year of surgery, pancreatic duct width and tumour type. RESULTS: Some 202/469 (43.1%) patients received PERT. After accounting for pathological variables and chemotherapy, PERT use was found to be independently associated with improved survival on multivariable analysis [HR 0.72 (95% CI: 0.52-0.99), p = 0.044] and on propensity matched analysis (p = 0.009). The effect of PERT upon improved survival was predominantly observed amongst patients with a dilated pancreatic duct (≥3 mm). DISCUSSION: PERT use was independently associated with improved survival following PD for cancer. The validity of this observation is supported by an effect largely confined to those patients with a dilated pancreatic duct. The nutritional status of patients undergoing PD for cancer needs further investigation and the effects of PERT require verification in further clinical studies.

Preliminary report of the (13)C-mixed triglyceride breath test to assess timing of pancreatic enzyme replacement therapy in children with cystic fibrosis.

BACKGROUND: Despite guidelines suggesting pancreatic enzyme replacement therapy (PERT) should be taken before or during a meal, it is currently unknown whether this has benefits over administration after a meal in individuals with cystic fibrosis (CF). METHODS: 18 children with pancreatic insufficient CF were randomised to two (13)C-mixed triglyceride ((13)C-MTG) breath tests to assess lipase activity with PERT administered 10min before and 10min after a meal. Results were expressed as percentage cumulative dose recovered (PCDR) of (13)CO2 and were compared with established values in healthy subjects. Gastric half emptying time (T½) was also assessed by a (13)C-octanoate breath test. RESULTS: There was no difference in mean PCDR of (13)CO2 between taking PERT before versus after the meal (p=0.68). Eleven subjects had a greater PCDR when PERT was taken before and 7 when PERT was taken after the meal. 6/8 subjects (75%) with a lower than normal PCDR at one time point normalised PCDR when PERT timing was changed. When PERT was taken after the meal, PCDR was higher in normal vs. fast T½ (p=0.04). CONCLUSIONS: Changing PERT timing can result in normalised lipase activity. Gastric emptying rate may influence optimal timing of PERT. Clinical Trial Registration Number - This study was undertaken prior to the registration process being a commonly required practice.

Comparison of two pancreatic enzyme products for exocrine insufficiency in patients with cystic fibrosis.

BACKGROUND: Zenpep (APT-1008) is a pancreatic enzyme product for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF). METHODS: Zenpep and Kreon, both containing 25,000 lipase units, were compared in a randomised, double-blind, crossover, non-inferiority study for CF-associated EPI in patients aged ≥12years. Patients on a standardised diet and stabilised treatment were randomised to two treatment sequences: Zenpep/Kreon or Kreon/Zenpep. The primary efficacy endpoint was the coefficient of fat absorption over 72h (CFA-72h). RESULTS: 96 patients (mean age 19.2years, 60.4% males) were randomised with 83 completers of both sequences comprising the efficacy population. Zenpep demonstrated non-inferiority and equivalence to Kreon in fat absorption (LS mean CFA-72h: Zenpep, 84.1% [SE 1.1] vs. Kreon, 85.3% [SE 1.1]; p=0.297). Safety and tolerability were similar. CONCLUSIONS: Zenpep is comparable with Kreon in efficacy and safety for the treatment of adolescents and adults with CF-associated EPI. NCT01641393.

Efficacy and Safety of Pancrelipase/Pancreatin in Patients With Exocrine Pancreatic Insufficiency and a Medical History of Diabetes Mellitus.

OBJECTIVES: The aim of this study was to perform exploratory analyses of the efficacy and safety of pancrelipase delayed-release capsules (Creon) in patients with exocrine pancreatic insufficiency (EPI) with (n = 36) and without (n = 18) concurrent diabetes mellitus (DM). METHODS: This was a retrospective, post hoc, subgroup (±DM) analysis of a double-blind, randomized, placebo-controlled trial of pancrelipase in patients with EPI due to chronic pancreatitis or pancreatectomy (total or partial). After a 5-day placebo run-in period (baseline), patients were randomized to pancrelipase (72,000 lipase units/meal, 36,000/snack) or placebo for 7 days. Outcomes included changes in coefficients of fat absorption (CFA) and nitrogen absorption (CNA) from baseline to the end of the double-blind period. RESULTS: Mean changes in nutrient absorption were greater with pancrelipase versus placebo in patients with DM (CFA, 36.0% vs 7.5%, P < 0.0001; CNA, 33.4% vs 3.7%, P = 0.0002) and without DM (CFA, 25.2% vs 12.3%, P = 0.0326; CNA, 39.1% vs 17.6%, P = 0.1187). Diabetes mellitus was not significantly associated with outcomes for CFA (P = 0.0802) and CNA (P = 0.2934). Incidences of adverse events, including hypoglycemia and hyperglycemia, were similar in the pancrelipase and placebo arms. CONCLUSIONS: Pancrelipase improved fat and protein absorption in patients with EPI due to chronic pancreatitis or pancreatectomy, with or without DM, and matched the safety profile previously reported.

Administration of Pancrelipase as Effective Treatment for Hepatic Steatosis After Pancreatectomy.

OBJECTIVES: To evaluate the incidence of hepatic steatosis after pancreatectomy and whether pancrelipase improves steatosis more effectively than other conventional digestive enzymes. METHODS: Patients who underwent distal pancreatectomy, pancreaticoduodenectomy (PD), or total pancreatectomy (TP) from August 2008 to July 2013 were included. Incidence of newly developed hepatic steatosis recognized by computed tomography and outcomes by treatment with pancrealipase or other enzymes were evaluated. RESULTS: A total of 473 patients were evaluated. Among 366 patients who did not take any digestive enzymes until the recognition of steatosis or the last follow-up date, hepatic steatosis was recognized in 3% (4/130), 17% (38/229), and 45% (3/7) of patients after distal pancreatectomy, PD, and TP, respectively, during the median follow-up of 641 days. Seventy patients including 25 patients taking digestive enzymes showed hepatic steatosis and were treated with pancrelipase (20 patients), other enzymes (19 patients), or no enzyme (31 patients). Cumulative improvement rate after 1 year of treatment in the 3 groups was 92%, 51%, and 56%, respectively, and that of the pancrelipase group was significantly better than the other 2 groups. CONCLUSION: The risk of hepatic steatosis should be a concern after PD and TP. Treatment with pancrelipase was more effective compared to other enzymes.

Dependence of PERT endpoint on endogenous lipase activity.

OBJECTIVE: To clarify and to understand the potential for misinterpretation of change in fecal fat quantitation during pancreatic enzyme replacement therapy (PERT) trials for treatment of exocrine pancreatic insufficiency. METHODS: Analysis of clinical trials submitted to the U.S. Food and Drug Administration (FDA) for approval of PERT that enrolled 123 cystic fibrosis adult and pediatric patients treated with Creon, Pertzye, Ultresa, and Zenpep. RESULTS CONCLUSIONS: The CFA% defines lipase activity as a percentage of converting substrate of "Total Daily Dietary Fat Intake." PERT trials performed to date have modified the definition to converting the "Shared Daily Fat Intake," generating "Partial CFA" for the exogenous lipase: the higher the activity of coexisting endogenous lipase, the lower the "Partial CFA" of exogenous measured. This review shows that "Partial CFA" is not CFA. Enrollment of patients with low HPLA during treatment may improve the interpretability of "Partial CFA" measured by PERT trials.

Long-term experience with ZENPEP in infants with exocrine pancreatic insufficiency associated with cystic fibrosis.

The objective of our study was to determine whether infants with cystic fibrosis who developed exocrine pancreatic insufficiency in early infancy would tolerate long-term treatment with ZENPEP (pancrelipase) delayed-release capsules, containing 3000 US Pharmacopeia units of lipase/capsule, and demonstrate consistent long-term growth. The most common treatment-emergent adverse events were diarrhea, vomiting, and constipation (mild or moderate). At study completion, median weight-for-age percentiles increased from 22nd to 49th, median length-for-age percentiles increased from 36.5th to 42nd, and median weight-for-length percentiles increased from 41.5th to 55.5th. Long-term treatment (up to 12 months) of infants with exocrine pancreatic insufficiency owing to cystic fibrosis with ZENPEP was well tolerated and associated with improved growth parameters. This is the first long-term study of pancreatic enzyme replacement therapy conducted in this patient population.

Randomised clinical trial: the efficacy and safety of pancreatin enteric-coated minimicrospheres (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis--a double-blind, placebo-controlled study.

BACKGROUND: Pancreatic exocrine insufficiency (PEI) results in maldigestion, leading to abdominal pain, steatorrhoea, malnutrition and weight loss. AIM: To assess the efficacy and safety of pancreatin (Creon 40000 MMS) in treating PEI due to chronic pancreatitis (CP). METHODS: This was a 1-week, double-blind, randomised, placebo-controlled, parallel-group, multicentre study in India. Men and women ≥18 years of age with proven CP and PEI [defined as a coefficient of fat absorption (CFA) ≤80% during run-in phase] were randomised 1:1 to pancreatin or placebo (two capsules orally per main meal, one with snacks). The primary outcome measure was change in CFA from baseline to end of double-blind treatment (analysis of covariance). RESULTS: Of 62 patients randomised (34 pancreatin, 28 placebo), 61 completed treatment; one patient in the placebo arm withdrew consent before completion. Patient characteristics were similar in both groups except for the proportion of men (pancreatin 82% vs. placebo 68%). Patients receiving pancreatin had a statistically significant greater improvement in fat absorption from baseline to the end of double-blind treatment compared with those receiving placebo, with a least squares mean change (95% CI) in CFA of 18.5% (15.8-21.2) vs. 4.1% (1.0-7.2), respectively. This resulted in a treatment difference of 14.4% (10.3-18.5); P = 0.001. Patients receiving pancreatin also had a statistically significant greater improvement in nitrogen absorption and greater reductions in mean stool fat, stool frequency and stool weight compared with those receiving placebo. Treatment-emergent adverse events occurred in 12 patients on pancreatin and in seven on placebo; none led to study discontinuation. CONCLUSIONS: The results provide evidence for the efficacy of pancreatin (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis, and confirm that this formulation is well tolerated, with a good safety profile, at the dose administered.

Efficacy and safety of PANCREAZE® for treatment of exocrine pancreatic insufficiency due to cystic fibrosis.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is critical for correction of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF). METHODS: This was a randomized, placebo-controlled PERT withdrawal study evaluating the efficacy and safety of PANCREAZE® (pancrelipase) in CF patients with EPI. Participants (n=49) entered an open-label, ≤ 14 day run-in phase, maintained a high-fat diet (100 ± 15 g/day), and received PANCREAZE® (10.5 or 21). Participants with a coefficient of fat absorption (CFA)≥ 80% (n=40) were then randomized (1:1) to receive either PANCREAZE® or placebo during a double-blind, ≤ 7 day withdrawal phase. RESULTS: PANCREAZE® improved fat absorption as shown by significantly lower mean ± SD change in CFA between open-label and double-blind phases for PANCREAZE® (-1.5 ± 5.88%; p<0.001) compared to placebo (-34.1 ± 23.03%). Protein absorption was similarly improved. No unexpected adverse events were reported. CONCLUSIONS: This study demonstrated PANCREAZE® was effective in treating EPI due to CF and was safe and well tolerated.

Treatment of infants and toddlers with cystic fibrosis-related pancreatic insufficiency and fat malabsorption with pancrelipase MT.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) improves nutritional status and growth in patients with cystic fibrosis (CF) with pancreatic insufficiency (PI). The current recommendation for infants and young children, who are not able to swallow the whole capsule, is to open the capsule and mix the beads in a spoon with some applesauce; however, the efficacy and safety data of this approach are currently lacking. The aim of this study was to assess the efficacy, palatability (ease of swallowing), and safety of 4 dose levels of pancrelipase microtablets (Pancrease MT) in infants and young children with CF-related PI. PATIENTS AND METHODS: This study was a phase II randomized, investigator-blinded, parallel-group pilot study in DNA-proven infants with CF and PI. The study design included a run-in period (days 1-5) and an experimental period (days 6-11). Pancrelipase microtablets (2-mm, enteric coated) were provided orally. Sixteen subjects, 6 to 30 months of age, were provided 500 U lipase/kg/meal for 5 days (baseline period). Subsequently, subjects were randomly assigned to 1 of 4 treatment groups (each n = 4), receiving 500, 1000, 1500, or 2000 U (Ph. EUR) of lipase/kg/meal, respectively, for 5 days (experimental period). The primary endpoint was medication efficacy assessed by the 72-hour fecal fat excretion, expressed as coefficient of fecal fat absorption (CFA), and 13C mixed triglyceride breath test. Secondary endpoints were safety and palatability. RESULTS: Overall compliance, defined as used study medication, was 89% to 99% for the entire study. None of the 4 dose regimens significantly influenced the CFA, relative to the baseline period (median range 83%-93%). During the run-in period the median cumulative % 13C was 11 (range -8 to 59). After randomization the median cumulative % 13C was 18 (range 14-23) in the 500-U, 14 (range -1 to 17) in the 1000-U, 10 (range 10-27) in the 1500-U, and 3 (range 1-49) in the 2000-U groups. Palatability was scored fair to good by the parents in each of the treatment groups. Gastrointestinal symptoms were reported in some patients, including common adverse events reported in clinical trials involving pancreatic enzyme therapy. No serious or other adverse events were reported. CONCLUSION: Treatment with Pancrease MT at a dosage of 500 U lipase/kg/meal resulted in a CFA of approximately 89% in pediatric subjects ages 6 to 30 months with PI resulting from CF. Pancrease MT doses were well tolerated and mean palatability was scored as fair to good. Present results do not indicate that a dosage higher than 500 U (Ph. EUR) lipase/kg/meal increases the coefficient of fat absorption in a cohort of infants 6 to 30 months of age.

Pancreatic enzyme products: digesting the changes.

OBJECTIVE: To review the pharmacology, dosage regimens, efficacy, and safety of currently marketed pancreatic enzyme products (PEPs). DATA SOURCES: Studies were identified by PubMed (1966-January 2011), clinicaltrials.gov, fda.gov, and International Pharmaceutical Abstracts. Search terms included pancreatic enzyme, lipase, Creon, Zenpep, Pancreaze, and exocrine pancreatic insufficiency (EPI). STUDY SELECTION AND DATA EXTRACTION: All human studies evaluating the efficacy of currently approved or potential PEPs were reviewed. DATA SYNTHESIS: PEPs are composed of porcine lipase, amylase, and protease and are used in patients with EPI secondary to cystic fibrosis, chronic pancreatitis, and pancreatectomy. In 1938, PEPs were exempted from the Food, Drug, and Cosmetic Act of 1938 and never underwent a formal Food and Drug Administration (FDA) review process. In response to reports of treatment failures during product interchange, the FDA conducted a review of available PEP products. This review found a large variability of response between the unapproved PEP products, which resulted in the FDA requiring approval of all PEP products by April 2010. The 3 delayed-release, enteric-coated PEPs currently approved by the FDA (Creon, Zenpep, and Pancreaze) have demonstrated efficacy and safety in EPI secondary to cystic fibrosis. Creon has also demonstrated safety and efficacy in EPI secondary to chronic pancreatitis and pancreatectomy. Cost difference between the 3 products is minimal. Treatment-related adverse events in clinical studies for all PEPs were less than or similar to those with placebo. CONCLUSIONS: At this time, Creon is an appropriate first-line agent, as it has been approved for chronic pancreatitis, pancreatectomy, and cystic fibrosis.

Efficacy of a novel pancreatic enzyme product, EUR-1008 (Zenpep), in patients with exocrine pancreatic insufficiency due to chronic pancreatitis.

OBJECTIVES: EUR-1008 (ZENPEP® [pancrelipase] Delayed-Release Capsules) delayed-release capsules is a novel, enteric-coated, porcine-derived pancreatic enzyme product. This study evaluated the efficacy and safety of 2 doses of ZENPEP in patients with chronic pancreatitis (CP) and exocrine pancreatic insufficiency (EPI). METHODS: The effect of ZENPEP on the coefficient of fat absorption (CFA) was investigated in a randomized, double-blind, dose-response, crossover study with placebo run-in (7-9 days) and 2 treatment periods (9-11 days) composed of a high dose (7 × 20,000 lipase units per day) and a low dose (7 × 5000 lipase units per day). RESULTS: Mean CFA was significantly higher with low- (88.9%) and high-dose (89.9%) ZENPEP versus placebo run-in (82%; P < 0.001; n = 72) with no difference between doses (P = 0.228, primary end point). In patients with baseline CFA less than 90% (n = 33), the high dose was significantly more effective (CFA: 84.1%) than the low dose (CFA: 81.1%; P < 0.001). Post hoc analysis revealed an increase in treatment effect with more severe EPI. Coefficient of nitrogen absorption (P < 0.001), body weight (P ≤ 0.021), and body mass index (P ≤ 0.020) also increased significantly with both doses compared with baseline. Percentage of days with EPI symptoms decreased with both doses. CONCLUSIONS: Our findings suggest that CP patients with EPI benefit from a low dose of ZENPEP, whereas the high dose might be needed for patients with more severe EPI.

[Efficacy and safety of pancrealipase delayed-release capsules (Creon) in patients with pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery].

In the article design, objectives, methods of conducting double-blind, randomized study which results prove efficacy and safety of new formulation of Creon are presented.

Safety and tolerability of a new formulation of pancrelipase delayed-release capsules (CREON) in children under seven years of age with exocrine pancreatic insufficiency due to cystic fibrosis: an open-label, multicentre, single-treatment-arm study.

Exocrine pancreatic insufficiency (EPI) is a deficiency of digestive enzymes caused by diseases such as cystic fibrosis (CF). Patients with EPI due to CF require pancreatic enzyme replacement therapy (PERT) in order to maintain adequate nutrition. A new formulation of pancrelipase delayed-release capsules (CREON) recently received US FDA approval and has demonstrated efficacy and safety in patients with CF aged > or =7 years. The objectives of this study were to observe the safety and tolerability of new formulation pancrelipase delayed-release capsules (study drug) versus the standard of care PERT (standard therapy) in children aged <7 years with CF and EPI. Secondary objectives were to assess the ease of accurate dosing of study drug, monitor clinical symptoms and compare the efficacy of both treatments. This was an open-label, multicentre, single-treatment-arm study in children aged <7 years with a confirmed diagnosis of CF and EPI. After the screening period (approximately 14 days), all patients entered a 3-day assessment period on their usual PERT (standard therapy), followed by the study drug treatment phase (10-14 days; target dose 8000 lipase units/kg bodyweight/day), which included a second 3-day assessment period. The safety and tolerability of both treatments were documented by recording adverse events (AEs). Clinical symptoms (mean daily stool frequency, abdominal pain, stool consistency and flatulence) were monitored and ease of accurate dosing, as judged by caregivers, was reported. Efficacy was determined by comparison of percent stool fat in spot stool samples collected during both 3-day assessment periods. Of the 19 patients who had informed consent from their parent/legally acceptable representative, one was withdrawn as a screen failure and was excluded from the safety and efficacy analyses; thus, 18 patients completed the study. The median age (range) was 23 (4-71) months and 13 (72%) were male. During study drug treatment, patients received a mean +/- SD dose in lipase units/kg bodyweight/day of 7542 +/- 1335 versus 6966 +/- 3392 on standard therapy. Overall, nine (50%) patients had at least one treatment-emergent AE (TEAE) whilst receiving either treatment. All TEAEs in this study were reported as mild and none resulted in patient discontinuation. The caregivers had a slight preference for study drug over standard therapy in terms of ease of accurate dosing: six (33.3%) caregivers thought the study drug was easier to dose while only one (5.6%) thought the study drug was harder to dose than standard therapy. Clinical symptom assessment results were similar between treatments. There was no clinically meaningful difference (significance not tested) between study drug and standard therapy in the mean +/- SD percent of stool fat: 28.1 +/- 9.9 and 27.9 +/- 8.9, respectively. In this study in children aged <7 years with EPI due to CF, the new formulation pancrelipase delayed-release capsules (CREON) were clinically comparable with standard therapy in terms of safety, tolerability and efficacy.