Prepopik - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Prepopik - Scientific Information

Manufacture: Ferring Pharmaceuticals
Country: United States
Condition: Bowel Preparation
Class: Laxatives
Form: Liquid solution, Powder
Ingredients: sodium picosulfate, magnesium oxide, anhydrous citric acid, otassium hydrogen carbonate, saccharin sodium, orange flavor which contains acacia gum, lactose, ascorbic acid and butylated hydroxyanisole or the cranberry flavor which contains maltodextrin, glyceryl triacetate (triacetin) and sodium octenyl succinated starch

Description

Prepopik (sodium picosulfate, magnesium oxide and anhydrous citric acid) for oral solution is available in 2 flavors, orange and cranberry flavor, and is provided in two packets. The contents of each is to be dissolved in 5 ounces of cold water and consumed.

Each packet for both flavors contains 10 mg sodium picosulfate, 3.5 g magnesium oxide and 12 g anhydrous citric acid. The product also contains the following inactive ingredients: potassium hydrogen carbonate, saccharine sodium and orange or cranberry flavors. The orange flavor contains acacia gum, lactose, ascorbic acid and butylated hydroxyanisole, and the cranberry flavor contains maltodextrin, glyceryl triacetate (triacetin) and sodium octenyl succinated starch. The following is a description of the three active ingredients:

Sodium picosulfate is a stimulant laxative.

Sodium picosulfate

  • Chemical name: 4,4´-(2-pyridylmethylene) diphenyl bis(hydrogen sulfate) disodium salt, monohydrate
  • Chemical formula: C18H13NNa2O8S2.H2O
  • Molecular weight: 499.4
  • Structural formula:
  • Sodium picosulfate

Magnesium citrate, which is formed in solution by the combination of magnesium oxide and anhydrous citric acid, is an osmotic laxative.

Magnesium oxide

  • Chemical name: Magnesium oxide
  • Chemical formula: Mg O
  • Molecular weight: 40.3
  • Structural formula: Mg O

Anhydrous citric acid

  • Chemical name: 2-hydroxypropane-1,2,3-tricarboxylic acid
  • Chemical formula: C6H8O7
  • Molecular weight: 192.1
  • Structural formula:

Anhydrous citric acid

Clinical Pharmacology

Mechanism of Action

Sodium picosulfate is hydrolyzed by colonic bacteria to form an active metabolite: bis-(p-hydroxy-phenyl)-pyridyl-2-methane, BHPM, which acts directly on the colonic mucosa to stimulate colonic peristalsis.

Magnesium oxide and citric acid react to create magnesium citrate in solution, which is an osmotic agent that causes water to be retained within the gastrointestinal tract.

Pharmacodynamics

The stimulant laxative activity of sodium picosulfate together with the osmotic laxative activity of magnesium citrate produces a purgative effect which, when ingested with additional fluids, produces watery diarrhea.

Pharmacokinetics

Sodium picosulfate, which is a prodrug, is converted to its active metabolite, BHPM, by colonic bacteria. After administration of 2 packets of Prepopik separated by 6 hours, in 16 healthy volunteers, sodium picosulfate reached a mean Cmax of 3.2 ng/mL at approximately 7 hours (Tmax). After the first packet the corresponding values were 2.3 ng/mL at 2 hours. The terminal half-life of sodium picosulfate was 7.4 hours. The fraction of the absorbed sodium picosulfate dose excreted unchanged in urine was 0.19%. Plasma levels of the free BHPM were low, with 13 out of 16 subjects studied having plasma BHPM concentrations below the lower limit of quantification (0.1 ng/mL). Urinary samples show that the majority of excreted BHPM was in the glucuronide-conjugated form. Magnesium oxide and citric acid react in water to create magnesium citrate. Baseline uncorrected magnesium concentration reached a maximum (Cmax) of approximately 1.9 mEq/L, which occurred at 10 hours post initial packet administration (Tmax). This represents an approximately 20% increase from the baseline.

Drug Interaction Studies

In an in vitro study using human liver microsomes, sodium picosulfate did not inhibit the major CYP enzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4/5) evaluated. Based on an in vitro study using freshly isolated hepatocyte culture, sodium picosulfate is not an inducer of CYP1A2, CYP2B6 or CYP3A4/5.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Prepopik. However, sodium picosulfate was not mutagenic in the Ames test, the mouse lymphoma assay and the mouse bone marrow micronucleus test.

In an oral fertility study in rats, Prepopik did not cause any significant adverse effect on male or female fertility parameters up to a maximum dose of 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on the body surface area).

Clinical Studies

The colon cleansing efficacy of Prepopik was evaluated for non-inferiority against a comparator in two randomized, investigator-blinded, active-controlled, multicenter US trials in patients scheduled to have an elective colonoscopy. In all, 1195 adult patients were included in the primary efficacy analysis: 601 from Study 1, and 594 from Study 2. Patients ranged in age from 18 to 80 years (mean age 56 years); 61% were female and 39% male. Self-identified race was distributed as follows: 90% White, 10% Black, and less than 1% other. Of these, 3% self-identified their ethnicity as Hispanic or Latino.

Patients randomized to Prepopik in the two studies were treated with one of two dosing regimens:

  • In Study 1, Prepopik was given by "Split-Dose" (evening before and day of) dosing, where the first packet was taken the evening before the colonoscopy (between 5:00 and 9:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second packet was taken the morning of the colonoscopy (at least 5 hours prior to but no more than 9 hours prior to colonoscopy), followed by three (3) 8-ounce glasses of clear liquid.
  • In Study 2, Prepopik was given by "Day-Before" (afternoon/evening before only) dosing, where both packets were taken separately on the day before the colonoscopy, with the first packet taken in the afternoon (between 4:00 and 6:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second packet taken in the late evening (approximately 6 hours later, between 10:00 PM and 12:00 AM), followed by three (3) 8-ounce glasses of clear liquid.

The comparator was a preparation containing two liters of polyethylene glycol plus electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets, administered the day before the procedure. All patients in both the Prepopik and comparator groups were limited to a clear liquid diet on the day before the procedure (24 hours before).

The primary efficacy endpoint was the proportion of patients with successful colon cleansing, as assessed by blinded colonoscopists using the Aronchick Scale. The Aronchick scale is a tool used to assess overall colon cleansing. Successful colon cleansing was defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool that were graded excellent (minimal suctioning needed for adequate visualization) or good (significant suctioning needed for adequate visualization) by the colonoscopist.

In both studies, Prepopik was non-inferior to the comparator. In addition, Prepopik provided by Split-Dose dosing met the pre-specified criteria for superiority to the comparator for colon cleansing in Study 1. The comparator in that study was administered entirely on the day prior to colonoscopy. See Tables 1 and 2 below.

Table 1: Proportion of Patients with Successful Colon Cleansing in Study 1 Split-Dose Regimen
PREPOPIK
Split-Dose Regimen
2L PEG+E*
with 2 × 5-mg bisacodyl tablets
Difference between treatment groups
% (n/N) % (n/N) Difference 95% CI
84.2% (256/304) 74.4% (221/297) 9.8% (3.4%, 16.2%)

* 2L PEG + E = two liters polyethylene glycol plus electrolytes solution.
Non-inferior and superior 2L PEG+E with 2 × 5-mg bisacodyl tablets

Table 2: Proportion of Patients with Successful Colon Cleansing in Study 2 Day-Before Regimen
PREPOPIK
Day-Before Regimen
2L PEG+E*
with 2 × 5-mg bisacodyl tablets
Difference between treatment groups
% (n/N) % (n/N) Difference 95% CI
83.0% (244/294) 79.7% (239/300) 3.3% (-2.9%, 9.6%)

* 2L PEG + E = two liters polyethylene glycol plus electrolytes solution.
Non-inferior