Impact of Metformin and Polysorbate 80 on Drug Absorption and Disposition

The study employs two-sub-studies that share a common placebo arm.

The objective of one sub-study is to assess the impact of metformin on pravastatin and chenodeoxycholic acid pharmacokinetics. We hypothesize that metformin represses the bile salt export pump (BSEP) in the liver, which excretes pravastatin and chenodeoxycholic acid from the liver into the bile.

The objective of the other sub-study is to assess the impact of polysorbate 80 on valacyclovir, chenodeoxycholic acid, and enalaprilat pharmacokinetics. We hypothesize that polysorbate 80 inhibits uptake transporters in the intestine, which absorb valacyclovir and chenodeoxycholic acid in the gut via the peptide transporter 1 (PepT1) and apical sodium-bile acid transporter (ASBT), respectively. Enalaprilat is passively absorbed but with low permeability, and thus serves as a passive absorption reference.

Study Overview

• Status: Completed
• Conditions: Bile Salt Export Pump (BSEP) Transporter; Polysorbate 80
• Intervention / Treatment: Drug: pravastatin and chenodeoxycholic acid, after metformin and placebo; Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Subject is healthy, as determined by screening evaluation that is not greater than 60 days before the first study visit.
• Subject is male or female between 18 and 65 years of age, inclusive.
• Subject is an acceptable candidate for venipuncture.
• Subject is willing to stop all non-routine OTC medications, as well as vitamins, dietary supplements, and herbals, for 24 hours prior to study drug administration and during pharmacokinetic study visits.

Exclusion Criteria:

• Subject has a significant medical disease (including cardiovascular, pulmonary, hematologic, endocrine, immunologic, neurologic, renal, gastrointestinal, metabolic, or psychiatric).
• Subject has a clinically significant history or presence of any clinically significant gastrointestinal pathology (e.g. chronic diarrhea, inflammatory bowel diseases), unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting), liver or kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism or excretion of study drugs.
• Subject has a history of liver or gallbladder disease, or history of myopathy
• Subject has a history of angioedema either with or without previous treatment with an angiotensin converting enzyme inhibitor.
• Subject was previously diagnosed with diabetes, or treated with antidiabetic agents
• Subject has a history of alcohol or drug abuse, which in the opinion of the PI or medical physician, could jeopardize the subject's health or would compromise the subject's ability to participate in this trial.
• Subject is pregnant, breast feeding, or trying to become pregnant.
• Female subject of childbearing potential is unwilling or unable to use a medically acceptable method of contraception throughout the entire study period and for one week after the study is completed. Medically acceptable methods of contraception that may be used by the subject and/or her partner are: oral birth control pill, condom with spermicide, diaphragm with spermicide, IUD, vaginal spermicidal suppository, surgical sterilization of patient or their partner(s), abstinence, or hormonal-based patches, ring, injections, and implants.
• Subject routinely uses (i.e. daily or weekly) prescription medication except hormonal birth control medication, routinely uses (i.e. daily or weekly) OTC medication, or routinely uses niacin to treat hypercholesterolemia. OTC medications do not include vitamins, dietary supplements, or herbals.
• Subject routinely uses (i.e. daily or weekly) acid blockers, antacids, anti-diarrhea, stimulants, appetite suppressants, or anti-nausea medication or other drugs that modulate GI function.
• Subject is currently taking metformin, valacyclovir, acyclovir, chenodiol, pravastatin, enalapril, enalaprilat, or medications known to interact with any of these medications.
• Subject has a history or allergy or sensitivity to metformin, valacyclovir, acyclovir, chenodiol, pravastatin, polysorbate 80, enalapril, enalaprilat, or history of any drug hypersensitivity or intolerance which, in the opinion of the PI or medical physician, would compromise the safety of the subject or the study.
• Subject has liver impairment as assessed by alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels greater than the upper limit of normal (ULN).
• Subject has renal impairment as assessed by creatinine clearance lower than 60mL/min/1.73m2, using the CKDEPI formula.
• Subject is not willing or able to be adherent to study protocol (e.g., study visits).
• Subject has a condition in which in the opinion of the PI or medical physician would increase risk to the subject or interfere with the integrity of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: placebo, then metformin, then polysorbate 80; Placebo is one twice a day, metformin is 500mg twice a day, and polysorbate 80 is 400mg twice a day	Drug: pravastatin and chenodeoxycholic acid, after metformin and placebo; single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg; Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo; single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg
Experimental: metformin, then polysorbate 80, then placebo; Placebo is one twice a day, metformin is 500mg twice a day, and polysorbate 80 is 400mg twice a day	Drug: pravastatin and chenodeoxycholic acid, after metformin and placebo; single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg; Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo; single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg
Experimental: polysorbate 80, then placebo, then metformin; Placebo is one twice a day, metformin is 500mg twice a day, and polysorbate 80 is 400mg twice a day	Drug: pravastatin and chenodeoxycholic acid, after metformin and placebo; single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg; Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo; single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg
Experimental: polysorbate 80, then metformin, then placebo; Placebo is one twice a day, metformin is 500mg twice a day, and polysorbate 80 is 400mg twice a day	Drug: pravastatin and chenodeoxycholic acid, after metformin and placebo; single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg; Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo; single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg
Experimental: placebo, then polysorbate 80, then metformin; Placebo is one twice a day, metformin is 500mg twice a day, and polysorbate 80 is 400mg twice a day	Drug: pravastatin and chenodeoxycholic acid, after metformin and placebo; single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg; Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo; single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg
Experimental: metformin, then placebo, then polysorbate 80; Placebo is one twice a day, metformin is 500mg twice a day, and polysorbate 80 is 400mg twice a day	Drug: pravastatin and chenodeoxycholic acid, after metformin and placebo; single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg; Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo; single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area-Under-the-Curve (AUC) of Pravastatin After Metformin	Pravastatin AUC after metformin, compared to pravastatin AUC after placebo. AUC units are concentration x time (i.e. ng/ml x h).	0-10 hours
Peak Plasma Concentration (Cmax) of Pravastatin After Metformin	Pravastatin Cmax after metformin, compared to pravastatin Cmax after placebo. Cmax units are concentration (i.e. ng/ml).	0-10 hours
Area-Under-the-Curve (AUC) of Chenodeoxycholic Acid After Metformin	Baseline-corrected chenodeoxycholic acid AUC after metformin. AUC Units are concentration x time (i.e. ng/ml x h). Baseline-corrected chenodeoxycholic acid is chenodeoxycholic acid concentration minus chenodeoxycholic acid concentration value at time zero (i.e. t=0).	0-10 hours
Peak Plasma Concentration (Cmax) of Chenodeoxycholic Acid After Metformin	Baseline-corrected chenodeoxycholic acid Cmax after metformin. Cmax units are concentration (i.e. ng/ml). Baseline-corrected chenodeoxycholic acid is chenodeoxycholic acid concentration minus chenodeoxycholic acid concentration value at time zero (i.e. t=0).	0-10 hours
Area-Under-the-Curve (AUC) of Acyclovir After Polysorbate 80	Acyclovir AUC after polysorbate 80. AUC units are concentration x time (i.e. ng/ml x h).	0-10 hours
Peak Plasma Concentration (Cmax) of Acyclovir After Polysorbate 80	Acyclovir Cmax after polysorbate 80. Cmax units are concentration (i.e. ng/ml).	0-10 hours
Area-Under-the-Curve (AUC) of Chenodeoxycholic Acid (CDCA) After Polysorbate 80	Baseline-corrected Chenodeoxycholic acid AUC after polysorbate 80. AUC units are concentration x time (i.e. ng/ml x h). Baseline-corrected chenodeoxycholic acid is chenodeoxycholic acid concentration minus chenodeoxycholic acid concentration value at time zero (i.e. t=0).	0-10 hours
Peak Plasma Concentration (Cmax) of Chenodeoxycholic Acid (CDCA) After Polysorbate 80	Baseline-corrected Chenodeoxycholic acid Cmax after polysorbate 80. Cmax units are concentration (i.e. ng/ml). Baseline-corrected chenodeoxycholic acid is chenodeoxycholic acid concentration minus chenodeoxycholic acid concentration value at time zero (i.e. t=0).	0-10 hours
Area-Under-the-Curve (AUC) of Enalaprilat After Polysorbate 80	Enalaprilat AUC after polysorbate 80. AUC units are concentration x time (i.e. ng/ml x h).	0-10 hours
Peak Plasma Concentration (Cmax) of Enalaprilat After Polysorbate 80	Enalaprilat Cmax after polysorbate 80. Cmax units are concentration (i.e. ng/ml).	0-10 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area-Under-the-Curve (AUC) of Endogenous Bile Acids After Polysorbate 80	For each of 15 endogenous bile acid, endogenous bile acid AUC after polysorbate 80, compared to endogenous bile acid AUC after placebo. AUC units are concentration x time (i.e. ng/ml x h).	0-10 hours
Peak Plasma Concentration (Cmax) of Endogenous Bile Acids After Metformin	For each of 15 endogenous bile acid, endogenous bile acid Cmax after metformin, compared to endogenous bile acid Cmax after placebo. Cmax units are concentration (i.e. ng/ml).	0-10 hours
Area-Under-the-Curve (AUC) of Endogenous Bile Acids After Metformin	For each of 15 endogenous bile acid, endogenous bile acid AUC after metformin, compared to endogenous bile acid AUC after placebo. AUC units are concentration x time (i.e. ng/ml x h).	0-10 hours
Peak Plasma Concentration (Cmax) of Endogenous Bile Acids After Polysorbate 80	For each of 15 endogenous bile acid, endogenous bile acid Cmax after polysorbate 80, compared to endogenous bile acid Cmax after placebo. Cmax units are concentration (i.e. ng/ml).	0-10 hours

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2021
• Primary Completion (Actual): November 1, 2021
• Study Completion (Actual): November 1, 2021

Study Registration Dates

• First Submitted: November 9, 2020
• First Submitted That Met QC Criteria: November 17, 2020
• First Posted (Actual): November 23, 2020

Study Record Updates

• Last Update Posted (Actual): July 16, 2024
• Last Update Submitted That Met QC Criteria: July 15, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: healthy volunteer; pharmacokinetics; excipient; transporter
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites; Gastrointestinal Agents; Protease Inhibitors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cathartics; Angiotensin-Converting Enzyme Inhibitors; Metformin; Valacyclovir; Enalaprilat; Enalapril; Chenodeoxycholic Acid; Pravastatin
• Other Study ID Numbers: HP-00090086

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No