Impact of Metformin and Polysorbate 80 on Drug Absorption and Disposition

Study Overview
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Brief Summary
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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.

Official Title
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Impact of Metformin and Polysorbate 80 on Drug Absorption and Disposition

Conditions
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Bile Salt Export Pump (BSEP) Transporter, Polysorbate 80

Intervention / Treatment
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* Drug: pravastatin and chenodeoxycholic acid, after metformin and placebo
* Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: placebo, then metformin, then polysorbate 80<br>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<br>* single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg<br>Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo<br>* single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg<br>|
| Experimental: metformin, then polysorbate 80, then placebo<br>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<br>* single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg<br>Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo<br>* single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg<br>|
| Experimental: polysorbate 80, then placebo, then metformin<br>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<br>* single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg<br>Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo<br>* single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg<br>|
| Experimental: polysorbate 80, then metformin, then placebo<br>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<br>* single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg<br>Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo<br>* single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg<br>|
| Experimental: placebo, then polysorbate 80, then metformin<br>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<br>* single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg<br>Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo<br>* single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg<br>|
| Experimental: metformin, then placebo, then polysorbate 80<br>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<br>* single oral dose of pravastatin 80 mg and chenodeoxycholic acid 250 mg<br>Drug: valacyclovir, chenodeoxycholic acid, and enalaprilat, after polysorbate 80 and placebo<br>* single oral dose of valacyclovir 500 mg, chenodeoxycholic acid 250 mg, and enalaprilat 20 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area-Under-the-Curve (AUC) of pravastatin | pravastatin exposure after metformin | 0-10 hours | 
| Peak Plasma Concentration (Cmax) of pravastatin | pravastatin Cmax after metformin | 0-10 hours | 
| Area-Under-the-Curve (AUC) of chenodeoxycholic acid after metformin | chenodeoxycholic acid exposure after metformin | 0-10 hours | 
| Peak Plasma Concentration (Cmax) of chenodeoxycholic acid after metformin | chenodeoxycholic acid Cmax after metformin | 0-10 hours | 
| Area-Under-the-Curve (AUC) of acyclovir | acyclovir exposure after polysorbate 80 | 0-10 hours | 
| Peak Plasma Concentration (Cmax) of acyclovir | acyclovir Cmax after polysorbate 80 | 0-10 hours | 
| Area-Under-the-Curve (AUC) of chenodeoxycholic acid after polysorbate 80 | chenodeoxycholic acid exposure after polysorbate 80 | 0-10 hours | 
| Peak Plasma Concentration (Cmax) of chenodeoxycholic acid after polysorbate 80 | chenodeoxycholic acid Cmax after polysorbate 80 | 0-10 hours | 
| Area-Under-the-Curve (AUC) of enalapril | enalapril exposure after polysorbate 80 | 0-10 hours | 
| Peak Plasma Concentration (Cmax) of enalapril | enalapril Cmax after polysorbate 80 | 0-10 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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healthy volunteer, pharmacokinetics, excipient, transporter