Clinical trial NCT01087749: Pharmacokinetic Study in Patients With Chronic Kidney Disease and Healthy Volunteers
Official title: Pharmacokinetic Study of Propranolol, Losartan, and Eprosartan in Healthy Volunteers and Patients With Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Kidney Disease
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
First posted: 2010-03-16
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL

Brief summary: The purpose of this study is to find out how chemicals in the blood of patients with chronic kidney disease affect how medications are removed from the body. The patient will take one dose of three different drugs, one on each week, for a total of three single doses. The investigators want to find out if these three different medications are affected in different ways by the chemicals in the blood of patients with kidney disease.

Detailed description: It has been demonstrated that proteins known as drug transporters in different human organs and tissues are important for a drug to be absorbed, distributed, metabolized, and eliminated (ADME)18. The chemical properties of drugs can affect whether it needs a transporter protein to enter the cell or not. It is not well known how these proteins are affected in chronic disease and how different drugs may be absorbed, metabolized, or eliminated differently in certain diseases. Preliminary studies suggest that some drugs (those requiring drug transporter proteins) may show altered elimination in the presence of uremic toxins. Uremic toxins are substances accumulated in the blood of patients with chronic kidney disease and many are not removed through hemodialysis (HD). We hypothesize that the different classes of drugs (BDDCS class1, 2, and 3) will have different degrees of changes in AUC, meaning that for a class 1 drug we would see less of a change in AUC than in a class 3 drug because a class 3 drug requires transporters. Previous studies can't make that comparison because they used different patients for each drug, so even if there were a change in a class 1 drug, it can't be compared to a class 3 drug. In order to get an accurate comparison, we will test the three drugs on the same patient and see how he AUC changes from drug to drug within the same patient comparing it to the healthy volunteer (taking the same three drugs).

Eligibility criteria: Inclusion Criteria:

* Male or Female 18-70 years of age.
* Healthy volunteers or chronic kidney disease (GFR\<40)
* Be able to provide written informed consent and comply with requirements of the study.
* Avoid eating grapefruit and drinking grapefruit juice from 7 days prior to the first study day until completion of the study.
* Abstinence from alcoholic beverages, caffeinated beverages and orange juice from 6pm the night before a study day until completion of the study day.
* Fast from food and beverages at least 8 hours prior to medication dosing.
* Be able to read, speak, and understand English.

Exclusion Criteria:

* Subjects with contraindications to taking the study drugs
* Subjects with known allergies to propranolol, losartan, or eprosartan.
* Subjects who smoke tobacco.
* Subjects with ongoing alcohol or illegal drug use.
* Subjects who are pregnant, lactating, or attempting to conceive.
* Subjects unable to maintain adequate birth control during the study.
* Subjects unable to follow protocol instructions or protocol criteria.
* Subjects with hematocrit \< 30mg/dL.
* Subjects who are insulin requiring diabetics.
* Subjects with low, or low normal blood pressure (systolic blood pressure \[BP\] \<100mmHg)
* Subjects with uncontrolled high blood pressure.

Primary outcomes:
measure: Pharmacokinetic parameters
timeFrame: 3 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: San Francisco,
country: United States
facility: Clinical Reserach Center, UCSF
state: California
Study officials:
affiliation: University of California, San Francisco
name: Leslie Z Benet, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Lynda Frassetto, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Lam JL, Shugarts SB, Okochi H, Benet LZ. Elucidating the effect of final-day dosing of rifampin in induction studies on hepatic drug disposition and metabolism. J Pharmacol Exp Ther. 2006 Nov;319(2):864-70. doi: 10.1124/jpet.106.108282. Epub 2006 Aug 11.
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citation: Martin DE, Chapelsky MC, Ilson B, Tenero D, Boike SC, Zariffa N, Jorkasky DK. Pharmacokinetics and protein binding of eprosartan in healthy volunteers and in patients with varying degrees of renal impairment. J Clin Pharmacol. 1998 Feb;38(2):129-37. doi: 10.1002/j.1552-4604.1998.tb04401.x.
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citation: Sun H, Huang Y, Frassetto L, Benet LZ. Effects of uremic toxins on hepatic uptake and metabolism of erythromycin. Drug Metab Dispos. 2004 Nov;32(11):1239-46. doi: 10.1124/dmd.104.000521. Epub 2004 Jul 30.
citation: Vanholder R, De Smet R, Glorieux G, Argiles A, Baurmeister U, Brunet P, Clark W, Cohen G, De Deyn PP, Deppisch R, Descamps-Latscha B, Henle T, Jorres A, Lemke HD, Massy ZA, Passlick-Deetjen J, Rodriguez M, Stegmayr B, Stenvinkel P, Tetta C, Wanner C, Zidek W; European Uremic Toxin Work Group (EUTox). Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int. 2003 May;63(5):1934-43. doi: 10.1046/j.1523-1755.2003.00924.x.
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