Ignite Creation Date:
2024-05-05 @ 11:57 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00187746
Status:
WITHDRAWN
Last Update Posted:
2012-11-21
First Post:
2005-09-14
Brief Title:
Effect of Age on the Renal Clearance of Adefovir
Sponsor:
University of California San Francisco
Organization:
University of California San Francisco
Study Overview
Official Title:
Effect of Age on the Renal Clearance of Adefovir
Status:
WITHDRAWN
Status Verified Date:
2012-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Budget exceeded for project
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Healthy African American subjects with normal hepatic and renal function will be administered 10mg adefovir dipivoxil in a fasting state Subjects will have blood and urine collections over the following 24 hours for the measurement of adefovir renal clearance To investigate the role of age in renal adefovir elimination 8 subjects will be enrolled from each of the following age groups 18-25 years and 48-55 years
Detailed Description:
There are two major routes of elimination for drugs - hepatic metabolism and renal elimination For small hydrophilic molecules the renal route predominates The renal function of patients taking these medications therefore determines the pharmacokinetics of and by extension the clinical response to these medications One of the most common causes of reduced renal function is a decline with age
Renal drug elimination is comprised of passive drug filtration active secretion and reabsorption which can occur by both active and passive processes The filtration function of the kidney approximated by the glomerular filtration rate GFR falls by 25-50 between the ages of 20 and 90 Turnheim 2003 The decline in renal function with age has been identified as a major cause of adverse drug reactions in the elderly population Lindeman 1995 Mühlberg 1999 To avoid overdosing and exaggerated responses from these medications algorithms have been established for dosing in patients with reduced renal function due to changes in glomerular filtration
However in a previous study looking at the pharmacokinetics of a drug cleared only by the renal route we made an observation that appeared to contradict the renal clearance declines with age dogma In this study Effect of Genetic Variation in the Renal Transporter OAT1 on the Renal Secretion of Adefovir we identified individuals with genetic variants in OAT1 a transporter that was believed to be involved in the active secretion of Adefovir All OAT1 non-synonymous genetic variants we identified were in the African American population We administered 10mg Adefovir dipivoxil to 10 African American subjects between the ages of 19 and 49 4 who had a genetic variant in OAT1 and six without one These subjects were identified from a parent study called SOPHIE NCT00187668 SOPHIE Studies Of Pharmacogenetics In Ethnically Diverse Individuals is a study where DNA was collected from Bay Area adults 18-40 years of age for the testing of drug response genes In addition to DNA donation subjects consent to be contacted for future studies
We collected blood and urine over 24 hours to calculate the total renal clearance and net secretory clearance of adefovir Although we saw no difference in the renal elimination of adefovir in the subjects attributable to OAT1 variants we found a correlation between the age and renal clearance Filtration calculated from the measured creatinine clearance remained constant in this population 112 mlmin 18 SD and the clearance of Adefovir increased with age Both the total renal clearance and net secretory clearance increased with age p0017 and p0010 respectively
This incidental finding is interesting as it may indicate an age-dependence of active drug elimination mechanisms However the sample size in this previous study is small and the observation may not be accurate We therefore have planned this confirmatory study to expand the study population As the initial finding was made in African American subjects we plan to enroll an additional 16 African American subjects 8 each from the following age groups 18-25 and 48-55 We will also genotype these individuals for variants in transporters and other proteins that may play a role in adefovir renal elimination If the unexpected finding of an age-related increase of adefovir renal clearance is observed in this study additional follow-up studies will be planned to examine whether the same holds true for other ethnic groups
Renal drug elimination is comprised of passive drug filtration active secretion and reabsorption which can occur by both active and passive processes The filtration function of the kidney approximated by the glomerular filtration rate GFR falls by 25-50 between the ages of 20 and 90 Turnheim 2003 The decline in renal function with age has been identified as a major cause of adverse drug reactions in the elderly population Lindeman 1995 Mühlberg 1999 To avoid overdosing and exaggerated responses from these medications algorithms have been established for dosing in patients with reduced renal function due to changes in glomerular filtration
However in a previous study looking at the pharmacokinetics of a drug cleared only by the renal route we made an observation that appeared to contradict the renal clearance declines with age dogma In this study Effect of Genetic Variation in the Renal Transporter OAT1 on the Renal Secretion of Adefovir we identified individuals with genetic variants in OAT1 a transporter that was believed to be involved in the active secretion of Adefovir All OAT1 non-synonymous genetic variants we identified were in the African American population We administered 10mg Adefovir dipivoxil to 10 African American subjects between the ages of 19 and 49 4 who had a genetic variant in OAT1 and six without one These subjects were identified from a parent study called SOPHIE NCT00187668 SOPHIE Studies Of Pharmacogenetics In Ethnically Diverse Individuals is a study where DNA was collected from Bay Area adults 18-40 years of age for the testing of drug response genes In addition to DNA donation subjects consent to be contacted for future studies
We collected blood and urine over 24 hours to calculate the total renal clearance and net secretory clearance of adefovir Although we saw no difference in the renal elimination of adefovir in the subjects attributable to OAT1 variants we found a correlation between the age and renal clearance Filtration calculated from the measured creatinine clearance remained constant in this population 112 mlmin 18 SD and the clearance of Adefovir increased with age Both the total renal clearance and net secretory clearance increased with age p0017 and p0010 respectively
This incidental finding is interesting as it may indicate an age-dependence of active drug elimination mechanisms However the sample size in this previous study is small and the observation may not be accurate We therefore have planned this confirmatory study to expand the study population As the initial finding was made in African American subjects we plan to enroll an additional 16 African American subjects 8 each from the following age groups 18-25 and 48-55 We will also genotype these individuals for variants in transporters and other proteins that may play a role in adefovir renal elimination If the unexpected finding of an age-related increase of adefovir renal clearance is observed in this study additional follow-up studies will be planned to examine whether the same holds true for other ethnic groups
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None