The Effects of BCRP Q141K on Allopurinol Pharmacokinetics and Dynamics

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT02956278
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH), Open Medicine Institute (Other)
• Enrollment: 27
• Location: 1
• Arms: 3
• Actual Duration (Months): 15.9
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

Subjects will undergo a placebo and allopurinol phase to better understand the effects of the reduced function BCRP Q141K variant on allopurinol pharmacokinetics and pharmacodynamics.

Condition or Disease	Intervention/Treatment	Phase
Chronic Gout; Hyperuricemia	Drug: Allopurinol; Other: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: The Effects of BCRP Q141K on Allopurinol Pharmacokinetics and Dynamics
• Actual Study Start Date: Nov 1, 2016
• Actual Primary Completion Date: Mar 1, 2018
• Actual Study Completion Date: Mar 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: BCRP Q141K CC Participants that are homozygous reference for BCRP Q141K receive at least one 300 mg dose of allopurinol followed by blood/urine collection for up to 72 hours post-dose.	Drug: Allopurinol; Other Names: Zyloprim Aloprim ; Other: Placebo; lactose placebo pill
Experimental: BCRP Q141K CA Participants that are heterozygous for the BCRP Q141K allele receive at least one 300 mg dose of allopurinol, with blood/urine collections up to 72 hours post-dose.	Drug: Allopurinol; Other Names: Zyloprim Aloprim ; Other: Placebo; lactose placebo pill
Experimental: BCRP Q141K AA Participants homozygous for the BCRP Q141K allele receive at least one 300 mg dose of allopurinol with blood/urine collection for up to 72 hours post-dose.	Drug: Allopurinol; Other Names: Zyloprim Aloprim ; Other: Placebo; lactose placebo pill

Outcome Measures

Primary Outcome Measures

1. Oxypurinol Renal Clearance [24 hours (Urine collected 0-4 hrs,4-8 hrs,8-10 hrs,10-24 hrs post-dose)]

   Renal clearance as defined by amount excreted in 24 hours/AUC from 0-24 hours

2. Percent Change Uric Acid [24 hours]

   Maximum percent change in uric acid after a single dose of allopurinol

Secondary Outcome Measures

1. Oxypurinol AUC [24 hours (Collections at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24 hours post-dose)]

   Area under the concentration time curve from 0-24 hours following a single dose of allopurinol (i.e. Day 1 of both protocols)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• self-identified as Asian/European ancestry

• generally healthy with approved lab values for CBC,HFP,RFP, and uric acid

• Subjects with the ABCG2 genotype, homozygous, heterozygous or homozygous for the major allele of rs2231142 will be recruited

Exclusion Criteria:

• vascular disease

• renal impairment

• medications/supplements that affect uric acid levels

• pregnant or lactating women

• prior history of allergic reaction to allopurinol or testing positive for HLA-B*5801 allele

• risk of urinary or gastric retention or narrow-angle glaucoma

• impaired hepatic function

• evidence of anemia

• evidence or diagnosis of congestive heart failure

• smokers

• subjects with a mutation other than rs2231142 in the ABCG2 genotype

• subjects taking hormonal contraceptives or other hormonal medications

• evidence of recreational drug use as determined by questionnaire

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Open Medicine Institute	Mountain View	California	United States	94040

Sponsors and Collaborators

• University of California, San Francisco
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Open Medicine Institute

Investigators

• Principal Investigator: Kathleen Giacomini, PhD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan: Single Dose Protocol - Nov 7, 2017
• Study Protocol and Statistical Analysis Plan: Multiple Dose Protocol - Sep 1, 2017

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02956278
• Other Study ID Numbers: 14-14550; R01DK103729
• First Posted: Nov 6, 2016
• Last Update Posted: Jun 23, 2020
• Last Verified: Jun 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of California, San Francisco: allopurinol
• Additional relevant MeSH terms: Hyperuricemia; Allopurinol

Study Results

Participant Flow

Pre-assignment Detail	As the intent of the protocol was to characterize the effect of the genetic variant, data were collected and analyzed per genotype variant regardless of number of doses received.

Arm/Group Title	BCRP Q141K CC	BCRP Q141K CA	BCRP Q141K AA
Arm/Group Description	Participants that are homozygous reference for BCRP Q141K receive one 300 mg dose of allopurinol followed by blood/urine collection for up to 72 hours.	Participants that are heterozygous for the BCRP Q141K allele receive one 300 mg dose of allopurinol, with blood/urine collections up to 72 hours.	Participants homozygous for the BCRP Q141K allele receive one 300 mg dose of allopurinol with blood/urine collection for up to 72 hours.
Period Title: Overall Study
STARTED	15	9	3
COMPLETED	9	7	3
NOT COMPLETED	6	2	0

Baseline Characteristics

Arm/Group Title	BCRP Q141K CC Genotype	BCRP Q141K CA Genotype	BCRP Q141K AA Genotype	Total
Arm/Group Description	All subjects that completed the protocol with the reference BCRP Q141K genotype (CC alleles)	All subjects that completed the protocol with the heterozygous BCRP Q141K genotype (CA alleles)	All subjects that completed the protocol with the homozygous BCRP Q141K genotype (AA alleles)	Total of all reporting groups
Overall Participants	9	7	3	19
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.9 (5.7)	29.0 (7.2)	27.3 (6.5)	27.7 (6.1)
Sex: Female, Male (Count of Participants)
Female	5 55.6%	1 14.3%	1 33.3%	7 36.8%
Male	4 44.4%	6 85.7%	2 66.7%	12 63.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	6 66.7%	7 100%	2 66.7%	15 78.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	1 11.1%	0 0%	0 0%	1 5.3%
More than one race	2 22.2%	0 0%	1 33.3%	3 15.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Oxypurinol Renal Clearance
Description	Renal clearance as defined by amount excreted in 24 hours/AUC from 0-24 hours
Time Frame	24 hours (Urine collected 0-4 hrs,4-8 hrs,8-10 hrs,10-24 hrs post-dose)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BCRP Q141K CC Genotype	BCRP Q141K CA Genotype	BCRP Q141K AA Genotype
Arm/Group Description	All subjects that completed the protocol with the reference BCRP Q141K genotype (CC alleles)	All subjects that completed the protocol with the heterozygous BCRP Q141K genotype (CA alleles)	All subjects that completed the protocol with the homozygous BCRP Q141K genotype (AA alleles)
Measure Participants	9	7	3
Mean (Standard Deviation) [L/hr]	1.9 (1.2)	1.4 (0.5)	1.6 (0.9)

2. Primary Outcome

Title	Percent Change Uric Acid
Description	Maximum percent change in uric acid after a single dose of allopurinol
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

Baseline and minimum SUA level after a single dose of allopurinol (i.e. Day 1) were used for the calculation (baseline-minimum)/baseline)

Arm/Group Title	BCRP Q141K CC Genotype	BCRP Q141K CA Genotype	BCRP Q141K AA Genotype
Arm/Group Description	All subjects that completed the protocol with the reference BCRP Q141K genotype (CC alleles)	All subjects that completed the protocol with the heterozygous BCRP Q141K genotype (CA alleles)	All subjects that completed the protocol with the homozygous BCRP Q141K genotype (AA alleles)
Measure Participants	9	7	3
Mean (Standard Deviation) [Percent Change from Baseline]	26.8 (5.9)	23.8 (7.0)	21.4 (2.5)

3. Secondary Outcome

Title	Oxypurinol AUC
Description	Area under the concentration time curve from 0-24 hours following a single dose of allopurinol (i.e. Day 1 of both protocols)
Time Frame	24 hours (Collections at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	BCRP Q141K CC Genotype	BCRP Q141K CA Genotype	BCRP Q141K AA Genotype
Arm/Group Description	All subjects that completed the protocol with the reference BCRP Q141K genotype (CC alleles)	All subjects that completed the protocol with the heterozygous BCRP Q141K genotype (CA alleles)	All subjects that completed the protocol with the homozygous BCRP Q141K genotype (AA alleles)
Measure Participants	9	7	3
Mean (Standard Deviation) [mcg*hr/mL]	95.9 (25.1)	99.1 (30.1)	108.5 (36.1)

Adverse Events

Time Frame	During the course of the protocol and up to 72 hours following the final dose of allopurinol
Arm/Group Title	BCRP Q141K CC		BCRP Q141K CA		BCRP Q141K AA
Arm/Group Description	Participants homozygous reference for BCRP Q141K receive one 300 mg dose of allopurinol followed by blood/urine collection for up to 72 hours.		Participants heterozygous for BCRP Q141Kr eceive one 300 mg dose of allopurinol followed by blood/urine collection for up to 72 hours.		Participants homozygous for BCRP Q141Kr eceive one 300 mg dose of allopurinol followed by blood/urine collection for up to 72 hours.
All Cause Mortality
	BCRP Q141K CC		BCRP Q141K CA		BCRP Q141K AA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/9 (0%)		0/3 (0%)
Serious Adverse Events
	BCRP Q141K CC		BCRP Q141K CA		BCRP Q141K AA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/9 (0%)		0/3 (0%)
Other (Not Including Serious) Adverse Events
	BCRP Q141K CC		BCRP Q141K CA		BCRP Q141K AA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/9 (0%)		0/3 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.