Title : Population Pharmacokinetics, Pharmacodynamics, and
Pharmacogenetics Modeling of Oxypurinol in Hmong Adults with Gout and/or
Hyperuricemia
Running title : PK/PD/PGx modeling of oxypurinol
Authors : Ya-Feng Wen, Pharm.D.1, Richard C.
Brundage, Pharm.D., Ph.D.1, Youssef M. Roman,
Pharm.D., Ph.D.2, Kathleen A. Culhane-Pera, M.D.,
M.A.3, Robert J. Straka, Pharm.D.,
FCCP1
Affiliations :
- Department of Experimental and Clinical Pharmacology, College of
Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Pharmacotherapy & Outcomes Science, School of Pharmacy,
Virginia Commonwealth University, Richmond, VA 23298, USA
- Minnesota Community Care, St. Paul, MN 55107, USA
Corresponding Author :
Robert J. Straka
Experimental and Clinical Pharmacology
University of Minnesota College of Pharmacy
308 Harvard St SE, Minneapolis, MN 55455
Email: strak001@umn.edu
ORCiD iD: 0000-0002-9541-7823
The authors confirm that the Principal Investigator for this paper is
Robert J. Straka and that he had direct clinical responsibility for
patients.
Data availability : Raw data is not available to the public due
to lack of patient consent for data sharing. NONMEM control files for
pharmacokinetics and pharmacodynamics modeling and R script for
allopurinol dose simulation are available in the supplemental text 1-4.
Funding : This work was supported by the University of
Minnesota, Office of Community Engagement of the Clinical and
Translational Science Institute for its funding via 2014 Collaborative
Pilot Grants No. 22556 and National Center for Advancing Translational
Sciences of the National Institutes of Health Award Number UL1TR000114.
The content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institutes of
Health.
Conflict of interest disclosure : All listed authors declare no
conflicts of interest.
Ethics approval : This study was approved by the Human Research
Protection Program at the University of Minnesota IRB (# 1408M53223).
Patient consent : Consent was obtained for all the study
participants prior to any study related activities.
ClinicalTrials.gov Identifier : NCT02371421
Key words : allopurinol, gout, population pharmacokinetics,
NONMEM, pharmacometrics
Word count : 4044
Table count : 3
Figure count : 3
What is already known about this subject
- Allopurinol exhibits large variability in pharmacokinetics and
pharmacodynamics.
- Patient characteristics and concomitant medications have been
identified as sources of the variability but have not accounted for
all of it.
- The impact of genetic variants has been explored but no significant
association has been established with population pharmacokinetics and
pharmacodynamics analysis.
What this study adds
Genetic variants in SLC22A12 were associated with oxypurinol
clearance and variants in PDZK1 were associated with
urate-lowering effect of oxypurinol.
The allopurinol maintenance dose to achieve target serum urate level
depends on patients’ body mass, renal function, and genetic variants
in SLC22A12 and PDZK1.