ABSTRACT
Aim : Quantify identifiable sources of variability, including
key pharmacogenetic variants in oxypurinol pharmacokinetics and their
pharmacodynamic effect on serum urate.
Methods : Hmong participants (n=34) received 100 mg allopurinol
twice daily for 7 days followed by 150 mg allopurinol twice daily for 7
days. Serum urates (SU) were obtained pre- and post-allopurinol. Serum
oxypurinol concentrations were obtained at times 0, 2, 4, and 6 hours
after the last dose. A sequential population pharmacokinetic
pharmacodynamics (PKPD) analysis with non-linear mixed-effects modeling
evaluated the impact of anthropometrics, concomitant medications, and
genetic variants on oxypurinol PKPD parameters. Allopurinol maintenance
dose to achieve target SU was simulated based on the final PKPD model.
Results : A one-compartment model with first order absorption
and elimination best described the oxypurinol concentration-time data.
Inhibitory of SU by oxypurinol was described with a direct inhibitory
Emax model using steady-state oxypurinol concentrations. Fat-free body
mass, estimated creatinine clearance and SLC22A12 rs505802
genotype were found to predict differences in oxypurinol clearance.
Oxypurinol concentration required to inhibit 50% of xanthine
dehydrogenase activity was affected by PDZK1 rs12129861 genotype.
Most individuals with both PDZK1 rs12129861 AA andSLC22A12 rs505802 CC genotypes achieve target SU with allopurinol
below the maximum dose, regardless of renal function and body mass. In
contrast, individuals with both PDZK1 rs12129861 GG andSLC22A12 rs505802 TT genotypes would require more than the
maximum dose, thus alternative medications.
Conclusion : The proposed allopurinol dosing guide uses
individuals’ fat-free mass, renal function, and SLC22A12 rs505802
and PDZK1 rs12129861 genotypes to achieve target SU.