Pharmacogenetics-based population pharmacokinetic analysis for dose optimization of ritonavir-boosted atazanavir in Thai adult HIV-infected patients

ABSTRACT

Background

This population pharmacokinetic–pharmacogenetic study aimed to investigate the optimal dose of RTV-boosted ATV (ATV/RTV) for Thai adult HIV-infected patients.

Methods

A total of 1460 concentrations of ATV and RTV from 544 patients receiving an ATV/RTV-based regimen were analyzed. The CYP3A5 6986 A > G, ABCB1 3435 C > T, ABCB1 2677 G > T, SLCO1B1 521 T > C, and NR1I2 63396 C > T were genotyped. A population pharmacokinetic model was performed using a nonlinear mixed-effect model (NONMEM®). Monte Carlo simulations were conducted to compare the percentages of patients achieving the therapeutic range of ATV through concentrations (C_trough).

Results

The apparent oral clearance of ATV (CL/F_ATV) without RTV was 7.69 L/h with interindividual variability (IIV) of 28.7%. Patients with CYP3A5 6986 GG had a 7.1% lower CL/F_ATV than those with AA or AG genotype. The CL/F_ATV decreased by 10.8% for females compared with males. Simulation results showed higher percentages (~70%) of patient receiving doses of 200/100 or 200/50 mg achieved the target ATV C_trough, while more patients (~40%) receiving a standard dose (300/100 mg) had ATV C_trough above this target.

Conclusions

Both CYP3A5 6986 A > G and female decreased CL/F_ATV in Thai HIV-infected patients. Simulations supported that the reduced dose of ATV/RTV was sufficient to achieve the target concentration for Thai population.

KEYWORDS:

• Atazanavir
• Pharmacogenetics
• Population Pharmacokinetics
• Ritonavir
• Thai patient

Author contributions

N Singkham contributed to data analysis and manuscript preparation. A Avihingsanon contributed to the study design, data collection, and manuscript preparation. RC Brundage contributed to data analysis and manuscript preparation. AK Birnbaum contributed to data analysis and manuscript preparation. N Thammajarukc contributed to drug concentration assay. K Ruxrungtham contributed to study design and manuscript preparation. T Bunupuradah contributed to study design, data collection, and manuscript preparation. Sa Kiertiburanakul contributed to data collection and manuscript preparation. P Chetchotisak contributed to data collection and manuscript preparation. B Punyawudho contributed to study design, data analysis, and manuscript preparation.

Declaration of Interest

All the authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported by Chiang Mai University and The Royal Golden Jubilee Ph.D. Program, The Thailand Research Fund (grant no. PHD/0114/2558).