Influence of CYP3A5 and SLCO1B1 Polymorphisms on Atazanavir/r Concentrations in Thai HIV-Infected Patients

Abstract

Aim: To evaluate the influence of genetic polymorphisms on plasma trough concentrations of atazanavir (ATV) and ritonavir (RTV). Patients & methods: The concentration-to-dose ratios were compared between different genotype groups of CYP3A5, ABCB1, SLCO1B1 and NR1I2 in 490 patients. Multiple regression analysis was used to examine the association between genetic and clinical factors and log-transformed concentration-to-dose ratio of ATV and RTV. Results: Higher concentrations of ATV and RTV were significantly associated with CYP3A5 6986 GG and SLCO1B1 521 TC or CC. Female patients had significantly higher ATV plasma concentration than male patients. Conclusion: Genetic polymorphisms and gender are factors affecting the variability of ATV and RTV concentrations in the Thai population. Thus, genetic testing is worth considering when atazanavir + low dose ritonavir is prescribed.

Keywords::

• atazanavir
• CYP3A5 6986A>G
• plasma concentrations
• polymorphisms
• ritonavir
• SLCO1B1 521T>C

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/pgs-2018-0196

Acknowledgments

We thank all patients participating in the LASA study, the LASA study group* and the HIV-NAT staff for their support.

*LASA study members Thailand: P Chetchotisakd, P Mootsikapun, S Anunnatsiri, R Kaewmart, V Lulitanond, P Seawsirikul, A Tiyabut, S Panil (Khon Kaen University, Khon Kaen); C Bowonwatanuwong, H Tantipong, P Yothipitak, U Ampunpong, S Soontaros (Chonburi Hospital, Chonburi); P Kantipong, S Saejung, S Petcharat, W Imsanguan, P Ussawawuthipong, R Jinasen, P Kumbua, N Khampachua, S Pongprapass, J Limlertjareonwanit (Chiangrai Prachanukroh Hospital, Chiang Rai); V Klinbuayaem, U Kumpeerapanya, P Leechanachai, P Klangsinsirikul, Y Siriwarothai, C Tunkham, P Tachorn, C Promping (Sanpatong Hospital, Chiang Mai); W Prasithsirikul, P Sutha, U Thawornwan, S Thongyen, A Narkkhoksung (Bamrasnaradura Infectious Disease Institute, Nonthaburi); S Kiertiburanakul, S Sungkanuparph, L Chumla, N Sanmeema (Ramathibodi Hospital, Bangkok); S Jirajariyavej, K Kongchan, P Sirimanuwat, R Wattanasopon, J Itsariyathanakorn, J Suthisiri (Taksin Hospital, Bangkok); W Munsakul, W Phesajcha, O Teansuwan, N Sae-kao, W Karakate (Vajira Hospital, Bangkok); N Leerattanapetch, P Pisuttimarn, D Aeksomtaramet, W Kamonmitr, J Tamangklang, M Mitchai, N Moolmanee, S Wimonklang, S Naprasert, T Khotphuwiang (Khon Kaen Hospital, Khon Kaen); M Techapornroong, S Tongsakulrungraeng, S Sriatcha, M Ratchatawijin, P Tearsonsern (Prapokklao Hospital, Chanthaburi); S Nimitvilai, P Kapol, S Bounyong, T Theerakul, R Sirithaemkhunti (Nakhon Pathom Hospital, Nakhon Pathom); S Banchongkit, N Yueannuwong, W Kaewvilai (Rayong Hospital, Rayong); S Mekviwattanawong, O Changsuphan, N Yungyuen, J Kirtma, J Padungpattanodom, K Wongsirikul (Pranangklao Hospital, Nonthaburi); K Ruxrungtham (Chulalongkorn University, Bangkok); K Ruxrungtham, A Avihingsanon, T Bunupuradah, V Sapsirisavat, J Ananworanich, N Kancheva Landolt, W Prasitsuebsai, A Uanithirat, S Ubolyam, A Mahanontharit, N Laopraynak, P Kaew-on, D Taechamahapun, C Ruengprasertkit, J Intasan, W Charoenporn, J Jamthong, B Thongpunchang, T Apornpong, S J Kerr (HIV Netherlands Australia Thailand Research Collaboration, Bangkok). Australia: W Lee, A Humphries, J Taylor, S J Kerr, D Cooper, S Emery (Kirby Institute for Infection and Immunity in Society, Sydney,NSW).

Financial & competing interests disclosure

K Ruxrungtham has received the Senior Research Scholar Award from the Thailand Research Fund and the Research Professor Fund from Chulalongkorn University, Bangkok, Thailand. K Ruxrungtham also received honoraria or consultation fees from Merck, Roche, Jensen-Cilag, Tibotec, Mylan and GPO (Governmental pharmaceutical organization, Thailand) as well as participated in a company sponsored speaker’s bureau from Abbott, Gilead, Bristol-Myers Squibb, Merck, Roche, Jensen-Cilag, GlaxoSmithKline and GPO (Governmental pharmaceutical organization). DM Burger served on advisory board and participated in a company sponsored speaker’s bureau for Merck, BMS, Janssen/Tibotec, Gilead, ViiV Healthcare and Abbvie. DM Burger has received research grants from Merck, BMS, Janssen/Tibotec and ViiV Healthcare. This study was supported by Chiang Mai University and the Royal Golden Jubilee PhD Program, The Thailand Research Fund (grant number PHD/0114/2558). The authors have no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

This study was approved by the Institutional Review Board of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand and the Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand. Written informed consent was obtained from all patients before enrollment.

Additional information

Funding

K Ruxrungtham has received the Senior Research Scholar Award from the Thailand Research Fund and the Research Professor Fund from Chulalongkorn University, Bangkok, Thailand. K Ruxrungtham also received honoraria or consultation fees from Merck, Roche, Jensen-Cilag, Tibotec, Mylan and GPO (Governmental pharmaceutical organization, Thailand) as well as participated in a company sponsored speaker’s bureau from Abbott, Gilead, Bristol-Myers Squibb, Merck, Roche, Jensen-Cilag, GlaxoSmithKline and GPO (Governmental pharmaceutical organization). DM Burger served on advisory board and participated in a company sponsored speaker’s bureau for Merck, BMS, Janssen/Tibotec, Gilead, ViiV Healthcare and Abbvie. DM Burger has received research grants from Merck, BMS, Janssen/Tibotec and ViiV Healthcare. This study was supported by Chiang Mai University and the Royal Golden Jubilee PhD Program, The Thailand Research Fund (grant number PHD/0114/2558). The authors have no other 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 apart from those disclosed. No writing assistance was utilized in the production of this manuscript.