The pharmacokinetics, pharmacodynamics and pharmacogenetics of Dolutegravir and Cobicistat in the treatment of HIV

Abstract

Dolutegravir (DTG), the second-generation Integrase Inhibitor (InSTI) and Cobicistat (COBI), the new pharmacological booster, were approved for the treatment of HIV in 2013-14. DTG changed the landscape of HIV therapy, raising standards for efficacy, safety and genetic barrier. It is now recommended as first line therapy in most major including universal guidelines and is the anchor drug for a number of new simplified ARV strategies. Meanwhile, COBI offers the opportunity to reduce pill burden in patients who require a boosted protease inhibitor, thanks to its co-formulation with atazanavir (ATV) and darunavir (DRV). It also has a lesser drug interaction profile than ritonavir (RTV), secondary to a lack of enzyme induction. Licensing data is often limited to highly selected study participants under strict trial conditions. The objectives of this thesis are therefore to address gaps in knowledge on the pharmacological behaviour of DTG and COBI in important real-life patient groups and clinical scenarios, including older people living with HIV (PLWH), women taking contraception, poorly adherent patients, DTG/DRV/COBI dual therapy candidates and genetically distinct populations. Five intensive pharmacokinetic (PK) studies were carried out, recruiting healthy volunteers and PLWH from four UK-based centers. Pharmacogenetic sampling from each DTG study was used in a final study to explore the impact of genetic variability in drug disposition genes on the PK of DTG. The intensive PK of DTG was described for the first time in PLWH aged 60 years and over, showing a significantly higher DTG Cmax (25%) versus younger subjects (median age 36yrs). Discontinuation rate secondary to neuro-psychiatric adverse events was 4.6% and seemed to relate to elevated drug concentrations, but the Cmax increase was not associated with measured sleep or cognitive changes over six months in those who did continue the drug. The PK forgiveness of DTG and COBI-boosted elvitegravir (EVG), ATV and DRV was then characterised in healthy volunteers, showing a 72-hour therapeutic PK tail for DTG, 36hrs for EVG, 30hrs for ATV and 24hrs for DRV when boosted with COBI. The PK impacts of DTG co-administration with DRV/COBI and of ethinylestrodiol/levonogestrel (EE/LNG) with ATV/COBI were also investigated. Findings showed minimal changes in DTG/DRV/COBI concentrations when administered together and a 25% decrease in EE C24 with no significant changes in LNG when EE/LNG was co-administered with ATV/COBI. Finally, a pharmacogenetic association between DTG PK and variants in the ABCG2, UGT1A1 and NRI1/2 genes was demonstrated, particularly when combined. The data presented in this thesis provides clinicians with key information on the pharmacology and safety of DTG and COBI in important patient groups and clinical scenarios. The significance and clinical validity of the data is discussed and an argument is made to support future research in DTG dose optimisation.