Dolutegravir (DTG) is a selective and potent HIV-1 integrase inhibitor and has potential for treatment of neonates with HIV infection and use as prophylaxis of perinatal transmission. Safety and pharmacokinetics (PK) of DTG have previously been studied in pediatric patients and current studies are investigating the appropriate dose in infants aged > 4 weeks. Dose optimisation in neonatal patients is complex and physiologically-based pharmacokinetic (PBPK) modelling may help inform knowledge gaps in the absence of empirical data. The aim of this study was to simulate the PK of DTG in neonates to help identify an appropriate dosing regimen using PBPK modelling.
The PBPK model was designed in Simbiology (MATLAB R2018a) incorporating neonatal maturation characteristics and a description of physiological and anatomical growth data from various sources. Experimental [i]in vitro[/i] data for DTG was integrated into the model to aid prediction of DTG PK in the neonatal population. DTG is predominantly metabolised by UGT1A1 and CYP3A4 and the PBPK model was qualified using clinical data from the surrogate substrates raltegravir (UGT1A1) and midazolam (CYP3A4) in neonates. Additionally, DTG adult and paediatric clinical data were used for the validation of the PBPK model. The model was assumed to be qualified if the simulated values were within 0.5-1.5 fold of the mean reported values as per convention for the approach.
A combination of different DTG single and multiple dose strategies were simulated in 100 healthy neonates with the aim of achieving plasma exposure comparable to therapeutic levels observed in paediatric patients (Ctrough: 0.90 mg/L and AUC24: 46 mg.h/L). The PK parameters are summarised in Table 1. Regimens 1-3 result in PK parameters comparable to those in paediatric patients, with convenient dosing schedules.
Due to the lack of clinical PK data, neonates represent a vulnerable population. Clinical trials in neonates are extremely difficult to conduct and dose prediction is therefore beneficial to inform trial design. The combination of rapid development and immature ontogeny make it difficult to easily scale existing doses. PBPK modelling allows these changes to be represented mathematically, and should result in more accurate predictions. The presented data can be used to inform neonatal clinical trials to help accelerate dose optimisation in this population.