New neonatal liquid formulations of dolutegravir have comparable bioavailability to dispersible paediatric tablet
These results were shown at the virtual International workshop on clinical pharmacology of HIV, hepatitis, and other antiviral drugs, 28–30 September 2020.
There are currently two approved originator (ViiV Healthcare) paediatric formulations of dolutegravir: 10 mg and 25 mg film-coated tablets and 5 mg dispersible tablets (for infants at least four weeks of age and weighing at least 3 kg).
This study evaluated two liquid formulations of dolutegravir that are under development: prototype A, 5-mg/mL dolutegravir suspension in miglyol, and prototype B, 2 mg/mL dolutegravir solution in glycerol. It analysed the pharmacokinetics and safety of the two liquid formulations vs the dispersible tablet after single dose administration to HIV negative men.
The study was open label, single centre, single-dose, non randomised, 3-period and fixed-sequence.  Participants received dolutegravir doses in three periods with at least 7 days washout between: Period 1, prototype A dolutegravir suspension; Period 2, two 5 mg dispersible dolutegravir tablets dispersed in water (reference); Period 3, prototype B dolutegravir solution. All doses were equivalent to 10 mg of dolutegravir.
Twenty-two HIV negative men aged 21–49 years old (mean 31.3 years) were included in the study. Their mean weight was 79.2 kg and BMI 25.4 kg/m2; 19 (86%) were white, 2 (9%) black and 1 (5%) Asian. Twenty-two received the dispersible tablet, 18 received prototype A liquid and 19 prototype B liquid.
The investigators looked at time concentration profiles over 72 hours. This evaluation of AUC0-inf, Cmax and AUC0-t found prototype A (miglol suspension) to have similar bioavailability to dispersible tablets (within bioequivalence range of 0.8 to 1.25). With prototype B (glycerol solution) both AUC parameters were also similar but Cmax had slightly higher relative bioavailability, with upper CI bound outside the range for bioequivalence: geometric mean square ratio 1.22 (90% CI 1.13 to 1.33).
Based on these relative bioavailability results, the investigators concluded that no dose adjustment of either liquid formulation will be needed for neonates.
There were no safety concerns after single dose administration in adult participants.
The manufacturer has chosen the miglyol suspension for further development.
As the options for neonates with HIV are few, this liquid formulation of dolutegravir is good news.
There are also two generic scored 10 mg dispersible paediatric dolutegravir tablets awaiting approval.
We hope that the role for this liquid formulation is now seen in low- and middle-income countries, where the need for paediatric formulations is greatest.
- Singh R et al. Comparison of relative bioavailability of Tivacy neonatal liquid formulations to pediatric dispersible tablets. International workshop on clinical pharmacology of HIV, hepatitis, and other antiviral drugs virtual meeting. 28–30 September 2020. Oral Abstract 8.
- ClinicalTrials.gov. Dolutegravir pediatric liquid formulation study.