Dispersible paediatric versions of dolutegravir provide higher bioavailability than immediate release formulations
Polly Clayden, HIV i-Base
Higher bioavailability was achieved with the paediatric dispersible tablet formulation of dolutegravir but the lower strength immediate release tablet showed similar bioavailability to the adult formulation.  There is also higher dolutegravir bioavailability and equivalent ABC/3TC bioavailability with the dispersible fixed dose combination tablet. 
Findings from pharmacokinetic (PK) evaluations of paediatric formulations of dolutegravir (DTG) in HIV negative adults, conducted by the originator manufacturer ViiV Healthcare, were shown at 19th International Workshop on Clinical Pharmacology.
Originator DTG is approved as a 50 mg, immediate release (IR) tablet for adults and adolescents. Lower strength 25mg and 10mg IR have been developed for paediatrics and a 5 mg dispersible tablet (DT) is currently in development.
The company evaluated the PK and safety of the alternative IR and DT vs either the 50 or 25 mg IR tablets, respectively after single-dose to HIV negative adults.
This was a phase 1, 2-part, open label, randomised, crossover study:
- Part 1.Participants randomised to receive 5 tablets of 10 mg IR (A) or one 50mg IR tablet (B, reference) over two dosing periods.
- Part 2.Participants received 5 tablets of 5mg DT as a dispersion and immediately taken (C) or 5 tablets of 5mg DT administered direct to mouth (D), or a 25mg IR tablet (E, reference) over 3 dosing periods.
There was at least seven-days washout between doses. Fourteen participantscompleted Part 1 and 24 Part 2 of the study.
This evaluation revealed, In Part 1, after 5 X 10mg DTG tablets, geometric mean systemic exposure for AUC(0-inf), Cmax, and AUC(0-t) of DTG were equivalent to that following 1 X 50mg DTG tablet. In Part 2, geometric mean systemic exposure to DTG were approximately 1.5-fold to 1.8-fold higher with treatments C and D than that observed following E.
GLS mean ratios of C vs E and D vs E for AUC(0-inf), Cmax, and AUC(0-t) were: 1.62 (90% CI 1.50 to 1.76) and 1.55 (90% CI 1.43 to 1.67), 1.79 (90% CI 1.62 to 1.98) and 1.80 (90% CI 1.63 to 1.99), and 1.63 (90% CI 1.50 to 1.77) and 1.55 (90% CI 1.43 to 1.68), respectively.
The terminal elimination half-lives for all formulations ranged from 15.5 to 16.2 hours.
The investigators noted that 5mg DT is suitable for further use in paediatric clinical trials of DTG.
ViiV Healthcare also produces a fixed dose combination (FDC) immediate release tablet of DTG/abacavir (ABC)/ lamivudine (3TC) approved in the US and the EU for adults and adolescents weighing at least 40 kg.
A lower strength, paediatric, dispersible FDC of DTG/ABC/3TC is currently in development.
As DTG is a metal-binding molecule, the divalent metal concentration in dispersion media and time lag following dispersion may affect its solubility and potentially bioavailability.
So, the evaluation was designed to look at relative bioavailability of the dispersible FDC compared to non-dispersible tablets of DTG and ABC/ 3TC taken with purified water with varying mineral contents and dispersion times.
This was a phase I, single-centre, single-dose, randomised, open-label, 5-period crossover, relative bioavailability study in HIV negative adults.
Participants received five single dose treatments that included four dispersible FDC tablets each containing ABC 150 mg/DTG 10 mg/3TC 75 mg, with varying mineral content of water (zero or high-mineral content) and dispersion times (immediately or after 30 minutes delay), as well as four non-dispersible tablets containing DTG 10 mg plus one non-dispersible ABC/3TC tablet (reference) under fasted conditions. There was a seven-day washout period between treatments.
After a single dose of dispersible FDC formulation, the relative bioavailability of DTG AUC0-inf and Cmax were 53– 58% and 56–59% higher respectively. But ABC and 3TC were bioequivalent to non-dispersible tablets of DTG plus ABC/3TC.
Neither mineral content of the water nor dispersion time affected the exposures.
Development of the dispersible paediatric FDC tablet is also continuing.
- Parasarmpuria R et al.Comparison of relative bioavailability of Tivicay immediate release and dispersible pediatric tablets to immediate Release Tivicay adult tablets. 19th International Workshop on Clinical Pharmacology, 22–24 May 2018, Baltimore. Poster abstract 29.
- Shaik Jet al. Effects of low and high mineral content water on the relative bioavailability of a co-formulated Triumeq (abacavir/dolutegravir/lamivudine) dispersible tablet in healthy adults.19th International Workshop on Clinical Pharmacology, 22–24 May 2018, Baltimore. Poster abstract 26.