Can a fraction of the dolutegravir dispersible tablet solution be used to dose neonates?

Abstract

Background: The smallest dolutegravir (DTG) dose approved is 5 mg once-daily in infants ≥4 weeks and weighing ≥3 to <6kg using a dispersible tablet (DT). Neonates (<28 days of life) may require a lower dose due to immature organ development. We evaluated the aqueous dispersibility of the generic DTG-DT 10 mg scored tablets (Viatris Inc.) to determine the possibility of uniform concentrations that could allow for lower daily doses in neonates. Methods: Each 5 mL polypropylene tube had DTG-DT 5 mg dissolved in 5 mL ultrapure water. Tubes were labelled with three ‘zones’ (bottom: 0-1 mL; middle: 1-3 mL; top: 3-5 mL). Suspensions were mixed by swirling, or swirling with either a syringe-pump, vortexing, or sonication. DTG concentration in each zone was determined using high-performance liquid chromatography. Tubes were rinsed with 1 mL acetonitrile to determine the residual drug. Acceptable criteria for percentage difference was set at ≤20% according to European Medicines Agency guidelines. Results: Dispersion of DTG-DT in water did not remain homogeneous, resulting in DTG concentrations that varied by over 50% across the three zones within the tubes. Rapid sedimentation was observed shortly after mixing. Furthermore, it was found that 24% to 35% of the DTG residue remained adhered to the tube after the aqueous dispersion had been eluted, highlighting the importance of the rinse step. Conclusion: Aqueous dispersion of the DTG-DT is not uniform and displays a high degree of sedimentation. It is therefore not possible to administer a fraction of the dispersion (lower DTG dose) to neonates by using this formulation.