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Brief Report: Can a Fraction of the Dolutegravir Dispersible Tablet Solution be Used to Dose Neonates?
Cassius M Phogole1, Adrie Bekker2, Tim R Cressey3
1Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
Insights
Aqueous dispersion of dolutegravir (DTG) dispersible tablets (DT) is not uniform, with rapid sedimentation. This formulation prevents accurate low-dose administration for neonates.
Area of Science:
- Pharmacology
- Pharmaceutical Sciences
- Pediatric Medicine
Background:
- The smallest approved dolutegravir (DTG) dose is 5 mg daily for infants.
- Neonates may require lower doses due to immature organ development.
- Evaluating aqueous dispersibility of 10-mg DTG dispersible tablets (DT) for potential neonatal dosing.
Purpose of the Study:
- To assess the aqueous dispersibility and uniformity of generic 10-mg DTG-DT.
- To determine if lower DTG doses can be accurately administered to neonates using this formulation.
Main Methods:
- DTG-DT tablets were dissolved in ultrapure water in labeled tubes.
- Suspensions were mixed using various methods (swirling, syringe pump, vortexing, sonication).
- DTG concentration in different zones was measured using HPLC; residual drug was quantified.
Main Results:
- DTG dispersion showed significant inhomogeneity, with concentration variations exceeding 50% across zones.
- Rapid sedimentation occurred post-mixing.
- 24%-35% of DTG residue adhered to tubes, emphasizing the need for rinse steps.
Conclusions:
- Aqueous dispersion of DTG-DT is non-uniform and exhibits high sedimentation.
- Accurate administration of fractionated doses for neonates is not feasible with this formulation.
Background:
The smallest dolutegravir (DTG) dose approved is 5 mg once-daily in infants ≥4 weeks and weighing ≥3 to <6 kg 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 labeled with 3 "zones" (bottom: 0-1 mL; middle: 1-3 mL; top: 3-5 mL). Suspensions were mixed by swirling or swirling with 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 criterion for percentage difference was set at ≤20% according to the 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 3 zones within the tubes. Rapid sedimentation was observed shortly after mixing. Furthermore, it was found that 24%-35% of the DTG residue remained adhered to the tube after the aqueous dispersion had been eluted, highlighting the importance of the rinse step.
Conclusions:
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.
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