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Dispersible Tablet Formulation of Dolutegravir Bioequivalent to the Granule Formulation

July 28, 2015

A dispersible tablet formulation of dolutegravir (DTG) has been developed as an alternative to the granule formulation for infants and young children. Pharmacokinetic (PK) data presented at IAS 2015 showed the tablet and granule formulations are bioequivalent.

The authors from ViiV Healthcare noted that the oral bioavailability of DTG is affected by metal cation-containing supplements. Besides comparing the two formulations, the study compared DTG PK when tablets are dispersed in either low mineral content (LMC) or high mineral content (HMC) water. The study also evaluated whether or not consuming the dispersed in water tablet immediately or after the solution had been standing for 30 minutes made a difference.

It was a randomised, open-label, 5-way, single-dose crossover study in HIV negative adults. DTG was administered at 20 mg as:

  1. Granules in purified water and consumed immediately
  2. Dispersible tablets (4 x 5mg) dispersed in low mineral content (LMC) water, consumed immediately.
  3. Dispersible tablets in high mineral content (HMC) water, consumed immediately.
  4. Dispersible tablets in LMC water, consumed after standing for 30 minutes.
  5. Dispersible tablets in HMC water, consumed after standing for 30 minutes.

All treatments were given under fasting conditions with washout periods of at least seven days in between.

The investigators performed safety evaluations and collected serial PK samples during each treatment period. They used non-compartmental methods to compare treatments by analysis of variance (ANOVA). The participants answered a palatability questionnaire after the first period.

A total of 15 participants were enrolled and completed all treatment periods: 4 women and 11 men with a mean age of 39 (SD 12.5) years; 11 white-Caucasian, 2 African American, 1 Asian and 1 white Arabic. Table 1 shows ANOVA results


Table 1. Summary ANOVA Results From Treatment Comparisons
Geometric least square mean ratio (90% confidence interval)
PK parameter B/A C/B D/B E/C
AUC(0-inf) 1.06 (1.02 to 1.11) 0.94 (0.90 to 0.99) 1.03 (0.98 to 1.07) 1.04 (1.0 to 1.09)
Cmax 1.12 (1.06 to 1.19) 0.92 (0.87 to 0.97) 0.99 (0.93 to 1.05) 1.05 (0.99 to 1.11)
C24 1.03 (0.97 to 1.09) 0.96 (0.90 to 1.02) 1.07 (1.00 to 1.13) 1.01 (0.95 to 1.08)


The study showed equivalent exposure with the two formulations, so found the DTG dispersible tablet to be bioequivalent to the granule formulation. DTG PK was not affected by water mineral content or 30-minute delay in dispersed tablet consumption. The dispersible tablet can be given under these conditions.

Adverse events were mild and did not cause any participants to withdraw from the study. No grade 2 to 4 laboratory toxicities were reported.

In the limited data collected on palatability, the majority of participants described the taste and mouth feel of the dispersible tablet as acceptable. But the granule formulation appeared to be more acceptable than the dispersible tablet.

The dispersible tablet is undergoing further development and the formulation is being adjusted to improve the taste.


Comment

DTG is being studied at a target dose of 1 mg/kg in infants (from 4 weeks of age), children and adolescents in IMPAACT P1093. [2] Research is currently ongoing in the 6 to 12 years of age cohort and the estimated primary completion date for the whole study is May 2018. The granules are being used in P1063 -- these will not be available commercially but the dispersible tablets will. Taste masking work on the dispersible tablets is also ongoing.

Expert groups have identified DTG as a priority for children (as well as adults) in low- and middle-income countries. The development of generic formulations of DTG for children should follow as swiftly as the originator company ViiV Healthcare and regulators allow.


References

  1. Song S et al. Relative bioavailability of a dolutegravir (DTG) dispersible tablet and the effect of low and high mineral content water on the tablet in healthy adult volunteers. 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015). 19-22 July 2015. Vancouver, Canada. Poster abstract MOPEB200.
  2. US National Institutes of Health. Safety of and immune response to dolutegravir (GSK1349572) in HIV-1 Infected infants, children, and adolescents.



This article was provided by HIV i-Base. Visit HIV i-Base's website to find out more about their activities, publications and services.
 


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