Long-acting ART for children is a deferred priority despite achievable dosing

Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted for different weight bands in children and adolescents.

Long-acting injectable antiretrovirals could be future alternatives to oral formulations and might help to address adherence. There is great interest in the potential use of these formulations in the treatment of paediatric HIV.

Clinical trials of new drugs in children and adolescents are delayed by both ethical and logistical barriers complicating the identification of appropriate doses. Physiologically-based pharmacokinetic (PK) modelling can inform dose finding before clinical trials are conducted.

Researchers from the University of Liverpool and Johns Hopkins conducted a study to simulate potential dosing strategies of long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3 to18 years) using such modelling.

The researchers developed whole-body physiologically-based PK models to act as the anatomical, physiological and molecular processes as well as age-related changes in children and adolescents using allometric equations.

The models were validated for the two long-acting injectable intramuscular agents in adults. The characteristics of children and adolescents were validated using available literature.

PK data generated through the physiologically-based PK simulations were similar to that observed in adult clinical data.

The researchers predicted optimal doses of long-acting injectable cabotegravir and rilpivirine using the release rate for existing clinical formulations, for different weight groups of children and adolescents.

They found the intramuscular loading dose and maintenance dose of cabotegravir across various weight bands in children weighing from 15-70 kg ranged from 200-600 mg and from 100-250 mg, respectively. For rilpivirine these ranged from 250–550 mg and from 150-500 mg, respectively.

“The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents” the researchers wrote.

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The paediatric investigation plan for these long-acting drugs includes their use in both treatment and prevention.

However, there is a waiver for young children less than two years (for treatment) and less than 12 years for prevention. But there is a deferral for children that are two years and above.

This means that these agents will only potentially be available for use in the paediatric population many years after they are likely to be approved for adults.

Rajith K et al. In silico dose prediction for long-acting rilpivirine and cabotegravir administration to children and adolescents. Clin Pharmacokinet. 24 May 2017. Epub ahead of print.
https://www.ncbi.nlm.nih.gov/pubmed/28540638