Regulatory Decision Summary for Tivicay

Health Canada considers that the benefit/risk profile of Tivicay is favourable for the treatment of human immunodeficiency virus (HIV-1) in INSTI-naïve children at least 6 years of age and weighing at least 15 kg. Tivicay is currently approved for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) in adults and in INSTI-naïve children weighing at least 30 kg.

To support the proposed use the sponsor presented population pharmacokinetics (Pop PK) analyses with data from a study to extend the indication of Tivicay for the treatment of HIV-1 infection (in combination with other approved antiretroviral agents) to children 6 years of age weighing at least 15 kg.

Tivicay provides advantages for use in this population as it has high barrier to resistance, is well tolerated at clinical doses and has no identified dose limiting toxicity. It can be administered once daily without the use of a pharmacokinetic booster which provides a major benefit to treatment compliance; an issue particularly important in pediatric populations. It has several years of post-marketing data available for adult populations and older pediatric populations and its safety and efficacy profile is considered well-characterized in adults. No significant differences in the safety profile of dolutegravir in pediatrics compared to adults have been observed at this time. There are fewer treatment options available to the HIV-1 infected pediatric population in Canada compared to the adult population. There is unmet need for an efficacious and well-tolerated therapy, particularly one with once-daily dosing and requiring no PK enhancement for pediatric populations at least 6 years of age and weighing at least 15kg.

The safety assessment provided in this submission does not demonstrate any significant safety risks to the pediatric population and the overall safety profile is considered similar to that observed in adults. Fewer subjects than specified in the protocol were enrolled in the safety analysis but since the overall safety profile of dolutegravir is considered well characterized, and post-marketing safety data in the proposed population has been collected in Europe for more than a year, the lower number of subjects than anticipated is not considered an impediment to approval at this time.

The most significant uncertainty in this assessment is in the low number of subjects in the intensive PK and population PK analyses in the 15-<20kg and 20-<30kg weight bands. The approval of the extension of the indication to these weight bands is based upon similarity of exposures of the proposed dosing in these pediatric weight bands to adult exposures. This was established with intensive PK and population PK analysis. A submission for approval in these weight bands was previously rejected due to a paucity of data and uncertainty regarding the acceptability of the population PK modelling. This report evaluates a resubmission with limited additional data and with updates to the population PK model. Overall, the intensive PK analysis in the 20-<30kg weight band and the population PK analysis in both the 15-<20kg and 20-<30kg weight bands establishes the similarity to the adult doses and supports the proposed dosing. The population PK model used was evaluated as the best possible model for this purpose compared to several other proposed models. Uncertainty remains due to the low number of samples used, particularly in the 15-<20kg weight band. The risk of over-exposure resulting in adverse events is considered low due to the known safety profile of Tivicay. The risk of under-exposure resulting in treatment failure and possible resistance exists however is considered to be limited based on the data and based on DTGs relatively high barrier to resistance.

Overall, given the significant benefit Tivicay would provide to the proposed patient population and considering the well characterized safety, efficacy and PK profile of Tivicay; the benefits that the extension to the indication would provide are considered to outweigh the potential risks, at this time.