The pharmacokinetics (how the body absorbs, distributes, metabolises and excretes drugs) of adult dolutegravir 50mg tablets given to children living with HIV weighing 20kg or more once daily were safe and similar to the current licensed dolutegravir dosing for children, Dr Pauline Bollen and colleagues at Radboud Institute for Health Sciences, Radboud University report.
Aidsmap reports that importantly, this allows for simplified practical dosing with rapid access in low- and middle-income countries. Previously, the only licensed dolutegravir drug formulations for children weighing between 20 and 40kg were 25mg and 10mg tablets.
Critically, they are unavailable in resource-poor settings where the prevalence of HIV is highest. Based on these findings the World Health Organisation (WHO) has already updated its 2019 dolutegravir paediatric dosing guidelines. In June, the US Food and Drug Administration approved 50mg adult tablets and 30mg dispersible tablets for children weighing 20kg or more.
In an accompanying comment Drs Helena Rabie and Lisa Jane Frigati at Stellenbosch University and Tygerberg Hospital, stress that in a fragmented and limited paediatric antiretroviral drug market the use of adult formulations and dosing: allows for closer alignment with adult regimens; reduces logistic challenges; reduces the likelihood of stock-outs nationally and at smaller clinics where fewer children are treated
simplifies prescribing; and simplifies administration by caregivers.
They note children in clinics often ask why they cannot be given one pill a day. Now many children will be able to take abacavir/lamivudine/dolutegravir or tenofovir/lamivudine/dolutegravir.
They also commend the use of a nested pharmacokinetic study which has enabled rapid translation of results into practice, benefitting approximately 500,000 children. “Although this is a huge leap forward, there is still a lot of work to do to ensure children with HIV can access improved regimens to the extent adults do,” conclude Rabie and Frigati. “Young children in particular remain disproportionately disadvantaged with the most limited access to appropriate formulations.”
Abstract
Background: Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV.
Methods: We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses.
Findings: Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir.
Interpretation: Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg.
Funding: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.
Authors
Pauline DJ Bollen, Cecilia L Moore, Hilda A Mujuru, Shafic Makumbi, Adeodata R Kekitiinwa, Elisabeth Kaudha, Anna Parker, Godfrey Musoro, Annet Nanduudu, Abbas Lugemwa, Pauline Amuge, James G Hakim, Pablo Rojo, Carlo Giaquinto, Angela Colbers, Diana M Gibb, Deborah Ford, Anna Turkova, David M Burger
[link url="https://www.aidsmap.com/news/sep-2020/adult-doses-dolutegravir-can-be-used-children-weighing-20-kg-or-more"]Full Aidsmap report[/link]
[link url="https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(20)30189-2/fulltext?rss=yes"]The Lancet HIV abstract[/link]
[link url="https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(20)30194-6/fulltext?rss=yes"]The Lancet HIV comment[/link]