Paediatric dolutegravir update

30 April 2019. Related: Conference reports, Paediatric care, CROI 26 (Retrovirus) 2019.

Polly Clayden, HIV i-Base

Dolutegravir (DTG) is currently approved for children and adolescents ages 6 years and above weighing at least 15 kg.

It is currently under investigation in the IMPAACT P1093 and ODYSSEY studies. As well as age cohorts, both studies are looking at World Health Organisation (WHO) weight bands and dosing strategies to support these.

Poster presentations at CROI 2019 included: pharmacokinetic (PK) and DTG dosing by WHO weight band for young children ages 6 months to 6 years with the paediatric 5 mg dispersible tablet; data supporting the use of the adult 50 mg film coated formulation for children 20 to 25 kg; real-life data from a clinic in Paris, showing similar safety and efficacy in children and adolescents from 5 years old to over 18; and modelling to help predict dosing in neonates.

Dosing 6 months to 6 years of age: IMPAACT P1093

The paediatric DTG 5 mg dispersible tablet (DTG-DT) formulation met target concentrations for children aged 6 months to <6 years, even with moderate intra-participant variability. [1]

DTG-DT is being evaluated in IMPAACT P1093 (NCT01302847), an ongoing phase 1/2 open-label dose-finding study.

Previously reported DTG dosing met target concentrations in children aged 4 weeks to <6 months but needed adjustment in children 6 months to <6 years. [2,3]

The IMPAACT P1093 team showed intensive pharmacokinetic (PK), 4-week safety and efficacy data of higher dosing for DTG-DT for children in the older age group.

Enrolment was stratified into two age cohorts: >6 months to <2 years and >2 to <6 years. DTG-DT was dosed once daily by WHO weight-band (Table 1).

Table 1: DTG dosing by WHO weight band

Participants were either ART-experienced and failing or ART-naive. They received DTG-DT alone or added to stable-failing or empiric initial background regimens. PK sampling was completed between days 5–10 under partial fasting conditions.

Based on adult exposures, targets were geometric mean (GM) C24h of 995 (range 697–2260) ng/mL and AUC24h of 46 (range 37–134) mg.h/L.

Ten children were enrolled into each cohort. At baseline, children in the >2 to <6 years age cohort (three girls) were median: age 3.6 years (range 2.1 to 6.0), weight 13 kg (range 9.3 to 17.5), CD4% 25.1 (range 0.3 to 42) and viral load 4.3 log₁₀ copies/mL (range 2.7 to 5.9). Those in the >6 months to <2 years age cohort (7 girls) were median: age 1.0 years (range 0.5 to 1.7), weight 7.5 kg (range 6.5 to 9.5), CD4% 31 (range 20 to 49) and viral load 4.1 log₁₀ copies/mL (range 2.5 to 6.1).

For age cohorts of >2 to <6 years and >6 months to <2 years, the GM (CV%) AUC24h (CV%) was 59.0 (62.2) mg.h/L 70.2 (49.6) mg.h/L and 59.0 (62.2) mg.h/L; Cmax was 5181 (44) ng/mL and 5702 (37.1) ng/mL; and C24h was 791 (105.1) ng/mL and 1094 (70.4) ng/mL, respectively. C24h levels varied from 104 to 4579 ng/mL.

Viral load was <400 copies/mL in 16/20 and <50 copies/mL in 8/20 participants after 4 weeks of treatment. The DTG-DT tablet was well tolerated.

Along with additional PK, long term safety and efficacy data the results will support regulatory approval for DTG in these age groups as well as WHO weight band recommendations.

Dosing for weight band 20 to <25 kg: ODYSSEY

Daily DTG 50 mg adult film coated tablet (DTG-FCT) and 30mg DTG-DT (6×5 mg) provide similar and acceptable PK profiles for children 20 to <25 kg. [4]

DTG is also being evaluated for children in the ongoing phase 3 ODYSSEY trial (NCT02259127). Substudies are looking at PK and safety of simplified weight band-based dosing of DTG for children receiving first- and second-line ART.

The EMA recommended dose of 25 mg DTG-FCT once daily in children weighing 20 to <30 kg, has previously been shown to lead to lower DTG exposures compared with those seen in adults.

This sub study evaluated PK and safety of 50 mg DTG-FCT and 30 mg DTG-DT in children weighing 20 to <25 kg. DTG-DT have higher bioavailability compared to DTG-FCT in adults (ratio 1.5 to 1.8).

Steady state 24h DTG PK profiles in fasted children taking once-daily 50 mg DTG-FCT or 30 mg DTG-DT were recorded at least seven days after switch from 25 mg DTG-FCT (main trial dose). DTG plasma concentrations were measured at t=0, 1, 2, 3, 4, 6 and 24h.

Results were compared to those in HIV positive adults receiving 50mg DTG-FCT once/twice daily, and children 20 to <25 kg receiving 25 mg DTG-FCT once daily.

Fifteen children with a median of approximately 9.5 years of age and enrolled in Zimbabwe and Uganda, were included in the analysis.

The 50mg DTG-FCT (n=7) and 30 mg DTG-DT (n=8) doses both gave GM Ctrough values comparable to adults receiving 50 mg DTG-FCT once-daily and higher than those in children 20 to <25 kg receiving 25mg DTG-FCT.

GM Cmax with both doses were higher than adult GM values for 50 mg DTG-FCT once and twice daily. GM AUC0-24h for both doses was between values seen in adults taking 50 mg DTG-FCT once daily and 50 mg twice daily.

After median follow-up of 12.9 weeks (IQR: 11.1 to 24.0) and 12.0 weeks (IQR: 6.6 to 18.6) receiving 50 mg DTG-FCT and 30 mg DTG-DT respectively, no children experienced grade 3/4, serious AE or discontinued DTG. Median time on DTG before starting the current dose was 34.8 (range 13.9 to 60.0) weeks.

Provided ongoing longer-term safety is acceptable, the ODYSSEY team suggested that these results support use of either dosing strategy in this weight band.

Adult 50 mg DTG-FCT could offer practical and accessible dosing for children 20 to <25 kg allowing rapid alignment of WHO-preferred ART regimens for adults and children >20 kg in low- and middle-income countries, they noted.

Similar safety and efficacy across age groups 5 to 18 years: Necker Hospital, Paris, France

Safety and efficacy of DTG were similar in children and adolescents ages 5–12, 12–18 and 18 years and above in a retrospective analysis conducted at a French paediatric clinic. [5]

The study analysed data from 109 participants, who started DTG-based ART between January 2014 and December 2017: 33, 51 and 25 in the 5 to 12, 12 to 18 and >18 years groups, respectively.

The primary endpoint was the proportion with viral load <50 copies/mL <3 months after starting DTG, for those with detectable viral load, and remained suppressed until the last follow-up visit for all participants.

At baseline, the majority of participants were ART-experienced (91.7%) and 12 (11%) had previous integrase strand transfer inhibitor (INSTI)-exposure. Four participants had documented INSTI-related mutations: E157Q in two, and N155H in two participants (who received twice-daily DTG).

Only 58.7% of participants had viral load <50 copies/mL for 6 months or more before starting DTG.

After starting DTG, 79.8% of participants achieved sustained virological suppression, with similar rates across the age groups, p=0.22. Duration of follow up was a median of 24 months in the two older groups and 12 months in the 5–12 years age group.

With reinforced adherence support, 88.1% achieved undetectable viral load at the last visit, with similar proportions across the groups, p=0.51.

Results for the INSTI-experienced participants with regard to sustained virological suppression and undetectable viral load at the last visit were: 91.7% and 100.0%, respectively.

There was no selection of new RAMs in the RT, protease or integrase gene in 22 participants with virological failure during follow-up.

Only one participant stopped DTG for severe drug-related side effects (dizziness, sleep disturbance).
Three grade 3 laboratory events were considered unrelated to DTG exposure (acute liver enzyme abnormalities, which resolved without stopping DTG).

Neonate dose: in silico prediction

Modelling suggests that appropriate doses for DTG in neonates range between 2 to 4 mg, resulting in plasma exposure comparable to those observed in older infants and children, according to data from the University of Liverpool, UK.

Current studies are investigating dosing in infants aged >4 weeks. Dose optimisation in neonates is complex and physiologically-based pharmacokinetic (PBPK) modelling might help to inform this. The investigators explained that neonates are a vulnerable population and the lack of clinical PK data complicates clinical management.

Rapid development and immature ontogeny mean that direct scaling of existing doses is not usually appropriate for this population. PBPK modelling allows these changes to be represented mathematically, and can support accurate predictions.

Clinical trials in neonates are extremely difficult to conduct and trial design might be de-risked by such dose prediction.

DTG is predominantly metabolised by UGT1A1 and CYP3A4 and the PBPK model was qualified using clinical data from the surrogate substrates raltegravir (UGT1A1) and midazolam (CYP3A4) in neonates. Adult and paediatric DTG clinical data were used for the validation of the model.

A combination of different DTG single and multiple dose strategies were simulated in 100 healthy virtual neonates (0–28 days of age) with the aim of achieving plasma exposure comparable to levels observed in paediatric patients: Ctrough 0.90 mg/L and AUC24 46 mg.h/L.

Based on the presented data, the PBPK model predicted that appropriate doses for DTG in neonates range from 2 to 4 mg, resulting in exposure comparable to those observed in paediatric patients.

The investigators suggested that these data can be used to inform neonatal clinical trials to help accelerate dose optimisation in this population.

comment

These studies are a useful addition to what we know about DTG in all paediatric populations and will help to inform approval, recommendations and further investigations.

That the 50 mg adult formulation could be used in children weighing 20 to <25 kg in low- and middle-income countries is important. But adult DTG dosing will usually be within a fixed dose formulation with TDF/3TC and the recommendation for children is with ABC/3TC.

As the current recommendation for DTG use with rifampicin-based first-line TB treatment requires twice-daily DTG 50 mg to overcome the drug-drug interaction with this co-treatment, national programmes are likely to procure 50 mg singles for this purpose. So it might be possible to facilitate this paediatric dosing strategy without too many complications.     

References

All references are to the programme and abstracts of the Conference on Retroviruses and Opportunistic infections (CROI) 2019, Seattle, 4–7 March 2019, unless otherwise stated.

1. Ruel T et al. PK and 4-week outcomes of dolutegravir dispersible tablets in HIV-infected children. Poster abstract 829LB.
   https://www.croiconference.org/sessions/pk-and-4-week-outcomes-dolutegravir-dispersible-tablets-hiv-infected-children (abstract)
   https://www.croiconference.org/sites/default/files/posters-2019/1430_Ruel_0829.pdf (poster)
2. Ruel T. Pharmacokinetic and 4-week safety/efficacy of dolutegravir (S/GSK1349572) dispersible tablets in HIV-infected children aged 4 weeks to <6 years: results from IMPAACT P1093. 10th International Workshop on HIV Paediatrics.  20 –21 July 2018. Oral abstract 2.
   http://regist2.virology-education.com/presentations/2018/10PED/16_ruel.pdf (PDF Slides)
3. Clayden P. Dolutegravir dispersible tablets for infants and young children: early PK, safety and efficacy. HTB. 24 August 2018.
   https://i-base.info/htb/34803
4. Bollen P et al. Adult dolutegravir 50mg tablets in children living with HIV weighing 20 to <25 kg. Poster abstract 830 LB.
   https://www.croiconference.org/sessions/adult-dolutegravir-50mg-tablets-children-living-hiv-weighing-20 (abstract)
   https://www.croiconference.org/sites/default/files/posters-2019/1430_Bollen_0830.pdf (poster)
5. Frange P et al. Similar efficacy and safety of dolutegravir between age groups of pediatric patients. Poster abstract 828.
   https://www.croiconference.org/sessions/similar-efficacy-and-safety-dolutegravir-between-age-groups-pediatric-patients (abstract)
   https://www.croiconference.org/sites/default/files/posters-2019/1430_Frange_0828.pdf (poster)
6. Bunglawala FS et al. In silico prediction of dolutegravir pharmacokinetics & dose optimisation in neonates. Poster abstract 827.
   https://www.croiconference.org/sessions/silico-prediction-dolutegravir-pharmacokinetics-dose-optimisation-neonates (abstract)
   https://www.croiconference.org/sites/default/files/posters-2019/1430_Bunglawala_0827.pdf (poster)