Dolutegravir dosing for infants and young children

9 December 2020. Related: Conference reports, Paediatric care, Paediatric Workshop 12 virtual 2020.

Polly Clayden, HIV i-Base

Dolutegravir (DTG) appears safe and effective in infants and children 4 weeks to 6 years old receiving 5 mg dispersible tablets (DGT-DT) in IMPAACT P1093 at week 24. [1]

Recent DTG paediatric approvals for this age group were informed by the Population PK (PopPK) developed with combined datasets from P1093 and ODYSSEY (PENTA 20). [2, 3, 4]

Findings from these two studies were presented at the virtual 12th International Workshop on HIV Pediatrics, 16–17 November 2020.

IMPAACT P1093

P1093 is an ongoing phase 1/2, non-comparative pharmacokinetic (PK) and safety study in children 4 weeks to 18 years of age. The data presented were from the 4 weeks to 6 years age group enrolled in three age cohorts: 4 weeks to 6 months; 6 months to 2 years; and 2 to 6 years of age. Children were treatment naive or failing therapy with viral load at least 1000 copies/mL.

After initial 4-week dose evaluation, in an intensive PK cohort, additional children were enrolled to assess long-term outcomes at proposed doses.

DTG-DT was dosed with 5 mg dispersible tablets according to age and WHO weight-band (see table 1) and given with a genotype-guided background regimen with at least one active agent.

Table 1: DTG dispersible tablet dosing by age and WHO weight band

The investigators performed clinical and laboratory assessments between day 5 and 13 and at weeks 4, 8, 12, 16 and 24 (+/- 3 days). Safety analysis included data to 30 April 2019.

Of 51 children enrolled from 9 countries (70% from African countries, 55% girls), baseline median viral load was 4.3 log10 copies/mL (IQR 3.3 to 5.8), CD4 count was 1866 cells/mm3 (IQR 1189 to 2384) and CD4 per cent was 24.2% (IQR 20.0 to 31.0). The majority (86%) were ART-experienced.

Thirty-four children (67%) had viral load results available at week 24. The proportion with <400 copies/mL at 24 weeks was: 29/34, 85% (95% CI 69 to 95). The proportion with <50 copies/mL was: 18/34, 53% (95% CI 35 to 70).

Stratified by age group, the proportions with <400 copies/mL were: 88% (95% CI 64 to 99) for 4 weeks to <6 months (n=17), 89% (95% CI 52 to 100) for 6 months to <2 years (n= 9), and 75% (95% CI 35 to 97) 2 years to <6 years (n=8).

For <50 copies/mL the respective proportions were: 41% (95% CI 18 to 67), 67% (95% CI 30 to 93), and 63% (95% CI 25 to 92).

CD4 changes were variable. Presenting author Theodore Ruel suggested these likely reflected multiple factors, including recovery and age-related normal changes.

No grade 3 or 4 adverse events were considered to be DTG related and none led to permanent discontinuation.

DTG-DT palatability was rated average, good, or very good for the majority (98%) of respondents.

Population PK: IMPAACT P1093 and ODYSSEY (PENTA20)

The recent DTG paediatric approvals use WHO weight-band based recommendations for once-daily dosing in children 4 weeks of age and above derived from combined datasets from IMPAACT P1093 and ODYSSEY (PENTA20). These doses were informed by the PopPK analysis.

ODYSSEY is a non-inferiority, phase 2/3 study comparing the efficacy and toxicity of DTG plus 2 NRTIs vs standard of care in infants and children.

Intensive and sparse PK samples following dosing with DTG film coated tablets (DTG-FCT), granules and DTG-DT formulations in the fasted state and without food restrictions were collected in P1093; intensive PK samples using DTG-FCT and DTG-DT in fasted state were collected in ODYSSEY.

Of 239 participants included, baseline age ranged from 0.17 to 17.5 years and weight from 3.9 to 91 kg, 50% were girls and 80% were black.

A PopPK model was developed with data from P1093 (1711 concentrations from 151 participants) and ODYSSEY (939 concentrations from 88 participants) to characterise PK, covariates and associated variability.

The final PopPK model simulated exposures across weight bands, doses, and formulations which were compared with adult reference data.

The model described study data and associated variability well with estimated mean (interindividual variability) CL/F=1.03L/h (29%) and V/F=13.6 L (107%).

Based on observed and simulated data, the investigators proposed dose stratification by age (<6 months and ≥6 months) in the 6 to <10 kg weight band (10 and 15 mg DTG-DT, respectively) to account for metabolic enzyme maturation.

The proposed doses for DTG-DT were as described above with 30 mg DTG-DT or 50 mg DTG-FCT in the >20 kg weight band.

At these doses, the simulated 24 hour concentration (C24h) was consistent across weight bands, similar to observed data, and met the minimum target concentrations of 0.697 ug/mL.

Also, simulated 24-hour area-under-the-curve (AUC24h) met the minimum target (46 h*ug/mL) across weight bands.

Simulated maximum concentration (Cmax) results were 0.96- to 1.79- fold those seen in adults at the approved dose of DTG 50 mg twice daily (4.15 ug/mL).

PK variability was higher in this paediatric population and no additional safety concerns were observed.

comment

Amid all the bad news, 2020 has been a relatively good year for paediatric HIV treatment.

As described in this issue, [5] the 10 mg scored generic formulation of DTG – dosed according to WHO weight bands – will soon be available in many low- and middle-income countries.  

References

1. Ruel T et al. Twenty-four week safety, tolerability and efficacy of dolutegravir dispersible tablets in children 4 weeks to <6 years old with HIV: results from IMPAACT P1093. 12th International Workshop on HIV Pediatrics (virtual meeting). 16–17 November 2020. Oral abstract 1.
   https://academicmedicaleducation.com/meeting/international-workshop-hiv-pediatrics-2020/video/twenty-four-week-safety-tolerability-and(webcast)
2. US FDA. PEPFAR database. Dolutegravir tablets for oral suspension. NDA 214521. 19 November 2020.
   https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=pepfar.page
3. Clayden P. EU approves dolutegravir 5 mg dispersible for children older than four weeks.HTB. 9 December 2020.
   https://i-base.info/htb/39474
4. Singh Ret al et al. Pediatric dolutegravir (DTG) dosing recommendations derived from combined P1093 and ODYSSEY population pharmacokinetic analysis. 12th International Workshop on HIV Pediatrics (virtual meeting). 16–17 November 2020. Oral abstract 2.
   https://academicmedicaleducation.com/meeting/international-workshop-hiv-pediatrics-2020/video/pediatric-dolutegravir-dtg-dosing(webcast)
5. Clayden P. New formulation of dolutegravir will make modern ART available for babies and young children at less than $120 a year. HTB. 9 December 2020.
   https://i-base.info/htb/39465