Paediatric formulations of ARVs: including an exciting new class

Polly Clayden, HIV i-Base

International guidelines recommend universal and immediate treatment of HIV-infected neonates, which poses a significant challenge given the lack of suitable formulations in this age group.

Three posters at CROI showed novel “sprinkle” formulations of two integrase inhibitors and a protease inhibitor.


Dolutegravir (DTG) is a promising integrase inhibitor currently in phase 3 of development. The compound is interesting for several reasons: once daily dosing for treatment naïve patients, low milligram dose (50 mg, so potential for co-formulation and low cost), adequate plasma exposure without boosting, few expected drug interactions, an expected different resistance profile to raltegravir and a very comprehensive development plan. 96-week phase 3 data was also presented at CROI 2012 (see above).

The developers – a partnership between Shionogi & Co and ViiV Healthcare – plan to study the compound in all paediatric age groups down to young infants, a population woefully short of appropriate antiretroviral formulations. DTG is currently being studied in children 6 – 18 years in IMPAACT P1093.

Parul Patel and colleagues presented findings from an evaluation of the single dose pharmacokinetics (PK) in healthy adults of a new oral granule formulation of DTG, in development for infants and young children. [1] The granules were given with and without 30 mL of various liquids and compared to the current tablet formulation given with 240 mL of tap water.

This was a single-centre, randomised, open-label, 5-way crossover study in 20 healthy adult subjects. Subjects received a single dose of DTG 50 mg as the phase 3 tablet and in 10 g of granule given: direct to mouth with no liquid; with purified water; with mineral water containing high caution concentrations (Contrex); or with infant formula milk. All formulations were administered in fasting state.

The study treatments were separated by seven days. Safety evaluations and serial PK samples were collected over 48 hours in each dosing period. The PK parameters of DTG were estimated using noncompartmental methods; geometric least squares (GLS) mean ratios and 90% CI were generated to compare treatments. Taste was assessed using a questionnaire that examined bitterness, sweetness and colour.

The investigators reported DTG exposures of the granule formulation were all moderately higher than the tablet formulation with or without liquids (55% – 83% and 62% – 102% for AUC 0-INF and Cmax respectively, see Table 1). Exposure was highest when the granule formulation was given with formula milk.

Inter-subject variability from the granule formulation was modest with a coefficient variation for AUC of 31-43%. DTG was well tolerated and there were no withdrawals due to AEs. The subjects rated the taste as acceptable for all treatments.

Table 1: Comparison of PK parameters of dolutegravir
Granule comparison to tablet GLS mean ratio (90% CI)
AUC 0-INF Cmax
Direct to mouth 1.58 (1.46 – 1.71) 1.62 (1.49 – 1.77)
With purified water 1.57 (1.45 – 1.69) 1.66 (1.52 – 1.81)
With mineral water 1.55 (1.43 – 1.67) 1.65 (1.51 – 1.79)
With formula milk 1.83 (1.69 – 1.98) 2.02 (1.86 – 2.20)

These data indicate that the DTG granule formulation can be given without restriction on the type of liquid or can be given alone. The taste was not considered to be a barrier to further development although the investigators noted that children’s preference could be different to that of adults. The granule formulation is being studied further in children in IMPAACT P1093.


The integrase inhibitor raltegravir (RAL) is approved as a 400 mg film-coated tablet for use in adults and for children aged 6 to 18 weighing > 10 kg, and 100 mg and 25 mg chewable tablets are approved for children > 2 to <12 years old at a maximum dose of 300 mg. [2]

The paediatric programme is ongoing in IMPAACT P1066 and an oral granule formulation is being studied in the youngest children and babies. Stephen Spector and colleagues from the study team presented intensive PK, and preliminary 24 weeks safety and efficacy data from cohort IV – 6-month- to <2-year-olds – receiving the RAL oral granule formulation. [3]

Nine HIV-infected children were enrolled in a dose-finding study. Entry criteria included HIV RNA >1000 copies/mL and either prior ART experience PMTCT failure. The children received weight-based RAL oral granule suspension at ~6 mg/kg, every 12 hours.

Intensive PK was performed between day 5 and 12 after which the site investigators optimised the children’s background regimen. A dose was selected for continued study using an AUC12 hr targeted design (geometric mean [GM] target range of 14 to 25 uM*h) with C12h target to exceed the RAL IC95 (31 nM). Virologic suppression was defined as HIV RNA <400 copies/mL or ≥1 log drop from baseline at 24 weeks.

One child’s PK data were excluded due to absorption issues. Of the remaining 8 children: 67% were male; 78% black; mean (SD) age, 13 months (6.3); log10 RNA, 5.68 copies/mL (0.95); CD4 percent, 21% (9%); CD4 count, 1338 cells (822); weight, 8.3 kg (2.6), dose, 5.94 mg/kg (0.42).

The investigators reported geometric mean values of: AUC12hr, 20 uM*h; Cmax, 10.7 uM; and C12h, 115 nM. These PK values are achieved study targets and are similar to those observed in 2 to < 12 year old children receiving chewable tablets. Of the 9 children enrolled, 3 had 16 grade >3 adverse events of which 2 were considered related to RAL.

One child had grade 1 spitting up after taking the study drug.

  • Patient 1: 3 low ANC and 7 reports of elevated lipase with concurrent acute Epstein-Barr virus (EBV) infection.
  • Patient 2: dyspnea non drug-related; concurrent drug related elevated bilirubin and hypoglycaemia.
  • Patient 3: low ANC, non drug-related.

At week 12, 78% (95% CI 40 to 97%) of the 9 children achieved virologic suppression. The children had a median gain in CD4 percent of 5% (95% CI –3 to 7%) and CD4 cells of 687 (95% CI –297 to 1237) cells/mm3 at week 12. By 24 weeks (n=7), 85% achieved virologic suppression and CD4 gain (n=8) was 5.3% (95% CI -4.0 to 18.8%) and 446 (95% CI 13 to 696) cells/mm3.

The 6 mg/kg every 12 hours dose was chosen for continued study in this age group.


A sprinkle formulation of lopinavir/r (LPV/r) – Lopimune – has been in development by the generic manufacturer Cipla for some time. The sprinkle formulation (40/10 mg LPV/r) consists of a finite number of mini tablets in a capsule, which is opened and sprinkled on soft food.

Jaideep A Gogtay and colleagues showed results from a randomised crossover PK study in healthy adults comparing a single dose of sprinkles from 10 capsules of LPV/r and a single dose of 5 mL Kaletra oral solution (each mL containing 80 mg lopinavir and 20 mg ritonavir).

Both formulations were administered with about 150 g porridge and 240 mL water. Blood samples were taken pre-dose and serially up to 36 hours and were analysed using a validated LCMS/MS method. PK parameters were calculated using a non-compartmental method using drug concentrations versus time profile.

Twelve subjects completed the study (ie the minimum sample size acceptable to regulatory authorities). Their PK parameters are shown in Table 2.

For LPV the Ln-transformed 90% confidence interval of the least square mean of the LPV/r sprinkles and solution for the PK parameters AUC0-t and AUC 0-IFN fall within the conventional bioequivalence range of 80 -125% while for Cmax it falls just outside. For RTV AUC0-t and Cmax fall just outside the range but AUC 0-∞ falls within it. However, the investigators noted that the differences were not large. Based on this pilot PK study, the sprinkle formulation is now being studied in HIV-infected children.

Table 2. PK parameters of lopinavir/ritonavir administered as sprinkles and oral solution
Drug Formulation AUC0-t ( AUC 0-INF ( Cmax (ug/mL)
Lopinavir Sprinkles 86.98 92.99 6.82
Solution 84.57 89.26 6.28
Ln-transformed 90% CI (T/R) 87.19 – 120.52 87.76 -122.54 91.31 – 131.02
Ratio of least square mean T/R Ln-transformed 102.51 103.71 109.38
Ritonavir Sprinkles 6.69 6.86 0.79
Solution 6.23 6.38 0.77
Ln-transformed 90% CI (T/R) 88.23 – 125.15 88.63 -124.6 80.4 – 135.96
Ratio of least square mean T/R Ln-transformed 105.08 105.09 104.55


These data represent great strides in paediatric drug development and, if approved, these formulations will offer important treatment options for the youngest age group. Integrase inhibitors would mean a new therapeutic class for young children that might overcome some of the shortcomings of the currently available drugs. The sprinkle formulation of LPV/r, is now being studied in CHAPAS 2 and also as part of a programme by Drugs for Neglected Diseases initiative (DNDi) to come up with an affordable regimen appropriate for children under two.

Data to guide the dosing of children less 3 years for efavirenz (EFV), the preferred first line anchor drug for older children and adults, remains elusive. A poster at this meeting showed that CYP2B6 genotype strongly influences EFV PK and safety in this age group. [5] Aggressive dosing (~40 mg/kg) produced therapeutic EFV concentrations in most (68%) children less than 3 years with GG/GT genotype, however, this leads to excessive exposure in those with TT genotype. These data suggest that optimal use of EFV in children less than 3 years requires pretreatment genotyping, and the study protocol has been amended to include this at screening. A related poster showed data from model predicting the PK of EFV in children with different CYP2B6 genotypes, with simulations that indicate that genotype- guided dose optimisation could be used in paediatric patients. [6] Although EFV could be important for use in HIV/TB coinfected infants, complex genotype screening, the risk of resistance from NNRTI exposure in PMTCT and the probability that boosted PIs will be universally recommended in RLS make it an unlikely option in this age group.

For older children, Abbott has developed a low dose tablet of LPV/r (100/25 mg). Another paediatric PK poster showed data from a small study of 8 children aged 4.5 to 9 years designed to evaluate the comparability, efficacy, and tolerability in stable patients switching to this tablet from the oral solution. [7] PK analysis showed mean LPV AUC and Cmax ratios between liquid and tablet formulations to be 1.01 and 1.02, indicating that overall, the concentrations achieved with the different formulations were essentially the same.

And recently there have been some important FDA approvals including tenofovir and raltegravir for children two years of age and above and darunavir for those three years and above, which we reported in the February edition of HTB. [8, 2, 9] Also for etravirine for children of six and above, including a new scored 25 mg tablet for paediatric use (see later in this HTB). Paediatric approval from the EMA is awaited for these drugs and unlike the US tenofovir is not approved for the 12 to 18 years age group. For details see Table 3.

For RLS it is hoped that first line treatment for children above three can be aligned with adults and dosed according to weight bands with tenofovir/3TC/EFV using suitable FDCs. A further children’s PK poster showed that tenofovir given in combination with 3TC/EFV achieved comparable plasma exposure to that achieved in adults. [10] The investigators also noted that concerns remain about bone and renal toxicities with this drug.

A final poster on paediatric PK reported from a study revealing lower than expected darunavir and etravirine concentrations when the two were given together to older children and adolescents 11 years of age and above. [11] The study highlights both the importance of studying drugs in combination – to determine the contribution of drug-drug interactions – and in different populations, in this case to determine whether the results are age-related. Whether these findings will affect clinical response requires further study.

Overall the data presented at CROI (and recent FDA approvals) shows promise for paediatric HIV treatment in the near future.

Table 3: Paediatric antiretroviral pipeline
Compound Company Class Formulation and dose Status and comments
Atazanavir (ATV) Bristol-Myers Squibb PI Oral powder 50mg sachet
Capsule 100, 150, 200, 300mg
Ongoing phase 2 in naïve and experienced children with or without RTV from 3 months to 6 years of age.
Darunavir (DRV) Janssen PI Oral suspension 100 mg/mL
75 and 150 mg tablets.
FDA approved > 3 years of age (waiver for children < 3).
Dosage of DRV and RTV is based on body weight and should not exceed the treatment experienced adult doses.
DRV/RTV ratios vary according to weight and treatment experience.
Dolutegravir (DTG) Shionogi / ViiV INI Older children tablets 10, 25, 50mg.
Granule formulation being evaluated.
Phase 1&2 from 6 weeks to 18 years of age.
Ph 1 PK completed.
Exposure of granules with different liquids exceeded that of tablets in healthy adults so can be given without liquid restriction or directly to mouth.
Elvitagravir/cobicistat (EVG/COB)
Gilead INI / booster / FDC To be decided.
Solid and liquid forms in development, separately and co-formulated as Quad (solid tablet only).
EVG treatment experienced 12 to18 years of age.
Integrated plans for paediatric studies under discussion.
Etravirine (ETR) Janssen NNRTI Dispersible tablets.
25 mg (scored), 100mg.
FDA approved for experienced children >6 years weighing >16 kg.
Phase 1&2 naïve /experienced 2 months to 6 years of age planned.
Lopinavir/ritonavir (LPV/r) Cipla PI Sprinkles.
40/10 mg (equivalent to 0.5 mL liquid).
Similar PK to liquid in healthy adults.
PK in children being evaluated.
Sprinkle regimen for use in infants <2 years in RLS in development.
Maraviroc (MVC) Pfizer / ViiV CCR5 inhibitor Oral suspension 20 mg/mL Phase 4.
Experienced CCR5 tropic 2 to12 years.
Raltegravir (RAL) Merck INI Oral granules for suspension 6mg/kg (100 mg sachet)
100 mg and 25 mg chewable tablets
FDA approved 400 mg tablet for children aged 6 to 18 weighing > 10 kg, and chewable tablets for aged > 2 to <12 at a maximum dose of 300 mg.
Awaiting EMA approval
Granules Phase 2, 2 weeks to 2 years of age. Achieved good target exposure in 6 months to <2 years of age, similar to that with older children.
Neonate passive PK study.
Rilpivirine (RIL) Tibotec / Janssen NNRTI Oral granules
2.5mg base/g
Phase 2 planned in children 0-12 children years of age.
Tenofovir (TDF) Gilead N(t)RTI Oral powder 40 mg /1 g
150 mg, 200 mg and 250 mg tablets
Recently FDA approved for 2 to <12 years of age.
Awaiting EMA approval for 2 to 18 years of age.


Unless stated otherwise, all references are to the Programme and Abstracts for the 19th Conference of Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle.

  1. Patel P et al. Pharmacokinetics of a dolutegravir paediatric granule formulation in healthy adult subjects. Poster abstract 985.
  2. FDA approve US paediatric dose for raltegravir. HTB Volume 13 Number 1/2 January/February 2012.
  3. Spector S et al. Raltegravir oral granules formulation in children 6 months to <2 Years of age: interim results from IMPAACT P1066. Poster abstract 987.
  4. Gogtay J et al. Pharmacokinetics of a novel formulation, lopinavir/ritonavir sprinkles meant for children in healthy human subjects: A pilot study. Poster abstract 982.
  5. Bolton C et al. Strong influence of CYP2B6 genotypic polymorphisms on EFV pharmacokinetics in HIV+ children <3 years of age and implications for dosing. Poster abstract 981.
  6. Siccardi et al. Pharmacokinetics of efavirenz dose optimisation in paediatric patients using an in vitro–in vivo extrapolation Model. Poster abstract 619.
  7. Piatt J et al. Pharmacokinetics in stable paediatric patients switching from liquid LPV/r to the paediatric 100/25-mg tablets: The Tiny Tabs Study. Poster abstract 983.
  8. Tenofovir label extended to paediatric indication. HTB Volume 13 Number 1/2 January/February 2012.
  9. FDA approve paediatric dose for darunavir. HTB Volume 13 Number 1/2 January/February 2012.
  10. Aurpibul L et al. Tenofovir pharmacokinetics when administered according to weight-band dosing in 15-kg HIV+ children receiving tenofovir/lamivudine/efavirenz once daily. Poster Abstract 984.
  11. King J et al. Low darunavir and etravirine exposure when used in combination in HIV+ Children and Adolescents. Poster abstract 986.

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