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TheBody.com/TheBodyPRO.com covers The 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012)

Pediatric Formulations of ARVs: Including an Exciting New Class

March/April 2012

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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.

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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 naive 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)

Quad (EVG/COB /TDF/FTC)

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 naive /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 to 12 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.


References

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.

    http://retroconference.org/2012b/Abstracts/44121.htm

  2. FDA approve US paediatric dose for raltegravir. HTB Volume 13 Number 1/2 January/February 2012.

    http://i-base.info/htb/16103

  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.

    http://retroconference.org/2012b/Abstracts/45219.htm

  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.

    http://retroconference.org/2012b/Abstracts/44330.htm

  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.

    http://retroconference.org/2012b/Abstracts/43250.htm

  6. Siccardi et al. Pharmacokinetics of efavirenz dose optimisation in paediatric patients using an in vitro–in vivo extrapolation Model. Poster abstract 619.

    http://retroconference.org/2012b/Abstracts/44316.htm

  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.

    http://retroconference.org/2012b/Abstracts/44693.htm

  8. Tenofovir label extended to paediatric indication. HTB Volume 13 Number 1/2 January/February 2012.

    http://i-base.info/htb/16106

  9. FDA approve paediatric dose for darunavir. HTB Volume 13 Number 1/2 January/February 2012.

    http://i-base.info/htb/16101

  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.

    http://retroconference.org/2012b/Abstracts/43602.htm

  11. King J et al. Low darunavir and etravirine exposure when used in combination in HIV+ Children and Adolescents. Poster abstract 986.

    http://retroconference.org/2012b/Abstracts/43429.htm

Links to external websites are current at time of posting but not maintained.

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This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
 


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