The Pediatric Antiretroviral Pipeline

September 2011

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Recent Changes

New FDA Tentative Approvals and WHO Prequalifications

Since last year's Pipeline Report there have been a number of new tentative approvals and prequalifications (see Table 3).17,18

The good news is that there are several formulations that include abacavir, both standalone products and as part of FDCs. Not such good news is that the only PI included is nelfinavir powder, which is barely used in rich countries and is not recommended in guidelines.

Table 3. FDA Tentative Approvals (TA) and WHO Prequalifications (PQ) of Pediatric Antiretrovirals, 2010-2011
DrugFormulation and StrengthSupplier/ApplicantFDA TAWHO PQ
AbacavirOral solution, 20mg/mlCiplaX*
AbacavirTablet, 60mgMatriXX*
AbacavirTablet for oral suspension, 60mgCiplaXX
Abacavir/lamivudineTablet for oral suspension, 60/30mg CiplaX 
Lamivudine/stavudineTablet, 60/12mgCipla X
Lamivudine/stavudineTablet, 30/6mgCipla X
Lamivudine/zidovudineTablet, 30/60mgMatriXX*
Lamivudine/nevirapine/zidovudineTablet for oral suspension, 30/50/60mgMatriXX*
NelfinavirOral powder, 50mg/1gCipla X
StavudinePowder for oral solution, 1mg/mLCipla X
* Formulations already prequalified by the WHO at the time of last year's review.

FDA Warning for Lopinavir/Ritonavir Oral Solution Use in Neonates

In February 2011, the FDA made changes to the Kaletra (lopinavir/ritonavir) oral solution product label to include a warning of potential toxicity in neonates. This was due to life-threatening side effects related to either lopinavir and/or the inactive ingredients propylene glycol and ethanol that had been seen in ten infants, eight of whom were preterm.19,20


This formulation should not be given to neonates before they are of a postmenstrual age (calculated from the first day of the mother's period until the baby's birth plus the time from the birth) of 42 weeks and a postnatal age of at least 14 days.

Reduced metabolism by the liver and reduced kidney function in newborns can lead to an accumulation of lopinavir as well as of alcohol and propylene glycol. Preterm babies may be at increased risk because they cannot metabolize propylene glycol.

This warning is important, as both maternal HIV and highly active antiretroviral therapy (HAART) are associated with preterm delivery (although infants exposed to maternal HAART are a small niche as very few infants will be infected if their mothers receive treatment).

Missing Drugs and Formulations

An important formulation in the generic pipeline at present is an alternative to the oral solution of lopinavir/ritonavir.

Cipla is developing a heat-stable sprinkle formulation of lopinavir/ritonavir that may fill this gap. This has been in development for a while now and has undergone a few changes. The sprinkles are tasteless and have a texture similar to granular sugar.

Bioequivalence studies are being undertaken in healthy adults. Pharmacokinetcs and tolerability studies comparing the sprinkles with liquid in 12-month- to three-year old children and with junior tablets in older children, up to four years old will be performed in CHAPAS 2.21

Acceptability of the formulation in young children is very important. The company is still deciding on how to package the 40/10mg dose. Cipla expects to apply for approval with the FDA at the end of 2011.

Darunavir is needed for third-line regimens or for second-line where lopinavir/ritonavir was used first-line. Preclinical studies -- showing dangerously high darunavir exposure and in turn adverse events in juvenile rats -- meant that pediatric studies were not conducted in children under three years old. Ritonavir boosting of darunavir does not lend itself to easily adjusted doses using WHO weight bands.

A 25mg tablet of ritonavir is included in WHO's Essential Medicines List but is not yet on the market.22 A 25mg sprinkle formulation is needed for very young children. A 50mg tablet would be useful for super-boosting (giving extra booster to achieve sufficient drug concentration in circumstances where this is reduced by drug-drug interaction) PIs. Super-boosting PIs, when they are given with rifampicin, is not straightforward and urgently needs better guidance and better formulations.

Other generics in development for treating children or considered to be a high priority by the Pediatric Antiretroviral Group of the WHO are shown in Table 4. FDCs that are not stavudine based are also a priority.

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This article was provided by Treatment Action Group and HIV i-Base. It is a part of the publication 2011 Pipeline Report.

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