WHO paediatric recommendations
Polly Clayden, HIV i-Base
Following an expert consultation in October 2006 WHO has produced new recommendations on the use and development of antiretroviral medicines for children and infants in which they state: There is an urgent need for affordable, safe, quality ARV formulations appropriate for paediatric use, particularly solid fixed dose combination (FDC) formulations to facilitate programming planning, improve adherence and facilitate scale up of HIV care for children, in line with a public health approach.
They have examined existing single and fixed dose ARV products, as well as future products with a view to determining ideal and acceptable formulations for the treatment and prevention of HIV infection in children.
In the recommendations, they strongly encourage development of child friendly fixed dose combinations (FDC) ie crushable, dispersible, granular, scored tablets or capsules particularly for infants and very young children.
WHO has developed a generic tool for paediatric dosing, using weight bands, which allows the target dose delivered to be assessed for any given single or combined product.
The tool is an Excel spreadsheet that allows for calculation of the intended delivered dose for any antiretroviral for a range of weight bands and their corresponding estimated body surface area (BSA) to examine whether the intended dose is above or below the target dose recommended. It can be adapted for single, dual or triple combinations.
The generic tool, although not completed, can be used to assess existing or potential products and to work out dosing schedules for any particular single or combination product.
The panel notes that the generic tool weight bands and dosing schedules calculated to deliver WHO target doses may differ from the manufacturers weight bands and dosing schedule.
The generic tool is currently being finalised and can be found at:
Smaller solid dosage forms do not currently exist and are urgently needed. All solid tablet forms should be scored to allow accurate division of the tablet, crushable or dispersible.
The panel identified some priority products, which they ranked according to urgency.
For infant MTCT prevention they prioritised, AZT12mg sachet granules and NVP 6mg sachet granules.
For treating infants and young children, they described as urgent: ABC 60mg scored: EFV 100mg scored, 600mg scored; AZT 60mg scored; ABC/3TC 60mg:30mg scored and AZT/3TC/ABC 60mg:30mg:60mg scored.
Considered high priority, were: d4T 7mg scored; ddI 125mg enteric coated, 200mg enteric coated; 3TC 30mg scored; EFV/FTC 100mg/35mg scored and FTC 35mg scored. Additionally, a heat stable 100mg RTV was considered important.
The panel noted that adult formulations are generally used for children above 25 kg (depending on the range of products available). If AZT 250mg tablets are available, these may be used instead of scored 100mg tablets.
For twice daily dosing where half a tablet is recommended they suggest this may be taken as one half of a tablet both am and pm, or as an uneven dose eg one tablet am and two tablets pm.
Newly developed FDCs for children
A range of FDCs are currently manufactured and the panel expect these will offer practical advantages over the current practice of using existing liquid single drug formulations and divided adult FDCs.
There are five new generic FDC tablets and one solution (containing nevirapine, d4T and 3TC) produced by Cipla Ltd, Ranbaxy Laboratories Ltd, Emcure Pharmaceuticals and Thai Government Pharmaceutical Organisation (GPO).
The panel analysed the dosing schedules that would be needed to achieve WHO intended delivered dose for each drug at each weight band. They note that the weight bands and dosing schedule that deliver WHO target doses may be different to the manufacturers weight bands and dosing schedule.
The panel agreed it is important to dose the FDCs to achieve a higher intended NVP dose bearing in mind recent data confirming that a minimum total daily dose of 320mg/m2 (160 – 200mg mg/m2 per dose given twice daily) is preferred.
They found that intended target dosing can be achieved using weight bands developed recommended tablet schedules for a range of FDC products. The panel felt that there is no intrinsic advantage to one product over another in terms of intended dose, provided the appropriate WHO dosing schedule for that product is followed. It is important to note that using any ONE existing FDC product, intended dosing for all ARV components for all weight bands may not be achieved.
The panel noted that as more data become available to guide paediatric dosing over the next few years, the products should be monitored as they are used and pharmacology studies should be undertaken. They wrote: The ideal FDC products requested would, once available, be expected to supersede the use of the existing FDCs, as they can be more conveniently dosed.
They listed as priority products for development: AZT/3TC/NVP 60mg:30mg:55mg scored; AZT/3TC 60:30 scored; d4T/3TC 7mg:30mg scored; d4T/3TC/NVP 7mg:30mg:55mg scored; NVP 55mg scored and LPV/r 90mg:22.5mg scored.
The panel also identified gaps in research that are need to be urgently addressed in order to guide the treatment of HIV in children. In a long list they included pharmacokinetic (PK) data for antiretrovirals used in treating children in resource limited settings when co-administered with TB drugs rifampicin or rifabutin. PK data for nevirapine for children<6 months. PK data to guide dosing of efavirenz for children <3 years and for efavirenz and nevirapine in different genetic populations of children.
Once daily dosing for 3TC for children younger than 3 years and once daily dosing of abacavir for children initiating ART. Dosing and medium and long term toxicity for tenofovir in children. They also identified research into the impact of nutritional status on the pharmacokinetics, pharmacodynamics, adverse events and efficacy in children with moderate to severe malnutrition for all antiretroviral drugs.
The WHO will communicate priority ideal products identified by the panel to the pharmaceutical industry and priority ranking of desired products and recommendations on existing FDCs products will be communicated to the prequalification programme.
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