New paediatric formulations of ARVs

30 October 2008. Related: Conference reports, Paediatric care, World AIDS 17 Mexico City 2008.

Polly Clayden, HIV i-Base

The complexities of using liquid formulations of paediatric antiretrovirals (such as transportation, storage, cost, taste and dosing) are a barrier to scale up of HIV treatment in children. The WHO and UNICEF have requested the development and registration of solid paediatric formulations. Four posters showed novel combination dose and single drug tablets suitable for paediatric use.

AZT and 3TC fixed dose combination tablet

GlaxoSmithKlein (GSK) have developed scored tablets of AZT 300mg/3TC 150mg (Combivir) for children >14kg and able to swallow tablets. [1]

Ivy Song and co-workers showed pharmacokinetic modelling, performed to support manufacturers’ dosing recommendations.

Doses were selected by weight bands using half and whole tablet regimens to provide daily AZT/3TC doses from -10% to +40% of those from the approved mg/m² (AZT) or mg/kg (3TC) dose of the liquid formulations (see table 1).

Table 1: Manufacturer recommended dose regimens of AZT/3TC scored tablets

Systemic drug exposures from these regimens were predicted using Monte Carlo simulations and reanalysis of historical data, and compared with historical exposure at approved doses in adults and children.

The investigators found the simulated AZT daily AUC for the scored tablet to be similar to historical controls while Cmax is 30-80% higher. Simulated 3TC daily AUC is 10-50% higher than historical controls while Cmax is higher than historical controls from BID dosing but similar to historical adult controls at approved 300 mg QD regimen.

Based on this model these dosing regimens of scored tablet are expected to provide similar safety and antiviral efficacy to 3TC and AZT at previously approved doses. The investigators note that there is a possibly of higher frequency of AZTassociated gastrointestinal effects (because of association with the higher Cmax) in some patients. They suggest that taking the whole tablet before bedtime may improve tolerability.

The manufacturer recommended doses overlap with but are “slightly more conservative” than the WHO recommendations for AZT/3TC (see table 2).

Table 2: WHO recommended dose regimens of AZT/3TC scored tablets

This formulation has been approved for use in the EU and review by the FDA is underway.

Dispersible fixed dose combination of 3TC/AZT/NVP

Ranbaxy laboratories have developed dispersible, scored 3TC/AZT/NVP fixed dose combination (FDC) Tablets for Oral Suspension (TFOS) for children. [2]

Raghuvanshi and co-workers summarised their findings from the prototype development. They describe the characteristics of this product as:

1. Dispersible into an oral suspension in 5 ml of water within 2 minutes.
2. Showing stability under accelerated conditions.
3. Similar in-vitro dissolution profile as that of three reference liquid products.
4. Complying to divisibility test.
5. Palatable and acceptable lemon flavor.
6. Having comparable pharmacokinetic parameters to individual reference liquid formulation under fasting conditions (n=18), (see table 3).

Table 3. Pharmacokinetic parameters of 3TC/AZT/NVP FDC compared to reference products

These investigations supported product feasibility for paediatric 3TC/AZT/NVP FDC. The investigators have completed the comparative bioavalability study for this product and it was filed for prequalification with WHO in November 2007.

Dispersible fixed dose combination of 3TC and d4T

Ranbaxy has also developed TFOS combining 3TC and d4T. [3]

They summarised the product characteristics:

1. Quickly dispersing into a suspension in 5 ml of water within 1 minute.
2. Having similar in-vitro dissolution profile as that of two reference liquid products.
3. Showing stability under accelerated conditions.
4. Having palatable and acceptable orange flavor.
5. Complying to divisibility test
6. Having comparable pharmacokinetic parameters to individual reference liquid formulation under fasting conditions (N=23) (see table 4)

The investigators concluded: “All the studied parameters of TFOS were satisfactory which support the product feasibility for paediatric therapy using lamivudine and stavudine FDC.”

Bioavailability of the 100mg etravirine tablet dispersed in water and of the 25mg tablet formulation

Tibotec have developed a 25mg paediatric tablet of etravirine (TMC125). Additionally the 100mg tablet can be dispersed in water.

Scholler-Gyure and co-workers evaluated the oral bioavalability of the 100mg tablet dispersed in water and of the compositionally proportional 25mg pediatric relative to the 100mg tablet swallowed whole. In addition to treatment in children, the investigators suggest this evaluation will support adult patients with swallowing difficulties. [4]

This study was an open-label, randomised, 3-period crossover trial in HIV-negative volunteers. Three single doses of etravirine were administered as:

• Treatment A (reference) – one 100mg tablet swallowed whole
• Treatment B – four 25mg tablets
• Treatment C – one 100mg tablet dispersed in 100mL water

37 volunteers participated (7 women). All treatments were received within 10 minutes of a standardised meal and were separated by 14-days wash-out periods.

Pharmacokinetics of etravirine were assessed over 96 hours after each administration and least square means ratios compared to reference (see table 5).

Table 5: Pharmacokinetic parameters and LSM ratios of etravirine

The investigators noted that the decrease of Cmax by 15% when etravirine is received as four 25mg tablets is not considered clinically relevant.

They reported that etravirine was generally safe and well tolerated. The most frequently reported adverse event was headache (n=8). One volunteer discontinued prematurely because of Grade 3 lipase increase during Treatment B. No other Grade 3 or 4 adverse events were reported.

They concluded that the 25mg tablet of etravirine is suitable for paediatric use. Additionally paediatric or adult patients requiring an alternative to swallowing tablets can disperse etravirine tablets in water. They added that the stability of etravirine in liquids other than water has not yet been determined.

References:

All references are to the Programme and Abstracts of the 17th International AIDS Conference, Mexico City, 2008.

1. Song H, Yuen G, Weller S et al. Development of Combivir (CBV) scored tablet: simplified dosing initiative for treatment of HIV infection in younger paediatric patient. 17th IAS, Mexico City, 2008. Abstract MOPE0186
2. Raghuvanshi RS, Jaiswal A, Chhabra A et al. Formulation development of novel dispersible fixed dose combination (FDC) of lamivudine, nevirapine and zidovudine for pediatric use. 17th IAS, Mexico City, 2008. Abstract MOPE0183.
3. Raghuvanshi RS, Jaiswal A, Veera R et al. Dispersible novel fixed dose combination (FDC) of lamivudine and stavudine for pediatric use. 17th IAS, Mexico City, 2008. Abstract MOPE0185.
4. Scholler-Gyure M, Kakuda TN, Van Solingen-Ristea RM et al. Bioavailability of the 100mg etravirine tablet dispersed in water and of the 25mg pediatric tablet formulation. 17th IAS, Mexico City, 2008. Abstract MOPE0184.