Bioavailability study results for new paediatric tablets for oral suspension, and caution against splitting adult doses

9 September 2006. Related: Conference reports, Paediatric care, World AIDS 16 Toronto 2006.

Polly Clayden, HIV i-Base

All discussion concerning obstacles to paediatric scale up – both at this conference and to date – has highlighted the lack of easily stored, low cost, age appropriate antiretroviral formulations for children.

As an interim measure many programmes prescribe divided adult fixed dose combinations (FDCs) but this is not without problems, and can yield suboptimal levels of nevirapine, particularly in very young children (see below). Obviously FDCs for children will be a welcome development.

Paediatric FDCs

At the pharmacology (PK) workshop in Lisbon earlier this year, independent investigators presented bioavailability data for Indian generic manufacturer Cipla’s Pedimune Baby and Pedimune Junior FDC tablets of NVP, 3TC and d4T, which led them to conclude that it would be acceptable to begin testing PK and dosing requirements of these formulations in African children even though the formal bioequivalence study by Cipla has not yet been completed. [1, 2]

Another Indian generic company, Ranbaxy has developed two new paediatric formulations of tablets for oral suspension (TFOS) “designed to disintegrate quickly into a uniform suspension in small volume of liquid media like water”.

A poster from Singla and co-workers from Ranbaxy described the formulation development of Triviro-LNS kid (3TC 20mg /nevirapine 35mg/d4T 5mg) and Triviro-LNS kid DS (3TC40mg / nevirapine 70mg / d4T 10mg) – which will provide NIH recommended doses of the drugs for children weighing 9-31kg. [3]

And in an oral presentation Manish Vermer reported findings from the company’s bioavailability study of a single dose of the Triviro-LNS kids DS formulation compared to reference propriety liquid formulations. [4]

The investigators reported that the tablet has: a break line, “to enhance accuracy of dosing”; “a pleasant orange flavour” and requires no specific measuring device or refrigeration. Time to dispersion is 40 seconds in a small amount of water.

The bioavailability study was an open label, single dose crossover study conducted in 36 fasting HIV negative adult males.

The investigators reported that the geometric mean ratios (% Test/Reference) of log-transformed parameters of AUC, Cmax and 90% confidence intervals were within 80 -125% interval, see Table 1.

They wrote “Therefore the two treatments were considered to be similarly bioavailable and they concluded “Ranbaxy’s novel paediatric triple ARV TFOS could be used in place of individual liquid formulations.”

Table 1: Ratio of LSM % (90% CI)

Divided adult fixed dose combination can yield suboptimal nevirapine dose for very young children

Several programmes reported favourable outcomes for children receiving adult fixed dose combination solid formulations of NVP, 3TC and NVP. [5, 6, 7, 8]

However, there are concerns with this strategy for very young children, for whom dose ratios for the different drugs are less analogous with those of adults, see Tables 1 and 2. Additionally smaller doses require quartered tablets and there are difficulties with accurate cutting.

Table 2: Drug ratios in Triomune and examples of WHO (2006) recommendations for children of different weights

Adult FDC will underdose NVP if 3TC and d4T doses are correct BUT overdose d4T and 3TC if NVP dose correct.

In an oral abstract Veronica Mulenga presented findings from an updated pharmacokinetic study (first presented at the PK workshop in Lisbon and reported in HTB in more detail [9,10]) that again highlights the need for caution in very young children, but included some pragmatic recommendations [11].

This study was conducted in a group of 127 Malawian and Zambian children aged 8 months-18 years.

Dr Mulenga summarised that divided Triomune resulted in adequate nevirapine concentrations in nearly all children prescribed doses >/= 300 mg/m2. But the youngest and smallest children were more likely to have subtherapeutic levels, particularly those receiving <300mg/m2/day, these children tended to receive quarter Triomune tablets.

She noted that malnourished children (with low BMI for age) had higher nevirapine concentrations. She suggested that these children could be older for the same dose and therefore metabolise nevirapine more slowly. Stunted children had lower nevirapine levels due to lower volume of distribution. She emphasised the need for further study of the effect of malnutrition on nevirapine PK.

Dr Mulenga recommended caution with using part of FDC adult formulations in children <3 years old. If they are used, doses should be chosen to achieve adequate nevirapine dose (though this may result in some overdosing of 3TC and d4T). Therefore it is preferable to use Triomune 30 rather than Triomune 40 to achieve higher nevirapine doses relative to d4T.

She made the case once again for the need for child specific FDCs containing appropriate ratios of drug doses for children. This group is conducting in-depth pharmacokinetic and adherence studies in HIV-infected children of NVP, 3TC and d4T receiving the Cipla FDC, Pedimune in Zambia; they will further study the effects of nutritional status on PK parameters.

Comment

It is important to note that the Ranbaxy Triviro-LNS kid and Triviro-LNS kid DS formulations still have lower amounts of nevirapine relative to the two NRTIs than required for very small children for whom dividing adult FDC is most problematic. Hence these formulations are not recommended for children <9kg.

The ratios of 3TC and d4T are also different also from those in Pedimune; this is because Pedimune was designed bearing in mind some recent data from the PENTA 13 pharmacokinetic study suggesting that the dose of 3TC may be rather low for children <6 years and that it may be better to keep the dose of d4T near the lower end.

Ranbaxy is not planning to do any PK studies in children and therefore the effects of malnutrition will not be assessed. Andrew Tomkins from the Institute of Child Health raised concerns about this in Toronto after the oral presentation. Although PK data from children is not a regulatory requirement from either WHO or FDA for paediatric FDCs, several researchers and paediatricians are concerned that this may be assuming the right dose when malnutrition raises complex issues around weight for age calculations. In conversation one paediatrician remarked that in any malnutrition ward in Africa about 60% children are likely to be HIV infected. This is a very common presentation of HIV in most resource-limited settings.

However, for children >9kg, it is likely that both Triviro-LNS kids and Pedimune (and dividing adult FDCs which has produced pretty good data for older children) will be reasonable.

Results from the CIPLA bioequivalence study conducted in HIV negative adult volunteers for registration requirements should be available very soon.

In summary:

• For youngest children liquid formulations or Pedimune baby are likely to be most reliable; PK studies using Pedimune will hopefully confirm this soon.
• For older children either the Ranbaxy, Cipla paediatric formulations or divided adult FDCs seem safe.
• We urgently need PK data from children with different degrees of malnutrition.
• We need these formulations to be licensed and pre-qualified by the WHO.

References:

1. L’homme R, Dijkema T, Warris A et al. Pharmacokinetics of two generic fixed dose combinations for HIV-infected children (Pedimune Baby & Pedimune Junior) are comparable to the branded products. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 23.
2. Pharmacokinetics for generic fixed dose combinations for children are comparable to the branded products. HIV Treatment Bulletin Volume 7 Number 6 June 2006.
3. Singla A, Rampal A, Garg M et al. Formulation development of novel fixed dose combination (FDC) of lamivudine, stavudine and nevirapine for paediatrics. XVI International AIDS Conference, Toronto, Canada.13 – 18 August 2006 Poster abstract MOPE0252.
4. Shankar G, Manaktala C, Verma M et al. Comparative Bioavailability study of a novel pediatric fixed dose dispersible tablet (FDDT) of lamivudine, stavudine and nevirapine versus individual marketed liquid formulations. XVI International AIDS Conference,Toronto, Canada.13 – 18 August 2006. Oral abstract WEAB0304.
5.  Chokephaibulkit K, Plipat, N, Cressey T et al. Pharmacokinetics of nevirapine in HIV-infected children receiving an adult fixed-dose combination of stavudine, lamivudine and nevirapine. AIDS: Vol 19(14) 23 September p1495-1499.
6. Pharmacokinetics of nevirapine in HIV positive children receiving Thai fixed dose combination. HIV Treatment Bulletin Volume 6 Number 10 October 2005.
7. AIDS Working Group, Epicentre, Médecins Sans Frontières. Very satisfactory outcomes can be achieved in children treated with highly active antiretroviral treatment under programme conditions in resource-limited settings: the experience of Médecins Sans Frontières. 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, 2005. Abstract WeOaLB0201.
8. Favourable outcomes in children treated with HAART in the MSF programmes. HIV Treatment Bulletin Volume 6 Number 9 September 2005.
9. L’homme R, Ellis R,J, Ewings F et al. Nevirapine concentrations in HIV-infected children treated with divided fixed dose combination tablets in Malawi and Zambia. 7th International Workshop on Clinical Pharmacology of HIV Therapy, 20-22 April 2006, Lisbon. Abstract 2.
10. Caution against dividing adult FDCs (Triomune) for young children. HIV Treatment Bulletin Volume 7 Number 6 June 2006.
11. Mulenga V, Ellis J, Ewings F et al. Nevirapine concentrations in HIV- infected children treated with divided fixed dose combination tablets in Malawi and Zambia. XVI International AIDS Conference, Toronto, Canada.13 – 18 August 2006. Oral Abstract WEAB0305.