Ranbaxy presents bioequivalence data on two paediatric fixed dose triple combination tablets

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Two fixed dose triple combination water-dispersible tablets produced by generic manufacturer Ranbaxy providing half- and quarter-doses of nevirapine, lamivudine and stavudine for paediatric use are bioequivalent to their proprietrary liquid formulations in adults, according to a study presented to the Sixteenth International AIDS Conference in Toronto on August 16th. The two formulations have already been approved by the Indian government, and have been submitted to the World Health Organisation (WHO) for inclusion on their pre-qualification list.

Several recent initiatives have begun to address the issue of lack of paediatric formulations in low-income countries, first highlighted two years ago at the Fifteenth International AIDS Conference in Bangkok by Médecins Sans Frontières (MSF) director Daniel Berman.

Last year, the Clinton Foundation announced a US$10m package to make cut-price paediatric drugs available to 10,000 children in at least ten low-income countries. In March, the United States' First Lady, Laura Bush, announced that the US government would lead an international public-private partnership to increase the range of HIV drugs available to treat children.

Glossary

paediatric

Of or relating to children.

generic

In relation to medicines, a drug manufactured and sold without a brand name, in situations where the original manufacturer’s patent has expired or is not enforced. Generic drugs contain the same active ingredients as branded drugs, and have comparable strength, safety, efficacy and quality.

low income countries

The World Bank classifies countries according to their income: low, lower-middle, upper-middle and high. While the majority of the approximately 30 countries that are ranked as low income are in sub-Saharan Africa, many African countries including Kenya, Nigeria, South Africa and Zambia are in the middle-income brackets. 

oral

Refers to the mouth, for example a medicine taken by mouth.

metabolism

The physical and chemical reactions that produce energy for the body. Metabolism also refers to the breakdown of drugs or other substances within the body, which may occur during digestion or elimination.

However, at the moment, splitting or quartering fixed dose antiretroviral combination tablets produced for adults by generic manufacturers like Cipla and Ranbaxy in order to approximate paediatric dosing has become common practice in many low-income countries, primarily because adult fixed dose tablets are cheaper to obtain and easier to administer than paediatric liquid formulations. Last year, MSF reported that many doctors find split tablets result in better adherence and more accurate dosing than liquid formulations .

Although a recent Thai study found that splitting adult fixed dose triple combination tablets that contain nevirapine (Viramune) may provide the appropriate nevirapine exposure for children of varying ages, a recent Malawian study found that this practice may result in significant under dosing of stavudine (Zerit) and lamivudine (Epivir).

The first bioequivalence data on a fixed dose paediatric triple coformulation tablet containing half and quarter the adult doses of nevirapine, lamivudine and stavudine (Pedimune Junior and Pedimune Baby), were presented last May by Cipla at the HIV Pharmacology Workshop in Lisbon with promising results.

In Toronto, Ranbaxy's Manish Verma presented single dose bioequivalence data on their two water-soluble paediatric fixed dose triple coformulation tablets: Triviro-LNS kid, which combines nevirapine 35mg, lamivudine 20mg, and stavudine 5mg; and Triviro-LNS kid DS,, which combines nevirapine 70mg, lamivudine 40mg, and stavudine 10mg.

An open label single dose crossover study compared the plasma concentrations of the three antiretrovirals in their proprietary liquid formulations with the two generic fixed-dosed combinations.

Seventeen fasting healthy adult males were given recommended paediatric doses of nevirapine (Viramune) oral suspension, lamivudine (Epivir) oral solution and stavudine (Zerit) oral solution, followed by a washout period, and then each of the two fixed-dosed combinations.

The investigators found that total drug exposure (AUC) and maximum drug levels (Cmax) of the liquids and fixed dosed formulations were within 80% to 125% of each other, leading them to conclude that they consider that their two fixed dose combination tablets to be bioequivalent to the individual liquid formulations.

However, questions from the audience showed some scepticism about the results. Several conference delegates asked whether Ranbaxy planned bioequivalence studies in children, given the differences in metabolism of drugs, especially in younger children.

A delegate from the Institute of Child Health in London commented: "I'm very concerned to hear you say that because the doses are bioequivalent in adults, you can give this to children." He said that child malnutrition could affect the dose required, since drug metabolism is also altered in malnourished individuals.

Audience members also highlighted the fact that the lower dose Ranbaxy product is not intended for children weighing less than 10kg; Manish Verma of Ranbaxy said that the company has plans to develop a product for the lowest body weight infants.

He emphasised that the tablets must be dispersed in water and could not be taken orally without dispersal in liquid, indicating the importance of clean water for dosing of these tablets.

References

Shankar G et al. Comparative bioavailability study of a novel pediatric fixed dose dispersible tablet (FDDT) of lamivudine, stavudine and nevirapine versus individual marketed liquid formulations. Sixteenth International AIDS Conference, Toronto, abstract WeAb0304, 2006.