Combination of three generic drugs in one pill meets bioequivalence criteria when compared with the branded drugs: Triomune vs d4T/3TC/NVP
Polly Clayden HIV i-Base
One of the most notable presentations at the Glasgow meeting was a pharmacokinetic evaluation of lamivudine, stavudine and nevirapine given as a fixed dose combination pill (Triomune) versus the same three drugs given separately in healthy human volunteers.
The study showed that Triomune met the requisite criteria for the conclusion of bioequivalence with regards to rate and extent of absorption.
Triomune is a combination pill manufactured by the Indian generic maker Cipla containing two NRTIs (stavudine 40mg and lamivudine 150mg) and one NNRTI (nevirapine 200mg), used twice daily.
This randomised, single dose study in 28 subjects, investigated the pharmacokinetic parameters between the triple combination product versus the respective reference products (originators drugs) in order to establish bioequivalence.
Dr Jaideep Gogtay and colleagues at Cipla in Mumbai, India, and at Lambda Therapeutic Research in Ahmedabad, India, reported that the drugs were administered under fasting conditions and a total of 26 serial plasma samples were collected up to 288 hours post-dose. Concentrations of lamivudine, stavudine and nevirapine were estimated from the plasma samples obtained after the administration of the test and reference formulations. Agents were considered bioequivalent if the 90% parametric confidence intervals constructed for ratios of means of log-transformed pharmacokinetic parameters AUC0-t and AUC0-t of the test and reference formulations were within the range of 80-125% and that for Cmax were within the range of 75-135% for all the three products, as per CPMP guidelines.
The investigators found that triomune “…met the requisite criteria for the conclusion of bioequivalence with regards to rate and extent of absorption.” The ratios of AUC0-t and AUC0-t for the three drugs were from 96.6% to 104.8%.
This presentation provoked some practical clinical questions from the floor, including Graeme Moyle of Chelsea and Westminster Hospital, London, who asked how this product was managed considering that it is recommended patients naïve to nevirapine have a lead–in period of a 200mg daily dose for two weeks. (Answer: the product has a warning that it is not intended for use in patients who are just initiating therapy with nevirapine – Cipla also manufacture the three drugs individually).
David Burger then raised the issue of using a lower dose of 30mg BID for patients below 60kg. (Answer: there are two formulations Triomune 30 and Triomune 40).
The researchers wrote: “It is concluded that the single tablet formulation containing lamivudine150mg/stavudine 40 mg/nevirapine 200 mg is bioequivalent to the reference compounds given separately.”
Gogtay JA, Manek V, Nayak VG A pharmacokinetic evaluation of lamivudine, stavudine and nevirapine given as a fixed dose combination pill versus the same three drugs given separately in healthy human volunteers. 6th international Congress on Drug therapy in HIV Infection 17-21 November 2002 Glasgow Abstract PL8.4
Interestingly it takes a generic drug maker to take the most significant step in helping patients to better adherence – combining all three of the antiretrovirals necessary for an HIV treatment regimen in one pill irrespective of manufacturing source. Why can’t western pharmaceutical companies put in the effort necessary to make this a reality for all patients? If alleviation of disease and suffering is the primary concern of these companies then collaboration and licensing agreements should be initiated to follow Cipla’s lead. The lack of initiative and effort in this direction as well as the development of “incestuous” one company only co-formulations suggests that market share and competition currently take a higher priority than patient care.
We would strongly urge pharmaceutical companies to make efforts to collaborate, particularly regarding protease inhibitors and PK enhancement. Both tipranavir and fos-amprenavir require such PK enhancement to reduce pill burden, but why reduce pill burden on the one hand and then increase pill count on the other by not including ritonavir in a co-formulation? Patient needs are paramount here.
The International Federation of Pharmaceutical Manufacturers in Geneva, which lobbies on behalf of the multinational drug companies, issued a statement saying “it would be unfortunate if the current plague of substandard and counterfeit medicines spread” because generics makers were on the health organisation’s list. Industry loves to confuse generic products (which are perfectly safe) with counterfeits.
It is legal in India to copy a medicine designed abroad and put it on the local market (as long as the companies can prove they use a different manufacturing process).
The scientific committee must be applauded for foregrounding this study at a conference with such a heavy pharmaceutical presence.