Dear friends,

Welcome to the lively subject of bioequivalence. As the name implies it means two products being equivalent. Equivalent means they should give the same rate and extent of bioavailability systemically. In simple words, if the plasma concentrations versus time profiles of two drug products are super imposable then they may be declared as bioequivalent. Now the importance of this term is this: A generic equivalent drug product may be marketed by a drug company only after proving that it is bioequivalent to the innovator product. This is true whether a generic company wants to register its drug with USFDA and sell it in USA or if it wants to sell it in India. How these tests are to be done if the manufacturer wants to sell in India are explained by the law(Appendix XXXVIII, Guidelines for bioavailability and bioequivalence studies).

This topic is an ocean and for this blog I am taking a single point; I am going to talk about some recent research into this field. Let us get going. While bioequivalence is not a big issue for some drugs (drugs which are highly soluble and highly permeable) , it is a very irksome issue in the case of some drugs ( less soluble and less permeable) and in the case of some drug products ( controlled release formulations). We call them as products showing variable bioavailability. In such situations we have to carefully design our trials and the drug control authorities are extra careful in studying our reports. One such issue is the case of antitubercular drugs. When a person is afflicted by tuberculosis he is started on a four drug regimen (rifampicin, isoniazid,pyrazinamide and ethambutol). Slowly as the disease is cured the number of drugs are brought down. The treatment goes on for 9 months. This is a terrific strain on the patient and his/her family and the 9 months are a tough time for them. Some patients do not totally comply and that may lead to multidrug resistant tuberculosis, which is a great nuisance for the patient, his/her family and their community. So compliance is important. So the pharmaceutical industry responded by manufacturing fixed dose combinations of the drugs.

The idea is that patient may not like swallowing four tablets but may prefer one or two tablets. So a patient who starts TB therapy has to swallow, early in the morning (Rifampicin has to be taken on fasting) two big tablets (which contain four drugs). But the hitch is coming now: WHO got concerned that the fixed dose combinations are not having required bioavailability and passed a recommendation that such FDC s may be used only after proving bioequivalence. The pharmaceutical companies are doing exactly that and independent researchers are also studying them. Let me present one such study to you.

Comparative bioavailability of rifampacin, isoniazid and pyrazinamide from a four drug fixed dose combination with separate formulations at the same dose levels. International Journal of Pharmaceutics, Volume 276, Issues 1-2, 19th May 2004, Pages 41- 49. Shrutidevu Agarwal, Inderjit Singh, Kanwal Jit Kaur, Shantaram R. Bhade, Chaman Lal Kaul, Ramesh Panchagnula.

Fixed dose combination (FDC) formulations were accepted and appreciated by the patients and resulted in better patient compliance. This is because a patient always prefers one tablet to two tablets. But this proposal has a hitch and that is the issue of possible variability in the bioavailability of rifampicin if it is placed in fixed dose combination. WHO and International Union against TB and lung Disease advise FDCS only if their bioavailability is proved. Against this background the authors cited above carried out a bioequivalence study of four TB drugs formulated as FDC tablet with the four drugs given separately at the same dose level. The comparison was between the drugs administered separately and as a combination. The study was conducted using 22 healthy male volunteers according to WHO recommended protocol. They reported that FDC formulation is bioequivalent with separate administrations and that it ensures the successful treatment of TB. I will also present one bioequivalence study that was done in our lab with the idea of finding out whether four generic products may be considered as bioequivalent and hence interchangeable.

"Comparative Bioavailability of four marketed Sparfloxacin formulation in Healthy Human Volunteers" E- Journal of Chemistry, Vol.1, pp.43-50, March 2004.K.Ravindra Rao, J. Vijaya Ratna and T. Manikya Rao

Abstract As we reported in the above cited journal, the aim of the study was to obtain the pharmacokinetic (PK)data of four marketed tablet formulations of sparfloxacin and compare their relative bioavailability with standard formulation. A single dose 4* 4 Latin square design was carried out in four healthy male volunteers.

Conclusion This study was carried out to determine the PK data of four marketed tablet formulations of sparfloxacin and compare their relative bioavailability. The dissolution profiles indicated that all brands of sparfloxacin released gradually almost 100% of the drug in 2 hrs. So it was concluded that all the products are equivalent regarding the in vitro drug release.The in vivo studies showed statistically significant difference regarding 3 out of 6 PK parameters. But when % bioavailability was studied it indicated that product D fell narrowly below the cut off point of bioequivalence. We concluded that the narrow difference is not clinically significant. So we concluded that products of sparfloxacin manufactured by four different pharmaceutical companies are bioequivalent.

So, I hope you see what tremendous importance bioequivalence has in the current scenario. With the example of antitubercular drugs I tried to show its importance from patient and society and public health point of view. With the other example I tried to show a industry and doctors' perspective. So, thank you and join me and tell me of instances which you heard regarding two identical drug formulations showing different clinical effects.

References:

1. Laws related to Drugs and Cosmetics by Vijay Malik, 12 th Edition. Appendix XXXVIII, Guidelines for bioavailability and bioequivalence studies, Central Drugs Standard Control Organization, Directorate General of Health Servixes, Ministry of Health and Family Welfare, Goverment of India, New Delhi,Vijay Malik, Twentieth edition, pp 1116-1140).

2. World Health Organization (WHO) Communicable Diseases Cluster. Fixed-dose combination tablets for the treatment of tuberculosis. 1999.

3. Comparative bioavailability of rifampacin, isoniazid and pyrazinamide from a four drug fixed dose combination with separate formulations at the same dose levels. International Journal of Pharmaceutics, Volume 276, Issues 1-2, 19th May 2004, Pages 41- 49. Shrutidevu Agarwal, Inderjit Singh, Kanwal Jit Kaur, Shantaram R. Bhade, Chaman Lal Kaul, Ramesh Panchagnula.

4. "Comparative Bioavailability of four marketed Sparfloxacin formulation in Healthy Human Volunteers" E- Journal of Chemistry, March 2004,Vol.1, pp.43-50. by K.Ravindra Rao, J. Vijaya Ratna and T. Manikya Rao.

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