Argentinian generic indinavir compares well with Crixivan

Systemic exposure to indinavir is similar whether using Crixivan brand name indinavir or a generic indinavir formulation from Argentina, according to a letter to the editor published in this month’s Journal of Acquired Immune Deficiency Syndromes.

The letter reports on the first independent bioequivalence study of the two indinavir formulations, conducted by researchers from Argentina working in collaboration with Dr. Julio Montaner of the British Columbia Centre for Excellence in HIV/AIDS in Canada.

Argentinian antiretrovirals

Argentina is one of the nations taking advantage of flexibility in trade-related aspects of intellectual property rules (TRIPS) that allow lower and lower middle income countries to license local companies to produce generic versions of life-saving medications. Poor countries may issue these compulsory licenses in the hope that the generic drug will be more affordable than the original product.

A few companies in Argentina are currently producing generic antiretrovirals. Inhibisam brand name indinavir is made by Richmond Laboratorios, which also markets generic formulations of nelfinavir and efavirenz within Argentina and a number of other Latin American countries. There are about 26,000 patients with AIDS on treatment in Argentina, about 16,000 currently have access to generic protease inhibitors through the Ministry of Health.

However, concerns have been raised about the safety and effectiveness of generic substitutes in developing countries, so clinical evidence is needed to demonstrate that the drugs behave the same as branded products in patients.

The trial

This “cross-over” study looked at ten patients in Buenos Aires who were taking their first antiretroviral therapy (ART) regimen based on indinavir (800mg) ‘boosted’ by ritonavir coadministration (100 mg) both twice daily, in combination with other antiretrovirals.

Initially, six of these patients were taking Inhibisam and four were on Crixivan. After remaining virologically suppressed (

Then patients were switched over to the other formulation of indinavir. Approximately fourteen days later, the concentration of indinavir in each patient’s blood was again measured and compared to their earlier concentrations.

Results

“On average,” the letter says, “indinavir exposures were slightly greater for the generic formulation” — however, this difference was not statistically significant. Generally, blood levels of indinavir were within therapeutic limits, although one patient on Inhibisam had lower than recommended indinavir levels at the 12-hour measurement. Conversely, four patients (three on Inhibisam and one on Crixivan) exceeded the maximum recommended concentration when blood levels of indinavir were at their peak.

Some variability in exposure to protease inhibitors between patients with HIV is fairly common and could be due to inherited differences in metabolism or differences in diet or adherence. Nonetheless, very high blood levels of indinavir could put patients at increased risk of kidney toxicity if patients do not drink enough water each day.

However, Inhibisam appears to be an effective HIV treatment. After the study concluded, the patients all continued on the generic formulation and viral loads remained below 50 copies per ml (median follow-up 12 weeks).

Conclusion

“In this series of patients on stable antiretroviral therapy,” the authors write: “Inhibisam matched pharmacokinetic exposures to Crixivan, at least in the context of RTV boosting.”

The introduction of Inhibisam also dramatically cut the cost of indinavir in Argentina. According to South American websites, the price of Inhibisam was approximately half that of Crixivan when it was first introduced three years ago. Merck subsequently reduced the price of Crixivan in Argentina (and many other developing countries). Today Inhibisam costs approximately 15% less than Crixivan in Argentina.

However, the cost of protease inhibitors, whether generic or originator product, still remains well above the cost for other antiretrovirals — effectively putting second line HIV treatment regimens out of the reach in most of the developing world.

With an increase in the scale of production, these prices could come down somewhat. But what is really needed is collaboration — including technology transfer — between generic and originator companies to meet the world’s need for antiretrovirals and other life-saving medications.