XEED™ is a fixed dose combination (FDC) of four drugs Rifampicin, Ethambutol,
Pyrazinamide and Isoniazid with proven bioavailability of Rifampicin for the treatment
of tuberculosis. It offers the convenience of a fixed dose combination, at the same time
ensuring optimal bioavailability of all the active drugs. It ensures release of Rifampicin & Isoniazid at different sites to avoid interaction leading to 42% enhanced bioavailability of Rifampicin as compared to conventional FDCs.
It is estimated that between 19% to 43% of the world population is infected with tuberculosis. As per recent forecasts, between 2000 and 2020, nearly one billion people will be newly infected, 200 million people will develop active tuberculosis, and 35 million will die from the disease - if control is not further strengthened. The HIV epidemic has also increased the risk of tuberculosis WHO & IUATLD recommend the use of FDCs to ensure the delivery of correct dosage and avoidance of monotherapy, thereby, preventing the development of Multi Drug However, it has been observed that the co-administration of Rifampicin with Isoniazid in the form of FDC or in loose combination, leads to a significant loss of bioavailability of XEED™ is a compression-coated tablet, wherein Isoniazid is present in the core and is
coated with special polymers for site-specific release and avoid the known adverse interaction with Rifampicin. The outer layer of the tablet contains Rifampicin, Ethambutol and Pyrazinamide. The tablets are further coated with selected polymers to prevent the degradation of the active drugs due to exposure to light and m Outer Coating to protect from
light and moisture
Rifampicin, Ethambutol,
Pyrazinamide Outer Layer
Specialized Polymer Coating for
Site Specific Release
Isoniazid core
3.1 Mechanism of action
The problem of bioavailability of Rifampicin has been solved by spatial control of release of both the drugs in such a way that the release takes place at different locations in GIT. The site-specific release of Rifampicin and Isoniazid prevents the drugs from coming in contact with each other in solution stage in the acidic pH of gastric region, thereby, preventing the degradation. XEED™’s innovative technology releases Rifampicin,
Ethambutol and Pyrazinamide in the stomach while the special polymer coating on the Isoniazid core prevents its release in the stomach, thereby avoiding any interaction between Isoniazid and Rifampicin. Rifampicin releases in acidic pH of stomach and gets absorbed immediately which ensures absolute bioavailability of Rifampicin. The Isoniazid core moves on to the proximal part of the intestine and the release of the drug takes place in the duodenum where pH rises above 5.0. The release of two drugs at different sites results in no loss of bioavailability of either of the drug. 4.1 Study I
The bioavailability of Rifampicin in XEED™ was compared to the reference
conventional preparation in a six volunteer pilot study. The Cmax and AUC (bioavailability) of Rifampicin from the XEED™ were found to be significantly higher
from the formulation containing conventional Rifampicin. 4.2 Study II
In an another single blinded, randomized, two-way, cross-over bioequivalence study carried out in 12 healthy volunteers, it was found that the Cmax and AUC (bioavailability) of Rifampicin from the XEED ™ formulation was found to be higher when compared to
Cmax of Rifampicin from the reference conventional formulation. No difference in Cmax & AUC (bioavailability) of Isoniazid was observed between the XEED ™ formulation and
Isoniazid of the reference conventional formulation. 4.3 Study III
Bioequivalence results from above pilot studies were strongly convincing and hence a third BA/BE study was planned in 24 healthy volunteers. They were evaluated in a 3-way crossover design for bioavailability of Rifampicin in the XEED ™ formulation against
conventional Rifampicin. It was reported that the XEED ™ had 42% higher relative
bioavailability of Rifampicin (with respect to AUC) than Rifampicin 450 mg (Rimactane) C o nv . F D C
T im e ( H rs )
Figure 1 : a relative bioavailability equal to 141.97% was observed for Rifampicin in case of XEED™ when compared with reference conventional formulations (in loose C o nv . F D C
T im e ( hrs )
Figure 1 : There was no loss in bioavailability of Isoniazid as Cmax and AUCs are same in both the cases, and as designed only Tmax has been delayed 4.4 Study IV
In order to evaluate the clinical significance of higher bioavailability of Rifampicin in the XEED™, a randomized, open-labeled, comparative, prospective, multi-centric Phase IV
study involving 420 TB patients (Male - 78.3%, Female - 21.7%) with clinical symptomatology of cough, fever, anorexia, haemoptysis, lethargy and weight loss was planned. The aim was to evaluate the safety and efficacy of the XEED™ against
conventional FDC, in the treatment of primary pulmonary tuberculosis. All the patients An early symptomatic relief in fever, cough (both productive and non- productive), night sweats and haemoptysis was observed in patients with the There was 91% improvement observed in the XEED™ group as compared to 70% in conventional FDC group, at the end of initiation phase (2 months) of Also, at the end of continuation phase 99% of subjects taking the XEED™ showed improvement as compared to 84% taking conventional FDC. At the end of IP
At the end of CP
Improved Deteriorate /
Deteriorate /
Table 1 : Overall improvement in fever, cough, night sweats, haemoptysis in
patients with XEED™ as compared to conventional FDC
There was a quicker radiological improvement seen in patients taking the XEED™. Subjects in the XEED™ group showed early significant improvement in all the defined markers of radiographs as compared to conventional group at day 45 Clinical study volunteers at one of the center of Phase IV study were also simultaneously evaluated for Rifampicin and Isoniazid levels in the XEED™ and conventional FDC. This was a parallel, non-cross over bioavailability study in 24 patients at the beginning of their clinical therapy at first therapeutic dose. These patients were admitted for a day after first dose of anti tubercular FDC and their blood levels were monitored for 12 hours thereafter. Equal numbers of subjects were given XEED™ and conventional FDC. It was observed that bioavailability of Rifampicin in XEED™ group was 20% higher as compared to Rifampicin in conventional FDC. Further, no difference in Isoniazid Cmax and bioavailability was observed. There was a significant delay in Tmax of Isoniazid in Product patents are filed in all major countries across the globe and patent is already Australia, Nigeria, North Korea, Poland, South Africa, Sudan, Tanzania, Turkey CTD compilation under process for regulated markets XEED™ 4

Source: http://www.panaceabiotec.com/licensing/XEED.pdf

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