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Sixth International CongressDrug Therapy in HIV Infection17-21 November, 2002
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Purpose of study: The most important factor determining virologic success in HIV therapy is patient adherence. In the last few years efforts have being made to improve adherence by the introduction of newer agents with reduced frequency of pill administration and fixed dose combination products. One such product introduced was Trizivr, which contains 3 NRTIs viz. zidovudine, lamivudine and abacavir. It is administered in a dose of one tablet twice daily. In India recently a novel triple drug combination containing 2 NRTIs viz. stavudine and lamivudine and one NNRTI viz. nevirapine was introduced. The present study investigated the pharmacokinetic parameters between the triple combination product versus the individual drugs in order to establish bioequivalence. Methods: A randomized, two-treatment, twoperiod, two-sequence, single dose, crossover bioavailability study was conducted in 28 healthy subjects to assess the bioequivalence of a combined lamivudine 150 mg/ stavudine 40 mg/ nevirapine 200 mg tablet (Test Product 'A', manufactured by Cipla Ltd., India) relative to that of the respective reference products (Reference products 'B': lamivudine 150 mg tablets manufactured by Glaxo Wellcome, UK; stavudine 40 mg capsules manufactured by Bristol Myers Squibb, UK; nevirapine 200 mg tablets manufactured by Boehringer Ingelheim, UK) administered separately under fasting conditions. A total of 26 serial plasma samples were collected up to 288 hours post-dose for both the periods. Concentrations of lamivudine, stavudine and nevirapine were estimated from the plasma samples obtained after the administration of the test (A) and reference (B) formulations using a validated LC-MS/MS method. The pharmacokinetic parameters Cmax, Tmax, AUC0-t, AUC0-¥, lz, t½ and AUC_% Extrapolated (residual area) were estimated for the individual components, followed by statistical comparisons to assess bioequivalence. Treatments 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 drug products, as per CPMP guidelines.
Summary of Results: Results are shown in the table given below. The Test Product (A) 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%.
| Lamivudine | Stavudine | Nevirapine | ||||
| A Test |
B Ref |
A Test |
B Ref |
A Test |
B Ref |
|
| Cmax (mcg/mL) |
1.41 ± 0.37 | 1.22 ± 0.3 | 0.64 ± 0.11 | 0.65 ± 0.11 | 1.82 ± 0.38 | 1.81 ± 0.36 |
| AUC0-t (mcg.h/mL) |
5.68 ± 0.97 | 5.44 ± 1.07 | 1.32 ± 0.22 | 1.36 ± 0.19 | 146.75 ± 34.29 | 148.85 ± 30.33 |
| AUC0-¥ | 6.02 ± 0.97 | 5.80 ± 1.14 | 1.49 ± 0.23 | 1.54 ± 0.22 | 156.95 ± 42.32 | 160.28 ± 37.95 |
Conclusion: Hence it is concluded that the single tablet formulation containing lamivudine150 mg/stavudine 40 mg/nevirapine 200 mg is bioequivalent to the reference compounds given separately.
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1 Cipla Ltd, Mumbai, India.
2 Lambda Therapeutic Research Ltd, Ahmedabad, India.
2002-11-17
PL8-4
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