Comparative Bioavailability Study of a Novel Paediatric Tablets For Oral Suspension (TFOS) of Lamivudine, Nevirapine and Stavudine Vs Individual Reference Liquid Formulation Gowrishankar R, Manaktala C, Verma M, Chhabra A, Juneja S Ranbaxy Laboratories Limited

3 Why Pediatric Anti-Retroviral (ARVs)?  Children (<15 years age) account for: 1/6 th of AIDS-related deaths 1/7 th of new HIV infections  Without treatment, 50% of HIV infected children die within 2 years & >90% within 3 years Every day 1800 new infections in children, mostly mother-to-child 1400 children die of AIDS-related illness To address pediatric HIV infection Reduce MTCT (most cost-effective) Provide Antiretroviral therapy * “

4 Adult FDC Formulations Pros  Easier availability  Affordable  Ease of storage Cons  Accuracy? (Not in line with recommended doses)  Difficult to titrate  Palatability? Liquids Pros  Accuracy of titration Cons  Multiple liquid medications  Dose measurement difficulties  Refrigeration  Higher transportation & inventory management costs  Limited availability Current treatment options

5 What do we need? Desired paediatric formulation: Delivers required ARVs in a single formulation Specific for pediatric dosing Adheres to current treatment guidelines Provide flexibility and accuracy of dosing Needs no specific measuring device Palatable Affordable Easily available

6 An Innovative TFOS Each TFOS contains: Lamivudine 20mg+Nevirapine 35mg+Stavudine 5mg Each TFOS contains: Lamivudine 40mg+Nevirapine 70mg+Stavudine 10mg

7 Triviro-LNS kid DT Reference dose TRIVIRO-LNS kid DS TFOS - Dispersed

8 The TFOS: Based on NIH* recommended NNRTI based triple drug regimen Provides recommended doses of the drugs for children weighing 9-31 kg Three ARVs in a one formulation for children To enhance  Flexibility and accuracy of dosing – break line was introduced  Palatability – Pleasant orange flavour Disperses in small amount of water  Needs no specific measurement device No refrigeration required Simplifies logistics & *Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection Nov, National Institutes of Health (NIH).(

9 TestResult Dispersion Time40 seconds Appearance of DispersionUniform Suspension TastePleasant, Orange flavor Subdivision of tabletComplies Results of various quality tests on TFOS: Stability Testing: Subjected to accelerated stability (40ºC/75% RH/6M) and Zone IV (30ºC/70%RH/9M) conditions in HDPE bottles & unit dose blisters Assays, RS, dissolution were tested periodically and were within specifications Pharmaceutical Evaluation

10 Dissolution Profile LAMIVUDINE

11 Dissolution Profile NEVIRAPINE

12 Dissolution Profile STAVUDINE

13 Bioavailability Study

14 Study Design An open label, balanced, randomised, two-treatment, two-period, two-sequence, single-dose, crossover bioavailability study in healthy, adult, male human subjects under fasting condition Products Evaluated Test (T) TFOS of Triviro-LNS kid DS (Lamivudine 40 mg, Nevirapine 70 mg, Stavudine 10 mg) manufactured by Ranbaxy Laboratories Limited, India Reference (R) 1. Epivir oral solution 10 mg/mL, containing lamivudine 10 mg/mL, manufactured by GlaxoSmithKline, USA. 2. Viramune oral suspension 50 mg/5 mL, containing nevirapine 50 mg/5 mL, manufactured by Boehringer Ingelheim Pharmaceuticals Inc, USA. 3. Zerit oral solution 1 mg/mL, containing stavudine 1 mg/mL, manufactured by Bristol-Myers Squibb, USA. Bioavailability Study

15 Number of Subjects 36 healthy adult male human subjects Washout Period 21 days between the administration of study drugs in each period Clinical Facility Clinical Pharmacology Unit, Majeedia Hospital, New Delhi, India Analytical Facility Clinical Pharmacology and Pharmacokinetics Department, R&D-III, Ranbaxy Laboratories Limited, Gurgaon, India Bioavailability Study

16 Dose Administration 240 mL of drinking water at ambient temperature after an overnight fast of at least 10 hours Test (T) TFOS of Triviro-LNS kid DS (Lamivudine 40 mg, Nevirapine 70 mg, Stavudine 10 mg) manufactured by Ranbaxy Laboratories Limited, India Reference (R) 1.Epivir oral solution 10 mg/mL, containing lamivudine 10 mg/mL, manufactured by GlaxoSmithKline, USA 2. Viramune oral suspension 50 mg/5 mL, containing nevirapine 50 mg/5 mL, manufactured by Boehringer Ingelheim Pharmaceuticals Inc, USA. 3. Zerit oral solution 1 mg/mL, containing stavudine 1 mg/mL, manufactured by Bristol-Myers Squibb, USA. Procedure for administration of Test One tablet was added to 10 mL of water in a glass approximately two minutes prior to scheduled dosing time. The contents were swirled to form a suspension and administered to the subject at the scheduled dosing time. The dosing glass was rinsed with remaining quantity of water two to transfer all the drug contents from the glass and administered to the subject. Bioavailability Study

17 Sampling Schedule The blood samples were collected pre-dose and at 0.167,0.25, 0.333, 0.5, 0.667, 0.833, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 12, 16, 24, 36, 48, 72, 96, 120, 144,168 and 192 hours post-dose in each period Analytical Procedure Lamivudine, Nevirapine and Stavudine in plasma quantitated using chromatographic procedures developed and validated at Ranbaxy Pharmacokinetic Parameters Evaluated AUC 0-t, AUC 0- , AUC 0-t / AUC 0- , C max, T max, K el and T 1/2 Statistical Analysis ANOVA, 90% Confidence Intervals and Ratio Analyses Bioavailability Study

18 Ratio of LSM (90% Confidence Intervals) Bioavailability Study Results

19 The geometric mean ratios (% Test/Reference) of log- transformed parameters of AUC, Cmax and 90% confidence intervals were within % interval Both rate and extent of absorption of Lamivudine, Nevirapine and Stavudine from Triviro LNS KID DS were comparable to equivalent doses of individual liquid formulations Both treatments exhibited similar tolerability under fasting conditions Bioavailability Study Results

20  Ranbaxy’s Novel Pediatric triple ARV TFOS could be used in place of individual liquid formulations  TFOS delivers Lamivudine, Nevirapine and Stavudine in doses recommended by NIH  TFOS is expected to enhance convenience of administration and compliance with therapy Conclusion

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