Pediatric ARV Formulation

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Comparative Bioavailability Study of a Novel
Paediatric Tablets For Oral Suspension (TFOS) of
Lamivudine, Nevirapine and StavudineVsIndividu
al Reference Liquid FormulationGowrishankar R,
Manaktala C, Verma M, Chhabra A, Juneja
SRanbaxy Laboratories Limited
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Why Pediatric Anti-Retroviral (ARVs)?

• Children (lt15 years age) account for
• 1/6th of AIDS-related deaths
• 1/7th of new HIV infections
• Without treatment, 50 of HIV infected children
  die within 2 years gt90 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

http//www.who.int/3by5/paediatric/en/index.htm
l
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Current treatment options

• 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

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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

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An Innovative TFOS
Each TFOS contains Lamivudine 20mgNevirapine
35mgStavudine 5mg
Each TFOS contains Lamivudine 40mgNevirapine
70mgStavudine 10mg
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TRIVIRO-LNS kid DS TFOS - Dispersed
Reference dose
Triviro-LNS kid DT
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• 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, 2005. National
Institutes of Health (NIH).(http//aidsinfo.nih.go
v/).
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Pharmaceutical Evaluation

• Results of various quality tests on TFOS

• Stability Testing
• Subjected to accelerated stability (40ºC/75
  RH/6M) and Zone IV (30ºC/70RH/9M) conditions in
  HDPE bottles unit dose blisters
• Assays, RS, dissolution were tested periodically
  and were within specifications

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Dissolution Profile
LAMIVUDINE
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Dissolution Profile
NEVIRAPINE
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Dissolution Profile
STAVUDINE
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Bioavailability Study
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Bioavailability Study
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.
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Bioavailability Study
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,
RD-III, Ranbaxy Laboratories Limited, Gurgaon,
India
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Bioavailability Study

• 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)
• 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.

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Bioavailability Study
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 AUC0-t, AUC0-?, AUC0-t/
AUC0- ?, Cmax, Tmax, Kel and T1/2 Statistical
Analysis ANOVA, 90 Confidence Intervals and
Ratio Analyses
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Bioavailability Study Results
Ratio of LSM (90 Confidence Intervals)
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Bioavailability Study Results

• The geometric mean ratios ( Test/Reference) of
  log-transformed parameters of AUC, Cmax and 90
  confidence intervals were within 80 -125
  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

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Conclusion

• Ranbaxys 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

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