Transcript Pediatric ARV Formulation - International AIDS Society

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
Why Pediatric Anti-Retroviral (ARVs)?

Children (<15 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 & >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
* http://www.who.int/3by5/paediatric/en/index.html
“
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Current treatment options
Liquids
Adult FDC Formulations
Pros
Pros
 Accuracy
of titration
Cons
 Multiple
 Dose
Easier availability

Affordable

Ease of storage
liquid medications
measurement difficulties
 Refrigeration
 Higher
transportation & inventory
management costs
 Limited

availability
Cons

Accuracy? (Not in line with
recommended doses)

Difficult to titrate

Palatability?
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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 20mg+Nevirapine 35mg+Stavudine 5mg
Each TFOS contains:
Lamivudine 40mg+Nevirapine 70mg+Stavudine 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.gov/).
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Pharmaceutical Evaluation
Results of various quality tests on TFOS:
Test
Result
Dispersion Time
40 seconds
Appearance of Dispersion
Uniform Suspension
Taste
Pleasant, Orange flavor
Subdivision of tablet
Complies
Lamivudine
Nevirapine
Stavudine
Mean Assay
SD
99.03%
2.13%
99.20%
3.64%
98.50%
1.60%
RSD
2.13%
3.67%
1.63%
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
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Dissolution Profile
Dissolution in 0.01N HCl/USP/Type II/75 rpm
110
100
% drug dissolved
90
80
70
60
LAMIVUDINE
50
40
30
20
10
0
0 min
10 min
15 min
30 min
45 min
Time in minutes
Epivir Oral Solution 50 mg/5ml
LNS Dispersible Tablets (Lamivudine)
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Dissolution Profile
Dissolution in 0.01N HCl/USP/Type II/75 rpm
110
100
90
% drug dissolved
80
70
60
NEVIRAPINE
50
40
30
20
10
0
0 min
10 min
15 min
30 min
45 min
Tim e in m inutes
Viramune Suspension 50 mg/5ml
LNS Dispersible Tablets (Nevirapine)
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Dissolution Profile
Dissolution in 0.01N HCl/USP/Type II/75 rpm
110
100
90
% drug dissolved
80
70
60
STAVUDINE
50
40
30
20
10
0
0 min
10 min
15 min
30 min
45 min
Tim e in m inutes
Zerit Pow der for Oral Solution 1mg/ml
LNS Dispersible Tablets (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, R&D-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)
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.
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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
chromatographic procedures developed and validated at Ranbaxy
using
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)
Parameters
ln Cmax
ln AUC0-t
ln AUC0-
Lamivudine
Nevirapine
Stavudine
115.27%
105.11 %
88.73 %
(106.84% - 124.38%)
(98.90-111.71%)
(83.42 – 94.39%)
107.90%
99.56%
91.87%
(100.87 – 115.41%)
(95.59– 103.69%)
(89.24 – 94.58%)
107.24%
100.84%
92.82%
(100.54%- 114.39%)
(96.77-105.08%)
(90.95 – 94.73%)
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Bioavailability Study Results
• The geometric mean ratios (% Test/Reference) of logtransformed 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
 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
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