International Partnership for International Partnership for Microbicides Microbicides Characterization of In Vitro Release and In Vivo Delivery of TMC120 with an Intravaginal Ring: Implications for Microbicide Delivery Joseph Romano, Ph.D. August 16, 2006
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Microbicide Delivery: Choice will be Key to Widespread Adoption of Microbicides
Characterization of In Vitro Release and In Vivo Delivery of TMC120 with an Intravaginal Ring: Implications for Microbicide Delivery Joseph Romano, Ph.D. August 16, 2006. Microbicide Delivery: Choice will be Key to Widespread Adoption of Microbicides. Diversity of delivery systems - PowerPoint PPT Presentation
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International Partnership for International Partnership for MicrobicidesMicrobicides
International Partnership for International Partnership for MicrobicidesMicrobicides
Characterization of In Vitro Release and In Vivo Delivery of TMC120 with an Intravaginal Ring: Implications for
Microbicide Delivery
Joseph Romano, Ph.D.
August 16, 2006
Microbicide Delivery: Choice will be Key to Microbicide Delivery: Choice will be Key to Widespread Adoption of MicrobicidesWidespread Adoption of MicrobicidesMicrobicide Delivery: Choice will be Key to Microbicide Delivery: Choice will be Key to Widespread Adoption of MicrobicidesWidespread Adoption of Microbicides
Reservoir vs. Matrix Type Vaginal RingsReservoir vs. Matrix Type Vaginal RingsReservoir vs. Matrix Type Vaginal RingsReservoir vs. Matrix Type Vaginal Rings
NNRTI developed by Tibotec/J&J, licensed to IPM (2004) Developed originally as therapeutic, 11 clinical studies
conducted via oral administration Highly potent ARV Low cytotoxicity, non-mutagenic, non-teratogenic Easily manufactured Stable drug substance Very economical IP clarity Gel formulation development
N
CH3
CH3H3C
H
N
N
N
H
CN
Daily Release of Dapivirine from a Silicone Daily Release of Dapivirine from a Silicone Elastomer Reservoir RingElastomer Reservoir RingDaily Release of Dapivirine from a Silicone Daily Release of Dapivirine from a Silicone Elastomer Reservoir RingElastomer Reservoir Ring
0
50
100
150
200
250
300
350
0 5 10 15 20 25 30
Days
Mic
rogr
ams
(ug)
10 mg
25 mg
50 mg
100 mg
0
500
1000
1500
2000
2500
0 5 10 15 20 25 30
Days
Mic
rog
ram
s (u
g)
10 mg
25 mg
50 mg
100 mg
Cumulative Release of Dapivirine from a Cumulative Release of Dapivirine from a Silicone Elastomer Reservoir RingSilicone Elastomer Reservoir RingCumulative Release of Dapivirine from a Cumulative Release of Dapivirine from a Silicone Elastomer Reservoir RingSilicone Elastomer Reservoir Ring
Dapivirine Group (N=10) Mean to EC501 Mean to EC50
1 Mean to EC501
Cervicovaginal epithelium (ng/gm)2
Vaginal ring area ND - ND - 121,208 367,296
Vaginal introitus ND - ND - 54,947 166,505
Cervix3 ND - ND - 42,338 128,297
Vaginal Fluids (ng/mL)4
Vaginal ring area 6,378 19,326 9,087 27,536 8,266 25,047
Vaginal introitus area 819 2,481 1,804 5,466 2,191 6,638
Cervix 1,480 4,485 3,195 9,683 915 2,772
Plasma (ng/mL) 0.03 0.09 0.03 0.09 0.04 0.11
1 EC50 is 0.33 ng/mL; 2 Tissues were collected as 3 mm punch biopsies, with 1 gm tissue assumed to be equivalent to 1 mL; 3 4 samples were not available for analysis, therefore N=6 for this group; 4 Values were converted from the 8 L samples (i.e. x125) collected per Sno-stripTM. ND= not done.
Dapivirine Levels in Clinical SamplesDapivirine Levels in Clinical SamplesDapivirine Levels in Clinical SamplesDapivirine Levels in Clinical Samples
TMC120 Concentrations
1.00
10.00
100.00
1,000.00
10,000.00
100,000.00
1,000,000.00
introitus(T)
cervix(T)
ring (T) introitus(S)
cervix(S)
ring (S) plasma
ng
/mL
(L
og
)
4 hours
24 hours
7 days
<50 pg/mL
EC50= 0.33 ng/mL
Dapivirine concentrations in vaginal fluids Dapivirine concentrations in vaginal fluids (Sno-Strip samples)(Sno-Strip samples)Dapivirine concentrations in vaginal fluids Dapivirine concentrations in vaginal fluids (Sno-Strip samples)(Sno-Strip samples)
EC50= 0.33 ng/mL
Sno-Strip Concentrations
10
100
1,000
10,000
100,000
4 hour 24 hour 2 days 3 days 5 days 7 days
ng/m
L (L
og)
introitus
cervix
ring
C131/IPM008: Conclusions & Next StepsC131/IPM008: Conclusions & Next StepsC131/IPM008: Conclusions & Next StepsC131/IPM008: Conclusions & Next Steps
Conclusions: TMC 120 was delivered via a vaginal ring at high multiples of EC50
TMC120 was detectable, but near LLOQ (5 pg/mL) in plasma samples from TMC120 treatment group.
Both active and placebo rings were safe and well tolerated.
Next Steps: IPM to conduct a ring acceptability study in Africa in 2006 Expanded safety studies with TMC120 in ring Alternative ring designs Development of manufacturing capability