microbicide delivery: choice will be key to widespread adoption of microbicides
DESCRIPTION
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 PresentationTRANSCRIPT
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
Diversity of delivery systems Semisolids/Solids
Gels Emulsions Films Tablets
Devices Vaginal rings Sponges Diaphragm
Oral
Vaginal RingsVaginal RingsVaginal RingsVaginal Rings
Attractive technology: 30+ days of drug delivery
Potentially reduces compliance burden
Easy to use
“Low” cost
Unknowns: Acceptability in relevant populations
Scale up manufacture
Feasibility of multi-drug combinations
Environmental impact
Reservoir vs. Matrix Type Vaginal RingsReservoir vs. Matrix Type Vaginal RingsReservoir vs. Matrix Type Vaginal RingsReservoir vs. Matrix Type Vaginal Rings
Courtesy or Karl Malcolm, QUB Matrix-type
Core-type
Cross-sectional profiles
TMC120Raman maps
TMC120 (Dapivirine): Background/StatusTMC120 (Dapivirine): Background/StatusTMC120 (Dapivirine): Background/StatusTMC120 (Dapivirine): Background/Status
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 Formulation: PharmacokineticsDapivirine Formulation: PharmacokineticsDapivirine Formulation: PharmacokineticsDapivirine Formulation: Pharmacokinetics
Gel in rabbits and macaques Tissue associated levels all much greater than EC50
even 24 hours post application Good distribution of drug throughout vagina Very low plasma levels
Human PK study (IPM004): Completed in Q1, 2006 Vaginal ring in humans (IPM008)
Good distribution of drug throughout vagina Very low plasma levels
C131/IPM008: Trial SummaryC131/IPM008: Trial SummaryC131/IPM008: Trial SummaryC131/IPM008: Trial Summary
Trial period: Start: 27 June 2005; End: 04 August 2005 Primary objective: Evaluate the feasibility of using a silicone
elastomer reservoir type vaginal ring to deliver the candidate microbicide TMC120.
Specific objectives:• Assess the safety and tolerability of 7-day use of a vaginal ring
containing TMC120.• Assess TMC120 concentrations in vaginal fluids, vaginal and
cervical epithelial tissue, and plasma during and after 7-day use.
Methodology: Randomized, double blind, placebo control design • 10 women with the dapivirine ring (25 mg)• 3 women with placebo ring
C131/IPM008: Safety SummaryC131/IPM008: Safety SummaryC131/IPM008: Safety SummaryC131/IPM008: Safety Summary
No consistent or clinically relevant changes in lab parameters were observed
• One treatment emergent grade 1 lab abnormality No clinically relevant changes in urinalysis or vital sign
parameters No mean changes in vaginal ecology pH
• Nugent scores unchanged between screen and Day 14 in 9/10 women in drug arm (1 improved); no change in 2/3 in placebo arm (1 worsened)
One clinically relevant abnormality on pelvic exam (cervical uterine ulcer on day 14)
• Doubtful as drug related
C131/IPM 008 Trial: AE SummaryC131/IPM 008 Trial: AE SummaryC131/IPM 008 Trial: AE SummaryC131/IPM 008 Trial: AE Summary
ARM N= per arm n= With Any AE
% with any AE
Placebo 3 2 66
25 mg TMC120
10 8 80
Total 13 10 77
Majority of AE’s were grade 1 (mild); 3 subjects with grade 2 (moderate) which were doubtful as related to drug
Four subjects with AE’s possibly related to drug; none were considered probable or very likely related to drug
No deaths, SAE’s, or AE’s leading to premature discontinuation were recorded
Drug Release: Specimen Type/ScheduleDrug Release: Specimen Type/ScheduleDrug Release: Specimen Type/ScheduleDrug Release: Specimen Type/Schedule
Plasma Blood draw: 4 hrs, 24 hrs, 7 days (pre)
Vaginal fluid Sno-strips: 4 hrs, 24 hrs, 7 days (pre)
Subgroups at 2, 3, and 5 days
Tissue Biopsies: 7 days (post)
Introitus Vaginal wall Endocervix
C131/IPM005: Specimen AnalysisC131/IPM005: Specimen AnalysisC131/IPM005: Specimen AnalysisC131/IPM005: Specimen Analysis
4 Hours 24 hours 7 days
Geo. Ratio Geo. Ratio Geo. Ratio
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
AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements
University of Ghent Steven Weyers Luc van Bortel Marleen Temmerman
Queen’s University, Belfast Karl Malcolm David Woolfson
Warner Chilcott Claire Gilligan Robert Patrick
Tibotec Jens van Roey
IPM Paul Coplan Karen Douville Richard Erwin Mark Mitchnick Zeda Rosenberg Joe Romano