DEVELOPING FLUBENDAZOLE FOR USE AS A MACROFILARIACIDE IN
FILARIASIS
OBJECTIVE 3. DOLF
FLUBENDAZOLE
• Binds to tubulin –preferentially to nematode tubulin over mammalian tubulin
• A benzimidazole – as a group it has a good track record for safety…..e.g. albendazole, etc.
• Licensed in Europe for intestinal helminth Rx
WHY FLUBENDAZOLE?
• ANIMAL STUDIES – Brugia in jirds – effective in a single dose
– Dirofilaria – effective in a single parenteral dose
– Has poor/no microfilariacidal effect
– Maybe has some prophylactic action (in Brugia)
• HUMAN STUDIES – Registered for use as an intestinal anthelminthic
– Mexico 1982 studies
(1983) An unpublished additional study – Mackenzie and Martinez-Palomo
FLUBENDAZOLE STUDIES IN CHIAPAS MEXICO 1981-1983
THIS STUDY HAD PROBLEMS WITH THE INJECTION SITE ABSCESSES
THE EFFECT OF FLUBENDAZOLE ON ADULT ONCHOCERCA VOLVULUS COMPARED WITH DIETHYLCARBAMAZINE
SAEs DURING FIRST 2 MONTHS OF THERAPY DEC (n= 9) FLUBENDAZOLE (n=8)
PRURITUS 9 0
RASH 9 0
LYMPHADENOPATHY 9 0
ANOREXIA 8 1
DIZZINESS 6 2
HEADACH 7 3
FEVER 8 7
INFLAMMATION AT SITE 0 8
EFFECT ON MICROFILARIAE Dominguez et al, 1983
MONTH 0 0.25 1 2 3 6 9 12
DEC 101 1 2 4 8 9 3 9
FLUB 21 31 35 31 4 >1 >1 0
MAJOR OPHTHALMOLOGIC COMPLICATIONS DURING THERAPY
DIETHYLCARBAMAZINE (n=9)
FLUBENDAZOLE (n=8)
LIMBITIS 8 0
PUNCTATE KERATITIS
9 1
UVEITIS 5 0
RETINAL PIGMENT EPITH ATROPHY
1 0
SOLUBILITY STUDIES PFIZER-MSU STUDY 2008
• COMPARED A STANDARD RANGE OF SOLUBILIZING EXCIPIENTS
• THE OPTIMAL SOLUBILIZING AGENT WAS PROPYLENE GLYCOL 40:60
DOMINOWSKI & MACKENZIE 2008
EXPERIMENTAL MODELS
• ORAL FORMULATION EFFECTIVE FOR TISSUE PARASITES (CYSTICERCOSIS) – LANUSSE et al.
• USERS DO NOT REPORT ANY TOXPATH ISSUES
HYDROXYPROPYL-β-CYCLODEXTRIN
OBJECTIVE 3 - DOLF
1. REVIEW THE LITERATURE
2. CONTACT RESEARCHERS & PHARMACEUTICAL PERSONNEL
3. DEVELOP A NEW B&M GATES PROPOSAL FOR NEW FUNDING
4. BEGIN PK/PD AND EFFICACY STUDIES WITH βCD FLUBENDAZOLE
5. COMPLETE A REPORT (DOSSIER) ON 1, 2 & 4
REVIEW OF LABORATORY MODELS Lowest dose used that was effective Range 1.5 – 100 mg/kg
THE EARLY DISCUSSIONS
• FOUND NO LIMITING ISSUES
• HAD MUCH SUPPORT AND INTEREST FROM A NUMBER OF MAJOR PHARMACUETICAL COMPANIES
• DNDi BECOMES THE LEAD PARTNER FOR THE SECOND STAGE GRANT (AIMING AT AN IND)
DOCUMENTATION
EXPERT REV ANTI INFECT THER 9 (5) 497-501 (2011)
OBJECTIVE 3 - DOLF
1. REVIEW THE LITERATURE - DONE (+ PUB)
2. CONTACT RESEARCHERS & PHARMACEUTICAL PERSONNEL - DONE
3. DEVELOP A NEW B&M GATES PROPOSAL FOR NEW FUNDING – DONE AND FUNDED
4. BEGIN PK/PD AND EFFICACY STUDIES WITH βCD FLUBENDAZOLE - UNDERWAY
5. COMPLETE A REPORT (DOSSIER) ON 1, 2 & 4 – DUE JAN 2012
PK-PD STUDIES WITH β CD
• CARLOS LANUSSE – TANDIL, ARGENTINA – RATS, JIRDS AND PIGS
• Flubendazole-hydropropyl-β-cyclodextrin – FBLZ-HPBCDoral
– FLBX-HPBCDsc
• Flubendazole-carboxymethyl cellulose – FLBZ-CMC (oral)
Experimental Design Species
• Rats and Jirds – Each formulation group n=44 – 5mg/kg dose rate – Blood plasma evaluated by HPLC
• Pre-treatment and 5, 15 & 30 minutes and 1,2,3,4,6,8, & 16 hours post treatment
• Pigs – Each formulation group n=4 – 2mg/kg dose rate – Blood plasma evaluated by HPLC
• Pre-treatment and 1,3,6,9,12,15,24, 48 & 54 hours post treatment
Pharmacokinetics
• HPLC analysis of blood plasma for Flubendazole and it’s metabolites:
– Flubendazole(FLBZ)
– Reduced-Flubendazole (R-FLBZ)
– Hydrolyzed-FLBX (H-FLBZ)
– Oxibendazole (internal standard)
Plasma concentration profiles Rats
0 2 4 6 8 10 12
0,0
0,5
1,0
1,5
2,0
2,5
3,0
FLBZ. AUC= 4.8 ± 0.8 µg.h/mL
H-FLBZ. AUC= 4.3 ± 1.3 µg.h/mL
R-FLBZ. AUC= 0.9 ± 0.1 µg.h/mL
FLBZ-HPBCD (oral)
Pla
sm
a c
on
ce
ntr
atio
n (
µg/m
L)
Time (h)
Plasma concentration profiles Rats
-2 0 2 4 6 8 10 12 14 16
0,0
0,3
0,6
0,9
1,2
1,5
1,8
FLBZ. AUC= 7.3 ± 0.6 µg.h/mL
H-FLBZ. AUC= 5.1 ± 0.7 µg.h/mL
R-FLBZ. AUC= 1.4 ± 0.1 µg.h/mL
FLBZ-HPBCD(SC)
P
lasm
a c
on
ce
ntr
atio
n (
µg
/mL
)
Time (h)
Plasma concentration profiles Rats
0 2 4 6 8 10 12
0,00
0,04
0,08
0,12
0,16
0,20
FLBZ. AUC= 0.9 ± 0.1 µg.h/mL
H-FLBZ. AUC= 0.5 ± 0.2 µg.h/mL
R-FLBZ. AUC= 0.2 ± 0.1 µg.h/mL
FLBZ-CMC
Pla
sm
a c
on
ce
ntr
atio
n (
µg
/mL
)
Time (h)
Pharmacokinetic Parameters Rats
Plasma concentration profiles Jirds
0 2 4 6 8 10
0,0
0,5
1,0
1,5
2,0
2,5
3,0FLUBENDAZOLE
Pla
sm
a c
on
ce
ntr
atio
n (
µg
/mL
)
Time (h)
FLBZ-HPBCD (sc)
FLBZ-HPBCD (oral)
Pharmacokinetic Parameters Jirds
Conclusions
• Flubendazole metabolic patterns and relative systemic exposure of the parent flubendazole and its metabolites differ among species.
• Flubendazole pharmacokinetic behavior can be markedly improved by changing the formulation
• The alterations in systemic exposure to flubendazole obtained with the cyclodextrin formulation (both oral and parenteral) is likely to have a great impact on clinical efficacy.
THE NEXT STAGE
B&M Gates Grant II
PHASE 2
• LED BY DNDi (Rob Don and Ivan Scandale)
• A “DEVELOPING” MULTI-COMPONENT TEAM
– REFORMULATION - Abbott (Chicago)
– PK/PD & Efficacy & Safety – MSU/McGill
– SAFETY – UNI CARDIFF & OTHERS
– PRODUCTION ISSUES - ?
- PLANNING FOR FIELD STUDIES - ?
TIMING OF PROJECT
DNDi- ABBOTT unpublished
Formulation Update
• Nanosuspension vs. cyclodextrin vs. solid dispersion
– All three formulations provided comparable exposure at low dose (2 mg/kg)
– Amorphous solid dispersion provided highest exposure, with lowest variability, at 20 mg/kg
• High variability with cyclodextrin formulation
• Lowest exposure with nano-suspension formulation
• Further dose escalation is not possible with cyclodextrin formulation (solubility limited to ~2 mg/ml)
• Solid dispersion formulation administered to rats at higher doses (50, 100 mg/kg) to profile dose response (analysis in progress)
Presentation Title Date
31
ADME preliminary results Absorption, Distribution, Metabolism and Excretion
• Stable in vitro (microsomes, hepatocytes)
• Modest protein binding
• High permeability
• Low potential for drug-drug interactions (as inhibitor)
Presentation Title Date
32 Company Confidential © 200X Abbott
SUMMARY - DOLF OBJ 3 + NEW PHASE
• Achieved 90% of the stated objective – Grant written, submitted and funded
– Base PK/PD completed
– Efficacy in jirds/rats to complete
• Second phase activities moving ahead rapidly – Reformulation has occurred
– Toxicology underway
– Efficacy studies arranged
• IND submitted by Jan 2013 (?)
VIEW
• We soon need to think about:
– How we move to human trials post a successful IND submission?
– How it would be used? Increasing the “menu” of tools for elimination and control programs, and for individual treatment
• A need for more Pharma partners – through a consortium?