THE DST/NWU PRECLINICAL DRUG DEVELOPMENT PLATFORM (PCDDP) AND AMR

South Africa-UK Antimicrobial Resistance (AMR) Drug Discovery Hub workshop

4-5 June 2019

Anne Grobler (Director), Rose Hayeshi & PCDDP team

DST/NWU Preclinical Drug Development Platform (PCDDP)

• Joint initiative between the DST and the North-West University, established 2011, aligned with

• National facility, innovation of pharmaceutical development focusing on preclinical drug development, formulation and diagnostics.

• Intended to teach postgraduates and to supply expertise and innovation to scientists and businesses, both locally and internationally.

Functions performed at the PCDDP

Preclinical drug development

Pharmaco-kinetics

Pharmaco-dynamics

Toxicity

Specialized studies e.g. xenografts,

metabolic studies

Behaviouralstudies

Micro-PET/CT studies

Radio-telemetric safety

pharmacology

Clinical drug development

Study design and ethics

Phase 1 clinical trials

Phase 2 clinical trials

Drug tolerability

Bioanalysis (LCMSMS)

Diagnostic development

Molecular diagnostic

prototyping

Cost effective tuberculosis diagnostic

Parkinson's biomarker

identification

Radiochemical ID of cardiovascular lesions & cancer

Formulation & dosage forms

Pheroid drug delivery system development

Combination Pheroid & nano-material systems

Improved efficacy & safety of formulations

Dosage form development

Postgraduate: Pharmaceutical

Sciences

Rodent models and facilities for infectious disease research

Ground Floor (GLP) Floor Plan

G 10

G 09

G

11 GP 4

G

12

G 25

GP 3 GP 2

NOT TO SCALE IVC RACK IVC BLOWER Metabolic Rack

P.M

ROOM

LADIESGENTSPREPARATION

AREA

Safety

Pharmacology

G18

G 17

RATS

G 15

RATS

G 13

THEATRE

INTERNAL PLANT ROOM

CLEAN CAGE STORAGE

G 16

G 14 - MICE

RECEPTION

OFFICE

OFFICECANTEEN

KIT

CH

EN

BEHAVIOURAL

STUDIES G 24

G 20 Metabolic and

PK Studies

G 22

MICE

DATA

ROOM G 26

BEHAVIOURAL

G 21

BEHAVIOURAL

G 23G 19

RATS

BEHAVIOURAL

WASH UP

BSL3 laboratory

GLPBasement Level (SPF) Floor Plan

K 19.1

K 1

NOT TO SCALE IVC RACK IVC BLOWER

K 13 - Mice K 12 - Mice K 11 - Mice

K 07

Rats

K 06

Rats

K 05

Rats

WASH UP AREA K 18

AIR SHOWER

STAFF

ROOM K 02

CLEAN CAGE STORAGE K 09

K 04 - Guinea PigsOFFICE

K 03

VACCINE

DEVELOPMENT

K 15

Mice

CAGE PREPARATION

K 10

K 08

Mice

K 14 - Guinea Pigs

QUARANTINE K 20

K 19.2

K 17.1

K 17.2

SPF

Environmental control: (BMS and DMS)Pressure cascade

• Healthy mice and rats for PK/PD studies

• Infection models• Kramnik mice- TB

• Immunodeficient mice- e.g. malaria

• Genital tract infection models- e.g. HSV2

• Potential for development and progression of resistance among the commensal bacteria of the human microbiome during anti-tuberculosis therapy in an animal model

Pheroid® drug delivery system to overcome AMR

+H2O-phase

+ API

long chain fatty acidsPEG-

ricinoleic acidα-

tocopherol

N2O

Pheroid® drug delivery system to overcome AMR

• Increased efficacy in vitro

• Increased bioavailability of

rifampicin, isoniazid and

ethambutol in mice

• Increased efficacy in

infectious mouse model,

shorter time to a effect,

longer maintenance of no

growth.

• Phase 1 : Significantly

improved bioavailaibility of

rifampicin, isoniazid,

ethambutol.

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8 9

µg

IN

H/m

l p

lasm

a

Time (hours)

0

2

4

6

8

10

12

0 1 2 3 4 5 6 7 8 9

ug

RM

P/m

l p

lasm

a

Time (hours)

Pyriftol

Projected 100%

Rifafour

In vitro results – enhancement factor due to changes in delivery

0

20

40

60

80

100

120

a b c d e f g h I j k l

RMP INH EMB

% G

row

th

Treatment

Control Drugs plus Pheroid Drugs alone

M.tb H37Rv in the BACTEC system

[RMP]: b=0.03125µg/ml, c=0.0625µg/ml,

d=0.125µg/ml (approx. MIC).

[INH]: f=0.005µg/ml, g=0.01ug/ml, h=0.02µg/ml

(approx. MIC)

[EMB] : j=0.125µg/ml, k=0.25µg/ml and l=0.5µg/ml.

(previous collaboration with Paul van Helden’s group; study performed by his Centre)

In vivo results: tuberculosis

➢ 12-40x improved in vitro efficacy for antituberculosis compounds (collaboration with Stellenbosch University).

A

D

M

E

➢ 3x improved in vivo bioavailability in rodents and humans for the

above.

➢ Improved body distribution; passive targeting to white blood cell

fraction.

➢ Protection of cellular viability of blood cells against side

effects.

➢ Slower clearance, thus longer drug half-life.

-200

0

200

400

600

800

1000

1200

1 2 3 4 5 6 7 8 9

% b

acte

rial

gro

wth

Days

1182Rifafour

1182Pheroid

Multi Drug Resistance

➢ 2x faster onset of action, 3x longer duration of effect in infected mice.

Drug sensitive reference strain H37Rv &

drug resistant strain 1182 in plasma of

patients, treated post plasma preparation

with Rifafour-e200 & Pheroid ®/ /drug to

mimic in vivo efficacy. The Pheroid ® /drug

dosage is 60% of that of Rifafour-e200.

Our pharmaceutical chemists design a new, cheaper, faster TB diagnostic instrument

TB Diagnostic

• Rapid yes/no diagnosis

• First and second line drug resistance profiling

• Live/dead differentiation

• Reduce false positives•Monitoring during treatment

THANK YOU