New and improved LPV/r based formulations for infants and young children

Marc Lallemant - IAS July 1st 2013

Malaria Leishmaniasis

Sleeping Sickness (HAT) Chagas Disease

Paediatric HIV

Helminth infections

DNDi: R&D to Respond to the Needs of Patients Suffering from Neglected Diseases…

Easy to Use Affordable Field-Adapted Non-Patented

6 New Treatments Developed Since 2007

From NVP to LPV/r based first-lines!

NVP based ART LPV/r + 2 NRTIs

FDCs availableBaby and junior dosingScored tabletsCan be crushed/dispersedEasy dosing

Liquid only currentlyBitter tasteNeurotoxic excipients

• 42% ethanol• 15% propylene glycol

Needs cold chainHeavy to carry, hard to hideDifficult dosingNeed for RTV super-boosting in TB/HIV co-infection

DNDi Paediatric HIV Program Objectives

Develop two solid first-line LPV/r-based fixed-dose combinations (FDC) with two NRTIs, 3TC plus ABC or AZT.

Well taste masked Heat-stable without refrigeration, long shelf life single strength for dosing throughout weight bands

Develop complementary granule of RTV to be added to the 4-in-1 LPV/r based FDCs during HIV and tuberculosis treatment

4:1 1:1 LPV/RTV ratio when on RIF

Formulation Challenges of Lopinavir and Ritonavir

High solubility Low solubilityHigh permeability ZDV, FTC

Low permeability 3TC, ABC RTV, LPV

LPV RTV

DNDi Initial Explorations Original LPV and RTV formulations were alcohol based oral

solutions and soft gel capsules (Abbott) Replaced for adults and older children with LPV/r tablets

(Abbott) Soluble polymer (copovidone)

Tablets cannot be used in young children as crushed they loose up to 50% bioavailability

Alternative options Prodrugs (eg. RTV)

o Nano particleso Nano dispersions

Encouraging PK in animalsPoor taste; 5 years minimum time line (NCE)

The Concept of 4-in-1 Granules

The DNDi-Cipla partnership

5 10 15 20 25

020

4060

8010

0

Bodyweight (kg)

Per

cent

age

of c

hild

ren

with

LP

V C

min

abo

ve 3

mg/

L

FDAWHOOur recommendation

4

% of patients with Cmin > 3mg/L

5 10 15 20 25

020

4060

8010

0

Bodyweight (kg)

Per

cent

age

of c

hild

ren

with

LP

V C

min

abo

ve 1

mg/

L

FDAWHOOur recommendation

4

WHO 2010FDAWHO 2010 modified

% of patients with Cmin > 1mg/L

WHO 2010FDAWHO 2010 modified

Weight band Dosing accepted by WHOTo be included in 2013 guidelines

US and European paediatric ARV PK databases merge; Developmental PK modelling; Exposure simulations:• New LPV/r dosing harmonizes WHO

weight band table for LPV/r and accompanying NRTIs.

New dosage of 4-in-1 FDC included in WHO urgently needed fomulations

am pm am pm am pm am pm am pm

ABC/3TC/LPV/r 30/15/40/10mg 2 2 3 3 4 4 5 5 6 6

AZT/3TC/LPV/r 30/15/40/10mg 2 2 3 3 4 4 5 5 6 6

DrugStrength of tab or

sprinkle sachet/capsule (mg)

Number of tablets by weight-band morning and evening

3–5.9 kg 6–9.9 kg 10–13.9 kg 14–19.9 kg 20–24.9 kg

4-in-1 Granules Development Timeline

LPV/R

Assemble 4-in-1 Registration stability

LPV/r granules vs. Liquid comparative bioavailability in healthy adult volunteers

Clinical batch 4-in-1

Accelerated stability

Bioequivalence in healthy adult volunteers (4-in-1)

Paediatric phase 2 LPV/r granules vs. liquid cross-over PK

Phase 2/3 paediatric pop PK, safety, efficacy study (4-in-1)

Dossier submission to FDA

2014 20152013

Industrial scale up

Cipla pharma

DNDi Clinical

Superboosting PK Study in South Africa

PK

PK

PK

6 months RIF based TB therapy

PI based antiretroviral therapy

6 months RIF based TB therapy

PI based antiretroviral therapy

PK

>= 1 month after RIF discontinuation

>1 month after RIF initiation

>1 month after RIF initiation

>= 1 month after RIF discontinuation

3 months after RIF discontinuation

RIF based TB therapy initiated first

Antiretroviral therapy initiated first

PK

PK

Limited data on pharmacokinetics, safety and efficacy of superboosted LPV/r 1:1 in young children

More data is needed to support superboosting in children of various ages and clinical conditions using the new rifampicin doses.

RTV Booster Development Timeline

Taste masked granulesRegistration stability

RTV granules vs. Liquid comparative bioavailability in healthy adult volunteers

Pivotal Bioequivalence HAV in healthy adult volunteers

Superboosting PK, safety, efficacy of newly developed RTV

Dossier submission to FDA

2014 20152013

Industrial scale up

2x2 PK

Superboosting PK, safety, efficacy of RTV liquid formulationCipla

pharma

DNDi Clinical

Registration – Feasibility - Access

Implementation studies to: Assess

Field effectiveness Safety Acceptability Instructions for use

Facilitate in country registration Facilitate program adoption

2012 2013 2014

SYRUPS TODAY

CHAPAS-2LPV/r

sprinkles

Registration of LPV/r sprinkles

Dual NRTIs dispersible

tablets

LPV/r +2NRTIs granules clinical batch FINAL 4-in-1

Brooklyn Chest Hospital – Cape Town

Thank you18

Photo: Anne Detjen

The DNDi pediatric HIV teamJanice LeeGwenaelle CarnJean René KiechelMarc Lallemant

DNDi teams in Geneva, New York, NairobiPenang, Tokyo, Delhi, Rio de Janeiro

PartnersCipla ltd, MSF, MRC, International Pediatric HIV networks

UNITAID, AFD, MSF International & Norway