Chlorproguanil-dapsone (LAPDAP) for uncomplicated

falciparum malaria

Peter Winstanley

Department of Pharmacology and Therapeutics, University of Liverpool, UK

Summary The synergistic antifolate combination of chlorproguanil with dapsone (CPG±DDS; LAPDAP) is being

developed by a public±private partnership as a low-cost treatment for uncomplicated falciparum

malaria. LAPDAP is rapidly eliminated from the body, giving it low selection pressure for drug

resistance. Clinical cases with sulphadoxine-pyrimethamine (SP)-resistant infections acquired in Africa

have been predicted to be responsive to LAPDAP, and clinical evidence is available to support this.

A regulatory dossier is being prepared for simultaneous submission to the UK Medicines Control Agency

and African licencing authorities. The team working on LAPDAP has also started to develop the triple

combination of chlorproguanil±dapsone±artesunate (CDA) as a low-cost combination therapy for

uncomplicated falciparum malaria. Although LAPDAP does not have regulatory approval (and

development of CDA is at an early stage), the development team is keen to communicate with public

health scientists to try to anticipate the policy and implementation hurdles that lie ahead. This short

paper outlines the current stages that LAPDAP and CDA have reached, and sketches the anticipated

public health issues.

keywords falciparum malaria, drug development, LAPDAP

correspondence Professor P. Winstanley, Department of Pharmacology and Therapeutics, University

of Liverpool, L69 3GE, UK. E-mail: peterwin@liv.ac.uk

Introduction

The inexorable spread of resistance to affordable anti-

malarial drugs poses one of the largest public health

problems for Africa. Many countries are faced with the

dif®cult problems of when to change from chloroquine as

®rst-line treatment or what to do about resistance to

sulphadoxine-pyrimethamine (SP). New treatments for

non-severe falciparum malaria are desperately needed in

Africa to replace SP, one of the last affordable drugs

(Winstanley 2000).

The combination of chlorproguanil with dapsone

(CPG±DDS; LAPDAP) was studied in ®eld trials

(Amukoye et al. 1996; Sulo et al. in preparation) after

initial laboratory work (Winstanley et al. 1995) had

established it as a promising drug candidate. CPG±DDS

is now being developed by a public±private partnership

of the University of Liverpool, the World Health

Organization (WHO) (TDR), the British government

(Department for International Development; DfID) and

GlaxoSmithKline. The process is being managed by a

product development team (PDT) within WHO-TDR

(The USDP/WHO/World Bank Program for Research

and Training in Tropical Diseases).

Two caplet oral dosage forms are being manufactured:

CPG 80 mg + DDS 100 mg per caplet, for adults, and

CPG 15 mg + DDS 18.75 mg per caplet for children. It is

hoped that LAPDAP will prove to be a safe, effective and

affordable addition to the pharmacopoeia for the treat-

ment of uncomplicated falciparum malaria. A phase III

clinical trial of LAPDAP, which will provide pivotal data

for the regulatory submission, with 2000 children with

malaria was recently completed in Nigeria, Kenya,

Malawi, Tanzania and Gabon. The regulatory dossier

will be submitted to drug regulatory authorities in UK

as the country of origin and in relevant African nations

in 2001.

Although regulatory approval of LAPDAP cannot be

taken for granted, the WHO PDT wants to start

assessing the possible role of LAPDAP in malaria control

strategies, and the policy/implementation hurdles that lie

ahead.

Tropical Medicine and International Health

volume 6 no 11 pp 952±954 november 2001

952 ã 2001 Blackwell Science Ltd

From existing data, what are the positive features

of LAPDAP?

LAPDAP is a synergistic combination of two antifolate

drugs, thus resembling SP. However, unlike SP, LAPDAP is

rapidly eliminated from the body (Winstanley et al. 1997),

giving it a low selection pressure for drug resistance

(Watkins & Mosobo 1993; Nzila-Mounda et al. 2000a).

Clinical cases with SP-resistant infections (including triple

mutants of dihydrofolate reductase (dhfr) ± Ser-108-Asn,

Asn-51-Ile and Cys-59-Arg) have been predicted to be

responsive to LAPDAP (Watkins et al. 1997; Nzila-Moun-

da et al. 2000b), and clinical evidence is available to

support this (Muttabingwa et al. 2001). In large-scale

clinical trials initially using a temporary formulation,

LAPDAP given daily for 3 days was an effective cure for

Plasmodium falciparum parasitaemia in children

(Amukoye et al. 1997; J Sulo, P Chimpen, J Hatcher,

JG Kublin, CV Plowe, ME Molyneux, K Marsh, TE Taylor,

WM Watkins & PA Winstanley, unpublished data).

What are the negative features of LAPDAP?

Because of its rapid elimination from the body (Winstanley

et al. 1997), a single dose of LAPDAP is inadequate

treatment for falciparum malaria (Amukoye et al. 1996),

being associated with a high risk of recrudescence. While

the current `daily for 3 days' LAPDAP regimen should be

practicable in an outpatient setting, it will be more

complicated than single-dose SP. Poor compliance with

LAPDAP would probably carry the risk of treatment

failure.

SP exerts strong selection pressure for resistance, and

readily selects mutations in both dhfr and the gene

encoding dihydropteroate synthetase (dhps), which is the

enzyme target of both sulphadoxine and dapsone (Watkins

& Mosobo 1993; N'Zila-Mounda et al. 2000a, b). Because

the mechanism of action of both treatments is the same, it

is likely that widespread use of SP will eventually select

resistance not only to itself, but also to LAPDAP. The Dhfr

quadruple mutants (Ser-108-Asn, Asn-51-Ile, Cys-59-Arg

and Ile-164-Leu) are likely to be LAPDAP-resistant or have

borderline sensitivity (Watkins et al. 1997). Thus, in areas

where SP is already widely used, LAPDAP monotherapy

may only have clinical utility for a short time.

Which features of LAPDAP still need clari®cation?

All drugs carry the risk of causing adverse drug reactions

(ADR). There is extensive clinical experience with both

CPG and DDS, but analysis of the phase III trial of

LAPDAP, which was undertaken primarily to study drug

safety, is incomplete at the time of writing. Haematological

ADRs to DDS have been reported and examination of this

has been a focus of the phase III trial of CPG±DDS. Given

that some ADRs are as infrequent as 1 : 20 000 and

regulatory dossiers usually contain ADR data from no

more than 2000 people, ADR pro®les are usually incom-

pletely understood when a new drug is registered. The

safety of all new drugs needs to be carefully studied after

launch. LAPDAP has not yet been formally studied in

pregnancy, and this obstacle to its widespread use will need

to be addressed.

Is widespread use of LAPDAP possible soon after

market authorization is granted?

In many ways, the development programme of LAPDAP is

breaking new ground: never before has an antimalarial

drug been developed primarily as a tool for malaria

control, and early consultation of public health scientists is

unusual. It is clear that decisions on the deployment of

LAPDAP will ultimately be made by national authorities,

which will need to have access to local experience and data

as well as the data presented in the regulatory dossier. Such

local data will probably only be obtained after regulatory

approval of the drug. The PDT envisages a series of Phase

IV post-marketing studies that would probably be con-

ducted under the auspices of national malaria control

programmes speci®cally to provide the information needed

by national decision-makers. This can most easily be

envisaged in those countries that maintain sentinel-site

testing of drug ef®cacy for national policy decisions. Phase

IV studies will address such issues as country-by-country

drug ef®cacy and safety (ADRs probably being published

by WHO and GlaxoSmithKline in a public domain

database), while also tackling such operationally important

issues as drug compliance. Phase IV work will need to be in

keeping with the requirements of the WHO Essential

Drugs List, and co-ordinated by a WHO-industry-

academic group.

Is artemisinin combination therapy (ACT) relevant

to LAPDAP?

The theoretical concepts underlying ACT have been set out

elsewhere (White 1998). The LAPDAP-PDT plans to

develop chlorproguanil±dapsone±artesunate (CDA) as a

triple combination tablet in the expectation that the

artesunate component will reduce the rate at which resist-

ance to LAPDAP emerges. But it will take longer to bring

CDA to market authorization than LAPDAP, and the triple

combination drug will be more expensive than LAPDAP.

Co-packaging of artesunate with LAPDAP is an alternative

Tropical Medicine and International Health volume 6 no 11 pp 952±954 november 2001

P. Winstanley LAPDAP for uncomplicated falciparum malaria

ã 2001 Blackwell Science Ltd 953

strategy: this would probably have the advantage of a more

rapid development programme. But such packaging would

probably present severe operational dif®culties in ensuring

that both components are taken properly.

How can we optimize access to LAPDAP by poor people?

The price of antimalarial drugs is a major determinant of

drug choice. Consequently, the PDT is committed to

developing LAPDAP as rapidly and inexpensively as

possible, while maintaining international quality standards

and permitting recovery of development costs. In the public

sector a 3-day adult course of LAPDAP will cost less than

US$ 0.50 (the ®nal price not yet having been ®xed). The

public sector is taken to mean government health facilities

as part of the development and implementation of national

malaria control programmes. Pricing of the drug for the

traditional private sector has not yet been decided, but

will be ®xed in the light of normal commercial

considerations.

It is likely that the PDT will want to explore ways in

which the distribution and use of LAPDAP might be

optimized. For example although LAPDAP will, initially at

least, be available on prescription only, the informal

private market (village shops and other non-health sector

drug outlets) cannot be ignored as a drug outlet in many

African countries. Although such drug access is often relied

upon in rural areas, it carries the risk of suboptimal drug

use such as incomplete dosage regimens. This will be a

subject for discussion between the LAPDAP-PDT and

public health scientists.

Conclusions

LAPDAP has not yet been approved by any national

drug registration authority, but will be submitted for

scrutiny in 2001. The team developing LAPDAP wants

to start raising the awareness of public health experts

earlier rather than later. In this way, it is hoped that policy

and implementation issues may be thought through in

advance, thus expediting access to LAPDAP for those

who need it.

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Tropical Medicine and International Health volume 6 no 11 pp 952±954 november 2001

P. Winstanley LAPDAP for uncomplicated falciparum malaria

954 ã 2001 Blackwell Science Ltd