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Table 2 An ideal Target Product Profile (TPP) for an anti-malarial combination therapy

From: Pharmacological considerations in the design of anti-malarial drug combination therapies – is matching half-lives enough?

Property

 

Attribute

Reference

Formulation & dose

Single-dose treatment regimen

Desirable

[17, 32]

 

Stable

Critical

[32]

 

Fixed-dose in a single formulation

Desirable

[32]

 

Orally, rectally and parentally applicable

Desirable

[32]

 

Dose of each drug high enough so that it will remain effective even if resistance is present to the other drug

Critical

This manuscript KPC#4

Mode of action

Effective against all stages of parasite development in the human host

Desirable

[32]

 

Active against hypnozoites and able to prevent relapse

Desirable

[17]

 

Transmission-blocking activity

Desirable

[17]

 

Robust to the evolution of resistance

Critical

[32]

 

Independent, or preferably synergistic, mode of action of drugs

Desirable

[32]; this manuscript KPC#4

 

Different metabolic target(s) of drug action

Desirable/Critical

This manuscript KPC#4

 

Negative patterns of cross resistance

Desirable

This manuscript KPC#6

Pharmacokinetics & pharmacodynamics (PK/PD)

Elimination half-lives of drugs should be approximately matched

Desirable

[32, 33]

The post-treatment drug activity profiles (based on elimination half-lives, dosages and drug sensitivity) should be matched

Critical

This manuscript KPC#1 (Figures 2 &3)

Low levels of inter-individual PK/PD variation to minimise drug activity profile mismatch in individual infections

Desirable

This manuscript KPC#2 (Figure 4)

 

Extended period of chemoprophylaxis post-treatment

Desirable

[15, 17]

 

Predictable metabolism via non polymorphic enzymes

Desirable

This manuscript KPC#5

 

No pharmacokinetic drug-drug interaction

Desirable

This manuscript KPC#5

Efficacy & safety

Large therapeutic index

Desirable

This manuscript KPC#3

Toxicity of drugs should be additive or antagonistic

Desirable

This manuscript KPC#3

 

Drug conversion and elimination should not share same metabolic pathway

Desirable

This manuscript KPC#3

 

Dissimilar type B adverse drug reaction profiles

Desirable

This manuscript KPC#3

 

Safe and well-tolerated

Critical

[32]

 

Efficacious and effective

Critical

[32]

Cost

Affordable/cheap

Critical

[17, 32]

  1. KPC: key pharmacological consideration.