. Author manuscript; available in PMC: 2023 Oct 2.

Published in final edited form as: Nat Rev Drug Discov. 2023 Aug 31;22(10):807–826. doi: 10.1038/s41573-023-00772-9

Table 5 |.

Decision criteria for advancing a new chemical entity from an early lead to the preclinical stage

	Early lead	Late lead	Preclinical candidate
Potency/efficacy	EC₅₀ (abs) <100 nM; SI >100×; profiled on liver stage, gametocytes and field isolates (Plasmodium falciparum and Plasmodium vivax); no cross-resistance with antimalarial drug or clinical candidate; MIR >10⁶; in vivo efficacy in NSG P. falciparum mouse model	EC₅₀ (abs) <10 nM; SI >1,000×; profiled against P. falciparum SMFA; in vivo efficacy in NSG mouse model and data modelled (Medicines for Malaria Venture pharmacometrics) to estimate in vivo EC₅₀; single oral dose prediction <500mg	Resistance risk defined; sequencing of in vivo recrudescent parasites
Pharmacokinetic properties	Solubility >100 μM; PK in mouse and rat: oral bioavailability >20%; in vitro metabolism (stability) predicting in vivo PK	Solubility >100 μM; PK in mouse, rat and dog: oral bioavailability >30%; human PK prediction; crystalline formulation used in PK studies	CYP450 inhibition and induction assays, CYP phenotyping, metabolite assays; full physical property and DMPK package; high dose PK in dog to inform for GLP safety studies
Safety	No overt toxicity in vivo and hERG >1 μM	Free hERG IC₂₀/free C_max >30; negative in five-strain Ames assay; acceptable phototoxicity risk; acceptable off-target pharmacology profile (100 screens); measured in vitro reprotoxicology assays	No haemolysis in NSG mouse model engrafted with low active G6PD-deficient human blood in vivo; negative in micronucleus assay; acceptable margin in 7-day rat safety study; acceptable margin in in vivo early embryo development study

C_max, highest concentration of a drug in the blood, cerebrospinal fluid or target organ after a dose is given; CYP450, cytochrome P450; DMPK, drug metabolism and pharmacokinetics; EC₅₀ (abs), half-maximal effective concentration (asexual blood stages); G6DP, glucose-6-phosphate dehydrogenase; GLP, Good Laboratory Practices; hERG, human ether-a-go-go-related protein; IC₂₀, concentration of a substance showing 20% inhibition relative to the maximum enzyme activity. MIR, minimum inoculum of resistance (minimum inoculum from which resistant parasites can be selected⁶⁴); NSG, NOD–SCID–IL2Rγ^null; PK, pharmacokinetics; SI, selectivity index; SMFA, standard membrane feeding assay.