Why Decreasing Lipophilicity Alone Is Often Not a Reliable Strategy for Extending IV Half-life

Abstract

The optimization of the pharmacokinetic profile of a drug is one of the crucial aspects of medicinal chemistry campaigns. When efficacy is driven by a continuous coverage of the minimum efficacious plasma concentration, half-life must be optimized to achieve the optimal pharmacokinetic profile. The consensus in the field is that decreasing clearance, as opposed to increasing volume of distribution, is a better strategy to prolong half-life. While both the pharmacokinetic theory and the need for an optimal safety profile support this approach, this needs to be integrated with practical indications concerning the strategy to optimize clearance. This work presents an extensive analysis of Genentech’s in vitro and in vivo rat pharmacokinetic data, which highlights how half-life optimization through simple modulation of lipophilicity is generally not a successful strategy. Decreasing lipophilicity without addressing a metabolic soft-spot will often lead to both lower clearance and volume of distribution without extending half-life.