The Art and Science of Drug Discovery

The quest for novel therapeutic agents to combat diseases is the cornerstone of pharmaceutical research. However, this journey is fraught with scientific complexities, risks, and staggering costs, rendering it a formidable challenge for pharmaceutical companies. The process of drug discovery and development demands meticulous attention to detail, as failure at any stage can result in significant setbacks. Understanding the underlying reasons for the high attrition rates of investigational new drug (IND) candidates is paramount to improving the efficiency and success of this arduous process.

Drug Termination: Insights from Investigational New Drug Studies

Investigating the termination of IND candidates sheds light on the primary hurdles encountered during drug development. Studies have revealed that unacceptable efficacy and safety issues remain the predominant reasons for the discontinuation of INDs. Furthermore, inappropriate pharmacokinetics poses a significant challenge, leading to the termination of a substantial number of candidates. These findings underscore the critical importance of early optimization of candidates and doses, particularly addressing pharmacokinetic and pharmacodynamic concerns.

Power of Preclinical Pharmacokinetics and Pharmacodynamics

Preclinical pharmacokinetics and pharmacodynamics play a pivotal role in optimizing candidate selection and predicting dosing regimens for initial clinical trials. A deep understanding of both the pharmacological target and drug disposition is essential for success in this endeavor. The equilibrium between free drug concentrations in plasma and at receptors serves as a fundamental principle guiding drug action. By leveraging this equilibrium, researchers can estimate in vivo potency, duration of action, and selectivity, thus informing critical decisions in drug development.

Bridging the Gap: Extrapolating Pharmacokinetics Across Species

Extrapolating pharmacokinetic data from preclinical studies to humans presents inherent challenges, necessitating the use of robust methodologies. Allometric scaling and physiological-based pharmacokinetic (PBPK) scaling are two primary approaches employed for this purpose. Allometric scaling, based on physiological parameters scaled to body weight, is particularly effective for predicting renal clearance. Conversely, PBPK scaling offers a more comprehensive model, incorporating intricate physiological and biochemical factors, thus providing a nuanced understanding of hepatic clearance.

Relating Dose to Potency and Pharmacokinetics

The interplay between drug potency and pharmacokinetics dictates the dosage required for therapeutic efficacy. Compounds with high intrinsic clearance necessitate correspondingly high potency to achieve clinical effectiveness at manageable doses. Understanding the relationship between these properties enables researchers to anticipate dose requirements and optimize drug candidates accordingly. Furthermore, elucidating the impact of plasma protein binding on free drug concentrations enhances our ability to correlate in vitro potency with clinical outcomes.

Charting a Course for Therapeutic Innovation

As pharmaceutical research advances, the intricacies of drug discovery and development continue to unfold. By embracing a multidisciplinary approach rooted in pharmacokinetic and pharmacodynamic principles, researchers can navigate the complexities of this journey with greater precision and efficacy. Ultimately, the convergence of scientific ingenuity, technological advancements, and strategic optimization holds the promise of unveiling transformative therapies to alleviate human suffering and propel medical progress into the future.

Study DOI: 10.1016/S0531-5131(01)00282-5

Engr. Dex Marco Tiu Guibelondo, B.Sc. Pharm, R.Ph., B.Sc. CpE

Editor-in-Chief, PharmaFEATURES