Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival

doi:10.1016/j.drudis.2011.12.020

Drug Discovery Today

Volume 17, Issues 9–10, May 2012, Pages 419-424

https://doi.org/10.1016/j.drudis.2011.12.020 Get rights and content

In an effort to uncover systematic learnings that can be applied to improve compound survival, an analysis was performed on data from Phase II decisions for 44 programs at Pfizer. It was found that not only were the majority of failures caused by lack of efficacy but also that, in a large number of cases (43%), it was not possible to conclude whether the mechanism had been tested adequately. A key finding was that an integrated understanding of the fundamental pharmacokinetic/pharmacodynamic principles of exposure at the site of action, target binding and expression of functional pharmacological activity (termed together as the ‘three Pillars of survival’) all determine the likelihood of candidate survival in Phase II trials and improve the chance of progression to Phase III.

Introduction

Enhancing survival of new molecular entities (NMEs) through the discovery and development lifecycle is a key productivity driver for the pharmaceutical industry. NME survival is significantly impacted by the continued issue of insufficient or lack of clinical efficacy as the principal cause of program termination during development 1, 2. Moreover, earlier evidence indicates that NME survival is at its lowest during Phase II development with small- and large-molecule survival of 38% and 53%, respectively, during Phase II for the period of 1993–2004 [3]. Indeed, the Centre for Medicines Research reports that, out of a group of 16 companies representing ∼60% of global R&D spend, the Phase II success rates for NMEs has fallen from 28% (2006–2007) to 18% (2008–2009), although success rates do vary between therapeutic areas and between small molecules versus biologics [4].

In an effort to uncover any systematic learnings that can be applied to improve Phase II decision-making and survival, a detailed analysis was performed on 44 Phase II programs at Pfizer that reached a decision point during the period 2005–2009. This manuscript discusses the findings of this analysis for the Pfizer dataset and illustrates the importance of acquiring data and knowledge on fundamental pharmacokinetic (PK) and pharmacodynamic (PD) principles to increase the likelihood of testing the mechanism of action and progressing beyond Phase II development.

Section snippets

Background

From 44 NME programs that reached a decision point during Phase II clinical development between 2005 and 2009, only 32% were deemed to have achieved a positive readout in their clinical proof-of-concept (POC) study by meeting the agreed POC criteria for that program. A structured interview, termed an after action review (AAR), was conducted with the teams supporting these programs with the aim of identifying all trends that could shed light on the reasons for such high attrition during Phase

Definition of the three Pillars of survival

For a development candidate to have potential to elicit the desired effect over the necessary period of time, three fundamental elements need to be demonstrated:

i.
Exposure at the target site of action over a desired period of time
ii.
Binding to the pharmacological target as expected for its mode of action
iii.
Expression of pharmacological activity commensurate with the demonstrated target exposure and target binding

Fundamental principle: drug exposure at the target site of action is necessary to elicit a pharmacological effect over a desired time period

Demonstration of free drug exposure at the target site of action at a level that exceeds pharmacological potency over the desired period of time gives maximum confidence that adequate exposure has been achieved. Every deviation away from this statement will introduce the risk that target exposure might not be adequate. Direct measurement of drug exposure at the target site of action is often not attainable experimentally and in these cases drug exposure is measured using blood samples.

Fundamental principle: target occupancy is a prerequisite for expression of pharmacology and target modulation

The highest level of confidence and direct evidence at the site of action that required levels of target binding were being achieved is most probably obtained from PKPD studies of in vivo occupancy measurements with positron emission tomography (PET) or radiolabeled ligands.

Some confidence can be derived in an indirect manner if the binding properties and potency against the target are well understood (including potential impact of species differences, polymorphisms or other target phenotypes)

Fundamental principle: functional modulation of the target is a prerequisite for expression of pharmacological activity to test the mechanism

The highest level of confidence and direct evidence at the site of action that sufficient levels of target modulation are being achieved is most probably obtained from PKPD studies of biomarkers that reflect expression of primary pharmacology at the site of action. Some confidence can be derived in an indirect manner if the functional pharmacological properties and mode of action of the compound are well understood, combined with a high degree of confidence in Pillars 1 and 2.

Use of three Pillars of survival to manage risk in Phase II clinical development

A simple matrix (Fig. 1) was developed by which the alignment with the three Pillars of survival could be used to assess the likelihood that the mechanism of action will be tested in the clinical POC study and thus give further confidence regarding the likelihood of attaining a positive POC with subsequent progress into Phase IIb. This matrix can be applied to individual programs and across a portfolio of programs, and the placement of a program in the matrix depends upon the data and knowledge

Pursuing an unprecedented target with low confidence in three Pillars

Dopamine is one of the key neurotransmitters in the central nervous system (CNS) and a range of neurological and psychiatric disorders have been associated with dysfunction of the dopaminergic system, for example Parkinson's disease, restless leg syndrome, schizophrenia, anxiety and bipolar disorders. Dopamine receptors are commonly divided into two clusters, the D1-like (D1 and D5 receptors) and D2-like (D2, D3 and D4 receptors) families. There has been considerable interest in the development

Developing high confidence in three Pillars of survival through preclinical and early clinical investigation

C–C chemokine receptor type 5 (CCR5), which belongs to the G-protein-coupled receptor superfamily, is an attractive target for HIV-1 therapy given that the genetic absence of surface-expressed CCR5Δ32 in the homozygous population leads to this population being highly protected against HIV-1 infection 13, 14; and the reduced cell-surface-expression in the CCR5Δ32 heterozygote population is associated with a slower disease progression [15]. From an antiviral perspective, CCR5 is the co-receptor

Concluding remarks

This analysis demonstrates that there are three fundamental PK and PD principles that collectively determine the likelihood of testing the mechanism of action and influencing the likelihood of candidate survival in Phase II. These fundamental principles, which we have termed the three Pillars of survival, are geared toward understanding the drug exposure, target binding and pharmacological activity at the target site of action in an integrated manner through application of PKPD and PBPK

Conflict of interest

The authors were all employees of Pfizer Limited at the time of conducting the research described in the manuscript.

Acknowledgments

We gratefully acknowledge the contribution of many colleagues in Pfizer Research and Development for their constructive input and review of the three Pillars of survival analysis.

References (26)

R. Liu
Homozygous defect in HIV-1 coreceptor accounts for resistance of some multi-exposed individuals to HIV-1 infection
Cell
(1996)
I. Kola et al.
Can the pharmaceutical industry reduce attrition rates?
Nat. Rev. Drug Discov.
(2004)
J. Arrowsmith
Phase III and submission failures: 2007–2010
Nat. Rev. Drug Discov.
(2011)
J.A. DiMasi
Trends in risks associated with new drug development: success rates for investigational drugs
Clin. Pharmacol. Ther.
(2010)
J. Arrowsmith
Phase II failures: 2008–2010
Nat. Rev. Drug Discov.
(2011)
S.M. Paul
How to improve R&D productivity: the pharmaceutical industry's grand challenge
Nat. Rev. Drug Discov.
(2010)
M. Wehling
Assessing the translatability of drug projects: what needs to be scored to predict success?
Nat. Rev. Drug Discov.
(2009)
M. Rowland
Physiologically-based pharmacokinetics in drug development and regulatory science
Annu. Rev. Pharmacol. Toxicol.
(2011)
S.J. Ramsey
Quantitative pharmacological analysis of antagonist binding kinetics at CRF₁ receptors in vitro and in vivo
Br. J. Pharmacol.
(2011)
E. Dula
Double-blind, crossover comparison of 3 mg apomorphine SL with placebo and with 4 mg apomorphine SL in male erectile dysfunction
Eur. Urol.
(2001)

D. Hepworth

Optimization of oral pharmacokinetics in the discovery of clinical candidates for the treatment of sexual dysfunction

N. Attkins

Pharmacokinetics and elucidation of the rates and routes of N-glucuronidation of PF-592379, an oral dopamine 3 agonist in rat, dog and human

Xenobiotica

(2010)

P.H. Van der Graaf et al.

Systems pharmacology: bridging systems biology and pharmacokinetics–pharmacodynamics (PKPD) in drug discovery and development

Pharm. Res.

(2011)

Cited by (542)

Repurposing of biologics and biopharmaceuticals
2024, Progress in Molecular Biology and Translational Science
The field of drug repurposing is gaining attention as a way to introduce pharmaceutical agents with established safety profiles to new patient populations. This approach involves finding new applications for existing drugs through observations or deliberate efforts to understand their mechanisms of action. Recent advancements in bioinformatics and pharmacology, along with the availability of extensive data repositories and analytical techniques, have fueled the demand for novel methodologies in pharmaceutical research and development. To facilitate systematic drug repurposing, various computational methodologies have emerged, combining experimental techniques and in silico approaches. These methods have revolutionized the field of drug discovery by enabling the efficient repurposing of screens. However, establishing an ideal drug repurposing pipeline requires the integration of molecular data accessibility, analytical proficiency, experimental design expertise, and a comprehensive understanding of clinical development processes. This chapter explores the key methodologies used in systematic drug repurposing and discusses the stakeholders involved in this field. It emphasizes the importance of strategic alliances to enhance the success of repurposing existing compounds for new indications. Additionally, the chapter highlights the current benefits, considerations, and challenges faced in the repurposing process, which is pursued by both biotechnology and pharmaceutical companies. Overall, drug repurposing holds great promise in expanding the use of existing drugs and bringing them to new patient populations. With the advancements in computational methodologies and the collaboration of various stakeholders, this approach has the potential to accelerate drug development and improve patient outcomes.
Trends, challenges, and success factors in pharmaceutical portfolio management: Cognitive biases in decision-making and their mitigating measures
2023, Drug Discovery Today
Effective portfolio management is crucial for innovation and sustaining revenue in pharmaceutical companies. This article holistically reviews trends, challenges, and approaches to pharmaceutical portfolio management and focuses, in particular, on cognitive biases in portfolio decision-making. Portfolio managers strongly rely on external innovation and face increasing competitive pressure and portfolio complexity. The ability to address biases and make robust decisions remains a challenge. Portfolio management practitioners most commonly face confirmation bias, champion bias, or misaligned incentives, which they seek to mitigate through expert input, team diversity, and rewarding truth-seeking. Ultimately, highest-quality portfolio management decision-making could be enabled by three factors: high-quality data, structured review processes, and comprehensive mitigating measures against biases in decision-making.
Rapid screening and in vivo target occupancy quantitative evaluation of xanthine oxidase inhibitors based on drug-target binding kinetics research strategy: A case study of Chrysanthemum morifolium Ramat.
2023, Biomedicine and Pharmacotherapy
Chrysanthemum morifolium Ramat. is a kind of food and drug dual-use traditional Chinese medicine possessing multiple pharmacological and biochemical benefits. In our study, a rapid and high-throughput method based on Surface plasmon resonance (SPR) biosensor technology was developed and verified for screening potential xanthine oxidase (XOD) inhibitors exemplarily in the Chrysanthemum morifolium Ramat. Coupled with ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS), 14 XOD-binders were identified. In the SPR-based biosensor and molecular docking analysis, most compounds exhibited a strong affinity and binding kinetic property (association rate constant, K_on and dissociation rate constant, K_off) for XOD and could be regarded as potential inhibitors. More importantly, to further accurately assess target occupancy of candidate compounds in vivo, a mathematical model was established and verified involving three crucial intrinsic kinetic processes (Pharmacokinetics, Binding kinetic and Target kinetic). Overall, the proposed screening and assessment strategy could be proved an effective theoretical basis for further pharmacodynamic evaluation.
Bias translation: The final frontier?
2024, British Journal of Pharmacology
PET Imaging of Peptide Probe Al[<sup>18</sup>F]F-NOTA-PCP1 for Monitoring the Engagement of PD-L1 Antibodies in Tumors
2024, Molecular Pharmaceutics
NAMED ENTITY RECOGNITION OF PHARMACOKINETIC PARAMETERS IN THE SCIENTIFIC LITERATURE
2024, bioRxiv

View all citing articles on Scopus

View full text

PerspectiveFeatureCan the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival

Introduction

Section snippets

Background

Definition of the three Pillars of survival

Fundamental principle: drug exposure at the target site of action is necessary to elicit a pharmacological effect over a desired time period

Fundamental principle: target occupancy is a prerequisite for expression of pharmacology and target modulation

Fundamental principle: functional modulation of the target is a prerequisite for expression of pharmacological activity to test the mechanism

Use of three Pillars of survival to manage risk in Phase II clinical development

Pursuing an unprecedented target with low confidence in three Pillars

Developing high confidence in three Pillars of survival through preclinical and early clinical investigation

Concluding remarks

Conflict of interest

Acknowledgments

Cell

Can the pharmaceutical industry reduce attrition rates?

Nat. Rev. Drug Discov.

Phase III and submission failures: 2007–2010

Nat. Rev. Drug Discov.

Trends in risks associated with new drug development: success rates for investigational drugs

Clin. Pharmacol. Ther.

Phase II failures: 2008–2010

Nat. Rev. Drug Discov.

How to improve R&D productivity: the pharmaceutical industry's grand challenge

Nat. Rev. Drug Discov.

Assessing the translatability of drug projects: what needs to be scored to predict success?

Nat. Rev. Drug Discov.

Physiologically-based pharmacokinetics in drug development and regulatory science

Annu. Rev. Pharmacol. Toxicol.

Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo

Br. J. Pharmacol.

Double-blind, crossover comparison of 3 mg apomorphine SL with placebo and with 4 mg apomorphine SL in male erectile dysfunction

Eur. Urol.

Optimization of oral pharmacokinetics in the discovery of clinical candidates for the treatment of sexual dysfunction

Pharmacokinetics and elucidation of the rates and routes of N-glucuronidation of PF-592379, an oral dopamine 3 agonist in rat, dog and human

Xenobiotica

Systems pharmacology: bridging systems biology and pharmacokinetics–pharmacodynamics (PKPD) in drug discovery and development

Pharm. Res.

Perspective
Feature
Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival

Quantitative pharmacological analysis of antagonist binding kinetics at CRF₁ receptors in vitro and in vivo