Principles and Practice of Pharmaceutical Medicine

Medicinal

chemistry

New

chemical

entity (NCE)

Binding

IC 50

Functional assay

EC 50

Criteria

met

Criteria

met

In vitro

intrinsic CL

First

in vivo

rat

study

In vivo

PK

PK

adequate

No

No

Ye s

Ye s

Project

group

evaluation

Project

group

evaluation

Criteria *^1

met

In vivo

efficacy

No

* 2

* 3

* 1

Phase I

trial

* 2

* 3

Project

group

evaluation

Candidate

drug

Restart at

chemistry

?

General

pharmacology

Toxicology

toxicokinetics

2

12

2

First

human

dose

Meets

safety

criteria

Ye s

Allometric scaling

Choose first dose and

administration route

Choose plasma target concentration

Choose dose escalation

schedule

Clinical

pharmacology

laboratory

Administer

doses

Measure

plasma

concentrations

1

Dose tolerated

PK adequate

PK model

adequate

No

Ye s

Ye s Ye s

?

Escalate

No Dose

No

Human PK model

Review/revise sample

times

Review/revise escala

tion schedule

2

Phase I

objectives

met?

Decision to

proceed

Phase

II

trial

Figure 8.8 Flow diagram for involvement of pharmacokinetic and pharmacodynamic mode/computer-generated
feedback into the iterative process of drug discovery from medicinal chemistry to the decision to enter phase II trials.
This is not a comprehensive flow diagram for all aspects of drug discovery – it is restricted to the components of the
process discussed in this chapter. This flow diagram emphasizes efficient involvement ofin vitroandin vivoexperi-
mental science and computer modeling, in review of data obtained in phase I studies, in the decisions related to
selection of the best compound for patient studies

8.4 COMMENTARY 97