Optimising in vivo pharmacology studies--Practical PKPD considerations.
BACKGROUND
It has become apparent in recent years that there is a need for a substantial improvement in the processes used to clarify the inter-relationships between a compound's pharmacokinetic (PK) characteristics, its target actions and its safety profile. This is particularly challenging because most of the techniques currently used to obtain meaningful data involve low efficiency animal studies. To maximize the value of such in vivo studies, time and resources need to be better utilized. One way of making major advances is to adopt an integrative approach to designing and analysing in vivo pharmacodynamic (PD) studies. In this paper we address experimental design issues related to maximizing the information content about target engagement. Refined integration of PK and PD (known as 'quantitative pharmacology' or a PKPD approach) is advocated, enabling clarification of the interdependence of a drug's pharmacological properties on its target physiological system(s) and its systemic exposure characteristics.


METHODS
Several in vivo pharmacological Case Studies are presented which are used to illustrate the discussion of issues of experimental design. The impact of rate, extent and mode of administration is discussed from a pharmacological viewpoint, and we examine the consequences of temporal differences between concentration and response from the perspective of experimental design. We also consider the importance of differences in plasma protein binding (PPB) on our ability to assess a pharmacodynamic property or safety margin, and examine the usefulness of measuring ex vivo PPB. Finally, we outline the value of implementing a clearly pre-determined, integrated work flow to generate, validate and maximize in vivo PKPD or preclinical disease model data, and summarize the key issues of experimental design.


CONCLUSIONS
Quantitative pharmacological reasoning focuses on concentration-response and response-time relationships with special emphasis on the impact of drugs on disease (Levy, 1993) and this perspective was written to raise awareness among in vivo scientists as to why PKPD integration is essential in their studies.
Gabrielsson
Johan
J
PKPD Section, Drug discovery DMPK & BAC, CVGI, AstraZeneca R&D Mölndal, S-43183 Mölndal, Sweden. Johan.Gabrielsson@AstraZeneca.com
Green
A Richard
AR
Van der Graaf
Piet H
PH
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism; D010599:Pharmacokinetics; D010600:Pharmacology / Q000379:methods* / Q000592:standards; D011485:Protein Binding; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D001798:Blood Proteins; D004364:Pharmaceutical Preparations; D011955:Receptors, Drug