Whitehead, Anne and Whitehead, John and Todd, Susan and Zhou, Yinghui and Smith, Michael K. (2008) Fitting models for the joint action of two drugs using SAS(R). Pharmaceutical Statistics, 7 (4). pp. 272-284. ISSN 1539-1604Full text not available from this repository.
Combinations of drugs are increasingly being used for a wide variety of diseases and conditions. A pre-clinical study may allow the investigation of the response at a large number of dose combinations. In determining the response to a drug combination, interest may lie in seeking evidence of synergism, in which the joint action is greater than the actions of the individual drugs, or of antagonism, in which it is less. Two well-known response surface models representing no interaction are Loewe additivity and Bliss independence, and Loewe or Bliss synergism or antagonism is defined relative to these. We illustrate an approach to fitting these models for the case in which the marginal single drug dose-response relationships are represented by four-parameter logistic curves with common upper and lower limits, and where the response variable is normally distributed with a common variance about the dose-response curve. When the dose-response curves are not parallel, the relative potency of the two drugs varies according to the magnitude of the desired effect and the models for Loewe additivity and synergism/antagonism cannot be explicitly expressed. We present an iterative approach to fitting these models without the assumption of parallel dose-response curves. A goodness-of-fit test based on residuals is also described. Implementation using the SAS NLIN procedure is illustrated using data from a pre-clinical study.
|Journal or Publication Title:||Pharmaceutical Statistics|
|Uncontrolled Keywords:||antagonism • Bliss independence • dose-response surface • drug combination • Loewe additivity • synergy|
|Subjects:||Q Science > QA Mathematics|
|Departments:||Faculty of Science and Technology > Mathematics and Statistics|
|Deposited By:||Mr Richard Ingham|
|Deposited On:||25 May 2010 11:54|
|Last Modified:||26 Jul 2012 17:25|
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