Dosage Regimen Design: Pharmacodynamic Considerations

Abstract

Pharmacokinetic methodology to define the time course of drug in an accessible biologic fluid is now well established as are models that relate concentration to effect. When steady-state conditions are not readily available to define a dose- or concentration-effect relationship, non-steady-state pharmacokinetic/pharmacodynamic models can be applied. Despite these methodologic advances, many aspects of clinical drug development and therapy do not readily lend themselves to pharmacokinetic/pharmacodynamic scrutiny. Barriers to this scrutiny include: drug assay problems or lack of an accessible biologic fluid that can be sampled to measure drug concentration; lack of a immediate pharmacologic effect in the clinic that can be related to concentration; and lack of a relationship between an immediate measurable pharmacologic effect and long-term clinical benefit. In the evaluation and application of any drug, the following questions are useful: 1) what is the pharmacologic effect of interest? 2) is it a positive (benefit) or negative (risk) effect? 3) are there more than one positive or negative effects of interest? 4) how is the effect measured and can the measurement be applied reasonably in a clinical setting? 5) is the effect immediate (for example, blood pressure reduction) or long-term (for example, prevention of stroke with an antihypertensive)? 6) can the effect be usefully related to a concentration to guide dosimetry? and 6) if a concentration/effect relationship is likely, can it be defined at steady state or must non-steady-state pharmacokinetic/pharmacodynamic models be constructed?(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term dosage regimen for stimulation-induced long-lasting desynchronization

“…Dosage regimen design is an integral part of pharmacokinetic methodology, aiming at an optimization of drug delivery and effects (Williams, 1992). By a similar token, we hypothesize that appropriate dosage regimens might further enhance the efficacy of RVS and SVS CR stimulation.…”

“…The development of proper dosage strategies and regimens enables favorable compromises between therapeutic efficacy and detrimental factors such as side-effects or treatment duration. This is relevant, e.g., for the development of pharmaceutical (Williams, 1992;Bertau et al, 2008;Peters, 2012;Dash et al, 2014) or radiation therapy (Symonds et al, 2012). Deep brain stimulation (DBS) is the standard treatment of medically refractory movement disorders (Benabid et al, 1991;Krack et al, 2003;Deuschl et al, 2006).…”

Pharmacokinetic and pharmacodynamic data and models in clinical trials

“…Comparisons with placebo, other drugs, or other galenical preparations in earlier development phases will be useful to assess the relevance of the marker as a surrogate for clinical response. For drug efficacy assessment, there are more and more PO endpoints available (34).…”

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization

“…The development of proper dosage strategies and regimens enables favorable compromises between therapeutic efficacy and detrimental factors such as side-effects or treatment duration. This is relevant, e.g., for the development of pharmaceutical (Williams, 1992 ; Bertau et al, 2008 ; Peters, 2012 ; Dash et al, 2014 ) or radiation therapy (Symonds et al, 2012 ). Deep brain stimulation (DBS) is the standard treatment of medically refractory movement disorders (Benabid et al, 1991 ; Krack et al, 2003 ; Deuschl et al, 2006 ).…”

“…Dosage regimen design is an integral part of pharmacokinetic methodology, aiming at an optimization of drug delivery and effects (Williams, 1992 ). By a similar token, we hypothesize that appropriate dosage regimens might further enhance the efficacy of RVS and SVS CR stimulation.…”