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A common design in drug-drug interaction studies is to give drug A on day 1, followed after a wash-out period by repeated dosing of drug B and a second dose of drug A at the end of the study (concomitant with drug B). By comparing AUC and Cmax on the first day (drug A alone) and last day (drug A in combination with drug B at steady state) one can evaluate if there is any changes in the PK of drug A. If one is looking into the effect of both drugs on each other, the dosing can be reversed after a wash-out period, starting with drug B, then repeated dosing with drug A to steady state and a last day dosing of both drugs.
Another study design I have come across is to dose drug A to steady state, let's say for 10 days. Starting on Day 6, drug B is also given for 5 days (also presumably to steady state). Drug A PK estimates are then compared between day 5 (at steady state before the co-administration period starts) and day 10 (after 5 days co-administration with drug B). The dosing can be reversed to investigate the effect of drug A on B.
Could someone explain to me what additional information is gathered using the second study design?
Toufigh Gordi, PhD
Clinical Pharmacology, PK/PD analysis consultant
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I think like any other clinical study first the DDI study's objectives should be clearly defined then the appropriate study can be designed considering the drugs characteristics. Knowing drugs characteristics is a very important starting point in the design of a DDI study as you'd use different design if your drug is a victim, perpetrator or both. Also, the nature of interaction (competitive, time-dependent, self-inhibition, induction, self-induction, ...) is another important element that help you to decide on the study design. There are lots of in vitro data that can be used to make more informed decisions on the study design but usually these are neglected!
Modelling and simulation is a good approach to decide on the best study/dosing strategy and also assess the level of information you can get out of your study, please see the following and the references therein:
Huang S-M and Lesko LJ (2009) Authors' Response. J Clin Pharmacol 49:370.
Masoud Jamei, PhD, SMIEEE Senior Scientific Advisor and Head of M&S, Simcyp Limited
Honorary Lecturer, School of Medicine, The University of Sheffield
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