Drug-Drug Interaction Studies: A year in review and growing trends
Director, Clinical Pharmacology Sciences
In the past year, both the FDA and the European Medicines Agency (EMA) issued revised guidelines on the conduct and analysis of drug-drug interaction studies (DDIs) to support the drug approval process. While some of the guidance carried over from previous versions, there were some notable additions which have impacted the scientific decision making process of sponsor organizations conducting these studies.
Both regulatory agencies have encouraged the generation of in vitro data from well-designed studies, to determine the relevant enzymes and transporters involved in a drug’s disposition, prior to conducting human studies. In addition, the agencies have introduced the incorporation of in silico approaches such as population pharmacokinetic modeling (PopPK) and physiologically-based pharmacokinetic modeling (PBPK) to better understand the mechanism of the interactions. These approaches are particularly useful when investigating the interaction in the presence of co-morbidities and normal changes associated with aging. These recommendations intend to improve the decision-making process in terms of which studies should be conducted in a human population.
As with all drug development programs, any opportunity to reduce cost and timelines must be considered when designing DDIs. Two design elements which meet these criteria and have gained popularity in recent years are fixed-sequence designs and fusion studies.
In the past many in vivo DDIs were conducted as randomized crossover designs. Most recently, however, there has been a trend towards fixed-sequence designs where two treatments are administered in a sequential order. Perhaps the most common design of this type is where a potential substrate, or “victim” drug, is administered alone and then again in combination with a potential “perpetrator”. The perpetrator is typically an inhibitor or an inducer (and sometimes both) of either a drug metabolizing enzyme or transporter protein. Depending on the pharmacokinetic properties and safety profile, these studies can be conducted with each drug being administered as a single-dose, multiple-dose or a combination thereof.
The popularity of this design is evident in the frequency sponsors have requested this approach. Figure 1 illustrates the proportion of DDIs conducted at Celerion in the last 12 months. These were conducted as fixed-sequence designs compared to parallel and randomized crossover designs.
Figure 1: Distribution of DDIs conducted as fixed-sequence vs. parallel cohort and crossover designs in 2012
This design is of particular benefit when the perpetrator exhibits a long half-life or when a known or potential enzyme inducer is being evaluated. A crossover design would require each sequence to dose for a sufficient number of days, to achieve maximal induction followed by a washout period to allow for normalization of enzyme production prior to next period. This could result in study duration in excess of one month. With a fixed-sequence design, the induction is already at maximal levels before the substrate is administered, obviating the need for a washout period.
Figure 2 provides an illustration of a 1-way fixed-sequence design where the effect of a single perpetrator on a single substrate is assessed.
This approach can alternatively be designed as a 2-way comparison to evaluate a reciprocal interaction. Figure 3 illustrates this.
In the event the substrate and perpetrator require a long duration of repeat dosing to achieve steady-state, an interaction could be evaluated in a parallel cohort design. However, parallel designs tend to require larger sample size to adequately power the study and do not allow a within-subject comparison. An important point to consider is when the reciprocal interaction is conducted under repeat-dose conditions, a washout period between periods 2 and 3 can be eliminated as Drug B has already reached steady-state.
As stated earlier, fusion studies have gained popularity largely due to the advantage of combining multiple objectives into one protocol. In short, a fusion design entails two or more parallel cohorts in which each cohort follows a unique treatment schedule. An example of a fusion DDI design is where 2 parallel cohorts undergo a fixed-sequence design with the same substrate but different inhibitors. This approach is particularly useful when the in-vitro data suggests that varying degrees of inhibition occur with different inhibitors and in-vivo studies will be required for both inhibitors. In this situation there are cost and time efficiencies as both panels will potentially take approximately the same amount of time to conduct, and can be run in parallel under one single protocol, as opposed to two unique protocols in sequence.
Table 4: Multiple panel/fusion designs in 2012
Subtracting the studies which were run as crossover designs, the vast majority of DDIs run as fixed-sequence studies incorporated multiple-panels. This observation is in line with Celerion’s experience in previous years and was reported in our Spring 2012 newsletter, where we observed approximately 67% of fusion studies conducted at Celerion were DDIs.
In summary, the fixed-sequence and fusion study approach are gaining popularity, in part out of practicality and due to potential cost and time-savings advantages. For more information, please contact us today.