Drug-Drug Interaction Studies
When developing drugs under investigational new drug applications (INDs), the need for Drug-Drug Interaction (DDI) studies is a critical consideration for pharmaceutical sponsors in any drug development program. As more prescription medications come to market, the impact and safety concerns of concomitant medication interactions with patients taking multiple medications increase with each new investigational drug being developed. FDA Guidance Clinical Drug Interaction Studies —Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions, “unanticipated, unrecognized, or mismanaged DDIs are an important cause of morbidity and mortality associated with prescription drug use and have occasionally caused the withdrawal of approved drugs from the market (1).” Therefore, evaluating an investigational drug’s inhibition and induction potential early in its development is essential to identify the extent of any interaction along with the drug’s risks and benefits.
Drug-Drug Interaction clinical trials commonly follow an open-label fixed sequence parallel or crossover design. With DDI studies, the primary focus is identifying how certain drugs known to inhibit or induce enzymes involved in breaking down drugs within the body affect the investigational drug being studied. Since these index perpetrators and index substrates do not always match the investigational drug in terms of delivery methods or composition, it is not always necessary to blind the volunteers to the investigational drugs. The importance instead is in determining whether these perpetrators and substrates cause either of the following effects:
- Levels of investigational drug in the body become too high and cause adverse effects when enzymes are inhibited
- The investigational drug is broken down too quickly and unable to reach levels in the body necessary to create the intended effect when enzymes are induced
Drawing from deep experience in clinical drug-drug interaction studies, the Dr. Vince Clinical Research (DVCR) team is skilled in the execution of DDI studies, from recruiting and retaining volunteers to procuring and preparing probes or other medications. Our Safety Team has been trained to rapidly identify and respond to potential side effects and interactions. Leveraging one of the most luxurious and state-of-the-art clinical pharmacology units to aid in volunteer retention, DVCR can execute study designs that include drugs with long half-lives and long domiciling periods. We have the resources to develop, direct, and deliver DDI study results to our pharmaceutical sponsors accurately and on time.
View the Final FDA Guidance for Clinical Drug Interaction Studies
DVCR’s DDI Experience
Dedicated Safety Team (ACLS certified) with experience in identifying, reporting and responding to adverse events and drug interactions
Pharmacy team with over 50 years’ combined research experience and familiarity with procurement and preparation of FDA-recommended probes and substrates
Team of directors and managers averaging a decade of experience in early clinical development including the conduct of dozens of DDI studies
Experience in conducting various drug-drug interaction trials including:
– Cytochrome P450 enzyme and transporter mediated drug interactions
– pH-dependent drug interactions with acid reducing agents
– Cocktail Approach drug interaction trials
- Includes the simultaneous administration of substrates of multiple CYP enzymes and/or transporters to study subjects. A cocktail approach can simultaneously evaluate a drug’s inhibition or induction potential for multiple CYPs and transporters
Reach Out Today
If you would like to receive more information regarding how our CRO can be leveraged for your upcoming drug-drug interaction study, please contact us.
One of the most crucial aspects of conducting drug-drug interaction studies is the procurement and preparation of probes or other drugs. The DVCR pharmacy team understands the importance of sourcing these drugs. With some suppliers still struggling to re-establish inventory levels, DVCR leverages multiple suppliers to obtain the FDA-recommended probe or other drugs that will be utilized for many DDI studies, such as midazolam, carbamazepine, rifampin and itraconazole. In particular, DVCR utilizes preferred suppliers with specialized teams designated for clinical trials. These teams understand the importance of utilizing the same lot number of the probe or other drug(s) for all required dosing for the entirety of the study.
Furthermore, our pharmacy team possesses extensive expertise in the handling and manipulation of study drugs for various routes of administration in DDI clinical trials. These include but are not limited to injectable formulations (e.g., IV, IM, Sub-Q), oral solutions and powder in capsule (PIC).
DVCR’s DDI Experience
Dedicated Safety Team (ACLS certified) with experience in identifying, reporting and responding to adverse events and drug interactions
Pharmacy team with over 50 years’ combined research experience and familiarity with procurement and preparation of FDA-recommended probes and substrates
Team of directors and managers averaging a decade of experience in early clinical development including the conduct of dozens of DDI studies
Experience in conducting various drug-drug interaction trials including:
– Cytochrome P450 enzyme and transporter mediated drug interactions
– pH-dependent drug interactions with acid reducing agents
– Cocktail Approach drug interaction trials
Includes the simultaneous administration of substrates of multiple CYP enzymes and/or transporters to study subjects. A cocktail approach can simultaneously evaluate a drug’s inhibition or induction potential for multiple CYPs and transporters
Reach Out Today
If you would like to receive more information regarding how our CRO can be leveraged for your upcoming drug-drug interaction study, please contact us.
One of the most crucial aspects of conducting drug-drug interaction studies is the procurement and preparation of probes or other drugs. The DVCR pharmacy team understands the importance of sourcing these drugs. With some suppliers still struggling to re-establish inventory levels, DVCR leverages multiple suppliers to obtain the FDA-recommended probe or other drugs that will be utilized for many DDI studies, such as midazolam, carbamazepine, rifampin and itraconazole. In particular, DVCR utilizes preferred suppliers with specialized teams designated for clinical trials. These teams understand the importance of utilizing the same lot number of the probe or other drug(s) for all required dosing for the entirety of the study.
Furthermore, our pharmacy team possesses extensive expertise in the handling and manipulation of study drugs for various routes of administration in DDI clinical trials. These include but are not limited to injectable formulations (e.g., IV, IM, Sub-Q), oral solutions and powder in capsule (PIC).
DDI Study Design
Should preclinical metabolism and transporter studies indicate one or more potential drug interactions, DDI trials must be built into the drug development timeline. Whether it is an inducer, inhibitor, or substrate of a particular metabolic or transporter pathway, it is critical to determine the in vivo effects early in the development plan.
Depending on the suspected enzyme/transporter, one or multiple DDI trials may need to be conducted. In some cases, a “cocktail” of two or more drugs can be used to gain information on multiple pathways.
The following table lists the common enzyme/transporters systems requiring assessment: (2)
- CYP Pathways
- CYP1A2
- CYP2B6
- CYP2C8
- CYP2C9
- CYP2C19
- CYP2D6
- CYP3A4/5
- Transporters
- P-gp
- BCRP
- OATP1B1
- OATP1B3
- OAT1
- OAT3
When designing drug-drug interaction studies, one of the following designs is typically used:
- Randomized crossover (e.g., substrate followed by substrate + inhibitor/inducer, substrate + inhibitor/inducer followed by substrate)
- One-sequence crossover (e.g., substrate followed by substrate + inhibitor/inducer
- Parallel (e.g., substrate in one group and substrate + inhibitor/inducer in another group)
While some drug-drug interaction studies follow a parallel study design, the crossover design tends to be favored as it reduces inter-subject variability, as indicated in the FDA Guidance (1).
Additionally, it may be necessary to conduct trials in subject populations with known metabolic patterns based on genetic testing. Including or excluding “poor metabolizers” and “ultrarapid metabolizers” in a trial may provide useful information. These types of trials rely on genotyping performed as part of the screening process but can add significant costs to a project. However, in those instances where a strong inhibition of a pathway is anticipated, genotyping individuals prior to dosing can improve safety margins.
Commonly Used Drugs for DDI Studies
- Midazolam
- Carbamazepine
- Rifampin
- Itraconazole
- Metformin
- Bupropion
- Rabeprazole
- Caffeine
Midazolam
Carbamazepine
Rifampin
Itraconazole
Metformin
Bupropion
Rabeprazole
Caffeine
Volunteer Recruitment and Retention for DDI Studies
With any drug-drug interaction study, recruiting and retaining volunteers is critical to the objectives, outcomes, and ongoing success of our sponsor’s drug development programs. In particular, for DDI study designs that require long domiciling periods, the retention of study volunteers is paramount in order to obtain the needed study data. DVCR recognizes the importance of volunteer retention in DDI studies and improves retention by offering luxurious amenities and safety features within our early phase clinical pharmacology unit including:
- Welcoming clinic lobby and waiting area with a modern design motif reminiscent of upscale hotel lobbies
- Spacious research suites with 90 high-end, handcrafted beds for overnight confinement, including 8 private suites for individual volunteer domiciling
- Gaming room utilizing multiple next-gen video game consoles and arcade-style gaming machines for volunteer entertainment throughout their in-house stay
- Premier VIP room with natural lighting and comfortable seating to create a relaxing environment that makes volunteers feel like they are at home
- Sports Bar themed dining area with 9 large screen televisions to enjoy viewing sporting events
- Video surveillance in volunteer areas, with crash carts and panic buttons strategically located throughout the facility to ensure volunteer safety
- Dedicated clinical staff well-trained in delivering quality customer service for our volunteers
These elements were incorporated into the design of our Phase 1 unit to create an elevated experience for study volunteers in which they feel safe and welcomed. It was DVCR’s intent to make our facility feel less like a hospital or research clinic, and more like a 5-star hotel which volunteers enjoy staying at whether their confinement is 4 days or 40 days.
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Volunteer Recruitment and Retention for DDI Studies
With any drug-drug interaction study, recruiting and retaining volunteers is critical to the objectives, outcomes, and ongoing success of our sponsor’s drug development programs. In particular, for DDI study designs that require long domiciling periods, the retention of study volunteers is paramount in order to obtain the needed study data. DVCR recognizes the importance of volunteer retention in DDI studies and improves retention by offering luxurious amenities and safety features within our early phase clinical pharmacology unit including:
- Welcoming clinic lobby and waiting area with a modern design motif reminiscent of upscale hotel lobbies
- Spacious research suites with 90 high-end, handcrafted beds for overnight confinement, including 8 private suites for individual volunteer domiciling
- Gaming room utilizing multiple next-gen video game consoles and arcade-style gaming machines for volunteer entertainment throughout their in-house stay
- Premier VIP room with natural lighting and comfortable seating to create a relaxing environment that makes volunteers feel like they are at home
- Sports Bar themed dining area with 9 large screen televisions to enjoy viewing sporting events
- Video surveillance in volunteer areas, with crash carts and panic buttons strategically located throughout the facility to ensure volunteer safety
- Dedicated clinical staff well-trained in delivering quality customer service for our volunteers
These elements were incorporated into the design of our Phase 1 unit to create an elevated experience for study volunteers in which they feel safe and welcomed. It was DVCR’s intent to make our facility feel less like a hospital or research clinic, and more like a 5-star hotel which volunteers enjoy staying at whether their confinement is 4 days or 40 days.
Timing of Drug-Drug Interaction Studies
The FDA Guidance on drug-drug interaction studies indicates that sponsors should consider conducting DDI studies following in vitro studies and before the investigational drug is administered to those patients who are likely to take concomitant medications that have the potential to interact with the investigational drug. DDI studies can begin as early as Phase I but continue well into Phase 3 should the need for additional evaluation of concomitant interactions arise further in the drug development program.
Sponsors should collect as much information regarding the potential for drug-drug interactions as early as possible in order to prevent patients from being unnecessarily excluded from clinical studies. Unnecessary protocol restrictions for concomitant medications could result in certain study populations enrolled that are not necessarily fully representative of the intended patient population. If sponsors fail to conduct adequate DDI studies, this can negatively impact the Agency’s ability to determine the risks and benefits of an investigational drug. Thus, this could lead to restrictions, additional requirements, and delays in approval by the FDA (1).
References
1 S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). (2020, January). Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry. Retrieved May 3, 2023, from https://www.fda.gov/media/134581/download
2 S. Food and Drug Administration. (2022, August). Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers. Retrieved May 3, 2023, from https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers