In our previous post: “In Vitro, In Vivo Drug Interaction Studies for NDAs and BLAs” we give an overview and introduction of drug interaction studies and summarize key points related to labeling. In another post, “How In Vitro Studies Help Inform Drug Interactions” we give an overview and introduction of in vitro studies. In this post, we focus on in vivo studies. All three posts are based on the 2012 Guidance, “Clinical Drug Interaction Studies – Study Design, Data Analysis, and Clinical Implications”
Overall, the guidance focuses on in vitro and in vivo studies of drug metabolism, drug transport, and drug-drug or drug-therapeutic protein interactions and is aimed at sponsors of new drug applications (NDAs) and biologics license applications (BLAs). If in vitro studies and other information indicate that in vivo drug-drug interaction studies should be conducted, you should consider the following 9 items:
1. Using a Population Pharmacokinetic Approach to Assess Interactions
PopPK analyses of data from large-scale clinical studies can help characterize the clinical impact of interactions (previously known and unknown) and determine recommendations for dosage modifications for the investigational drug as a substrate (i.e., a victim of interaction), but are less likely to be useful in assessing the investigational drug’s role as a perpetrator. PopPK approaches can be considered conclusive in certain cases utilizing carefully designed study protocols. Simulations using PBPK models can help optimize study design and detailed information on dosage and timing should be documented for co-administered drugs.
2. In Vivo Study Design
Studies can use randomized crossover, 1-sequence crossover, or parallel design. There may be a reason to have an extra period when the interacting drug is removed to assess effect duration. Studies may use single or multiple doses for either or both the substrate (S) and investigational drug (I), as appropriate.
3. Study Population
Studies should use healthy volunteers or members of the intended patient population. Consideration should be given to the subject’s genotype for the specific enzyme or transporter being evaluated or when the subject lacks the major polymorphic clearance pathway, or where pathways involve enzymes or transporters with polymorphisms.
4. Choice of Substrate and Interacting Drugs
The choice of substrate (victim) and interacting drug (perpetrator) is driven by the interaction under investigation. The guidance focuses on CYP- and transporter-mediated interactions and offers multiple tables characterizing various drugs as strong or weak inhibitors/inducers, substrates, etc. for use as victim or perpetrator, as appropriate.
The Cocktail Approach (a mixture of multiple CYP enzymes and transporters in one study) provides a way to evaluate an investigational drug’s inhibition or induction potential provided that:
- Substrates are specific for individual CYP enzymes or transporter
- There are no interactions among these substrates
- The study is conducted in a sufficient number of subjects
Positive results from a cocktail approach may require further evaluation to provide quantitative exposure changes (e.g., AUC, Cmax) if initial evaluation only assessed the changes in the urinary parent to metabolite ratios.
Cases of complex drug interactions involving multiple enzymes and/or transporters can become difficult to interpret; many drugs commonly used in interaction studies impact multiple pathways (e.g., ritonavir inhibits CYP3A, induces UGT, and inhibits P-gp). Interaction studies assessing the impact of multiple CYP inhibitors may be advisable if 1) the investigational drug has plasma concentration-dependent safety concerns, 2) is cleared by multiple CYP enzymes, and 3) the predicted residual or non-inhibitable drug clearance is low. If a single inhibitor has already triggered a major safety concern, there is no additional value in studying the effects of multiple inhibitors.
5. Route of Administration
For an investigational drug, it is generally advisable to use the intended clinical route. Where multiple routes are intended, evaluate the needs of each. It is important to consider the oral route if CYP3A is involved.
6. Dose Selection
Use the maximum planned or approved dose and the shortest dosing interval of the interacting drug. Where safety concerns require lower doses, discuss sensitivity limitations in the protocol and study report.
Appropriate PK measures (AUC, Cmax, Tmax) for the substrate (and relevant metabolites) should be obtained for every study, and sampling should be sufficient to accurately determine the relevant parameters. The PK of the interacting drug (inhibitor/inducer) may be of interest if the study is looking for a two-way interaction. In certain instances, reliance on pharmacodynamic endpoints in addition to pharmacokinetic measures and/or parameters may be useful.
8. Statistical Consideration and Sample Size
DDI studies should address the clinical significance of effects based on PK/PD and be reported as a 90% confidence interval about the geometric mean ratio of the observed PK measure with and without the interacting drug (tests of significance such as p-values are considered inappropriate). Where no effect is observed, specific no effect boundaries should be recommended. The FDA refers to two approaches for defining no effect boundaries:
- Based on population average dose-related and/or individual concentration-response relationships from PK/PD models to define a degree of difference caused by the interaction that is of no clinical consequence.
- Use a default no effect boundary of 80-125% for both the investigational drug and the approved drug. The FDA considers this a conservative standard and a substantial number of subjects would need to be studied to meet it.
Sample size selection depends on how small an effect is clinically important to detect or rule out, the inter- and intra-subject variability in PK measurements, and possibly other factors or sources of variability not well recognized.
9. Considerations for Drug-Therapeutic Protein Interaction Studies
The FDA guidance includes the following 3 general considerations for investiating in vivo drug-therapeutic protein (TP) interactions:
- If an investigational TP is a cytokine or cytokine modulator, studies should be conducted to determine the TP’s effects on CYP enzymes or transporters.
- For TPs that will be used in combination with other drug products (small molecule or TP) as a combination therapy, studies should evaluate the effect of each product on the other.
- When there are known mechanisms or prior experience with certain PK or PD interactions, appropriate in vitro or in vivo assessments for possible interactions should be conducted.
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