Submission of comments on 'Concept paper on a revision of the Guideline on the investigation of drug interactions' (EMA/CHMP/694687/2016)

Transcription

1 30 th June 2017 Submission of comments on 'Concept paper on a revision of the Guideline on the investigation of drug interactions' (EMA/CHMP/694687/2016) Comments from: Name of organisation or individual The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Please note that these comments and the identity of the sender will be published unless a specific justified objection is received. When completed, this form should be sent to the European Medicines Agency electronically, in Word format (not PDF). 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0) Facsimile +44 (0) Send a question via our website An agency of the European Union European Medicines Agency, Reproduction is authorised provided the source is acknowledged.

2 1. General comments the Agency) General comment (if any) General comment #1 It would be extremely valuable if the upcoming EMA guideline on the investigations of drug interaction is aligned between regulatory agencies, in particular between the EMA, the FDA and the PMDA. Lack of alignment results in additional, unnecessary in vitro or in vivo studies, including clinical studies. Agreement on a common, scientifically justified set of standards to improve the overall efficiency of the drug development process would be helpful. General comment #2 We have concurred that to avoid overly prescriptive selection criteria, the examples provided in the lists of in vitro substrates and inhibitors as well as in vivo substrates and inhibitors across Appendices IV-VII of the current 2012 Guideline were not meant to be inclusive of all possible in vitro or clinical probes for evaluation. Proposed change (if any): Given the expansion of the knowledgebase and formulary, we recommend updates and additions, beyond that identified in Line 32, to lists of in vitro and in vivo substrates, inhibitors and inducers. This may include lists, classified by potency (e.g. strong, moderate, weak), as appropriate, for in vivo inhibitors and inducers of drug metabolizing enzymes, as well as examples of in vivo inhibitors, inducers and substrates of transporters. General comment #3 Section 5 (Pharmacokinetic Interactions); pp. 7/59 of the current Guideline states In the area of HIV there have (if applicable) 2/14

3 the Agency) General comment (if any) been cases of unexpected interactions. When developing a drug in such an area, in vivo interaction studies should be considered with commonly combined drugs having a relatively narrow therapeutic window while more knowledge is gained on the mechanism behind the unsuspected interactions in the field. Proposed change (if any): It remains unclear what the definition and criteria for these unexpected interactions may be and examples for which in vivo studies would be expected or those settings whereby interactions could be suitably discharged with other modalities (e.g. PBPK). (if applicable) 3/14

4 2. Specific comments on text Line number(s) of Line 24 (Inhibition and induction of enzymes in the intestine: specifying cutoffs for poorly soluble drugs) If cut-off values are deemed necessary, to assess the estimated gut concentration we recommend that EMA consider other approaches, beyond dose/250 ml, when the dose is not soluble in 250 ml, [e.g. use maximum solubility determined in a more physiological buffer such as simulated intestinal fluids (fed condition)] for any calculation. This would be a more realistic approach for compounds with low solubility. Lines (Specific in vitro study design recommendations for in vitro induction studies: number of concentrations to study) The current EMA DDI guideline recommends At least three different concentrations should be used. We agree that three different concentrations would be the minimum to show the absence of induction (<2-fold increase in mrna). If defining induction parameters, the in vitro induction study should include enough concentrations of the test inducer to adequately describe the concentration-response curve to best obtain the EC50 and Emax values. Defining these values will also depend on limitations in vitro provided by aspects of test inducer solubility and cell viability. Line 27 (Transport as rate limit for elimination: in vivo study design considerations) IQ agrees that it is important to understand whether active transport is the rate limiting step for the elimination of drugs, which could be assessed via mechanistic clinical DDI studies. This should be restricted to the transporters which have well established literature data and validated study approaches, such as OATP1B. If EMA has sufficient internal data, it would be helpful to give some guidance (e.g. a table summarizing examples of 4/14

5 specific inhibitors for each transporter to separate liability of transporter-mediated DDI from metabolism). Line 28 (The addition of a table to present in vitro drug-drug interaction (DDI) information) Proposed change (if any): Clinical microdosing studies (Prueksaritanont et al Clin Pharmacol Ther. 2017,101(4): ; Maeda et al. Clin Pharmacol Ther. 2011, 90(4):575-81) are emerging as a mechanistic approach to identify the rate-limiting step of hepatic uptake vs. metabolism. If the PK of the NCE (new chemical entity) can be extrapolated from a microdose to the therapeutic dose, dedicated clinical DDI studies with the NCE at the therapeutic dose may not be needed. Clarification of the EMA view of such an approach would be helpful in the revision to the current 2012 Guideline. We agree that a table format would be useful to summarize in vitro DDI parameters (e.g. unbound Ki or IC50 values) and the outcome from all static model DDI predictions. In addition to static modelling predictions, it would be beneficial if the agency was open to looking at a table summarizing the outcome from any PBPK modelling that the sponsor may have conducted. An example of a table(s), perhaps separately for in vitro and in vivo data, may be reasonable for general guidance; however, this tabulation should not be mandated with Applicants given the flexibility in the method of presentation. Lines (Specifying a cutoff (two-fold) for the inhibition constant Ki shift to conclude mechanism based inhibition, It is important to note that typically inhibition shift studies are conducted during IC50 studies. The distinction between IC50 and Ki values is very important. While a 2-fold change in IC50 values can be considered important and as such could be attributed to an irreversible inhibition (timedependent), the robustness of the assay should be demonstrated to minimize inter-assay variability as a 5/14

6 including details regarding the pre-incubation duration) contributing factor. Sponsors should consider showing assay robustness in order to use IC50 shift data for decision making. Determination of K I and kinact should ideally be conducted by traditional methods. Compounds have been shown to be time-dependent inactivators (TDI) with IC50 shift values of 1.5 using a 30- min pre-incubation (Berry and Zhao 2008 Drug Metab Letters 2:51-59), indicating that the use of such values as a cut-off for identifying a compound as a TDI may be appropriate. An initial TDI screen (Wong et al., 2016 Xenobiotica, 46:11, and Zimmerlin et al. (2001) Drug Metab Dispos 39: ) may also be used. The loss of activity assay (% inhibition at 30 min, 10 um) was suggested to be a predictor of in vivo DDI and had a low potential for false negatives or positives. Cut-off values are proposed in each of the publications. Line 31 (In vitro induction screening: update on study design recommendations ) Incubation durations for the induction study are typically 2-3 days, as surveyed across Pharma companies (Chu et al., Drug Metab Dispos : ). Since mrna responses precede protein, mrna measurements should be more than adequate at 48h of treatment. Treatment durations of 72h do not appear to offer an improved mrna induction response over 48h (Zhang et al., Drug Metab Letters , ). Longer incubation times may present more issues, particularly for those test compounds with cell viability issues. Even shorter incubation times (e.g. 24h) may be adequate to assess induction parameters if adequate positive control data is provided. It is proposed that the positive control rifampicin be used at a concentration of at least 10 µm as CYP3A4 should be maximally induced at this concentration with an EC50 of ~ 1 6/14

7 µm (Einolf et al., 2014 Clin Pharmacol Ther 95: Supplemental Table S1) and also to be consistent with the FDA guideline. Even though phenobarbital is an indirect activator of CAR, it should suffice as a positive control for activation through the CAR receptor in the primary human hepatocyte system. Proposed change (if any): Incubations are performed with daily addition of the investigational drug. The duration of the incubation is generally 2-3 days. The positive controls used should be as selective as possible and be chosen based on current scientific knowledge. Currently, rifampicin ( μm) is recommended as positive control for PXR, CITCO ( 100 nm) or phenobarbital ( 750 µm) for CAR, omeprazole (50μM) for the Ah-receptor and dexamethasone (50μM) for GR. Line (Transporter inhibition screening: update of the list of transporters to screen from a pharmacokinetic perspective) It is believed that the current guidance adequately covers the majority of drug transporters that have demonstrated the potential to mediate clinically relevant pharmacokinetic drugdrug interactions based on current knowledge. There has been growing evidence to support the in vivo relevance of MATE1 and MATE2K-mediated DDI for dual MATE1/MATE2K inhibitors (Hillgren et al., Clin Pharmacol Ther. 2013; 94:52-63). We recommend MATE1 and MATE2K be included in the list of transporters for which every investigational drug is characterized for the inhibition potency. However, it should be noted that selective inhibition of MATE1 or MATE2K does not appear to influence the PK of victim drugs (Hibma et al., Clin Pharmacokinet. 2016; 55(6): and Morrissey et al., Clin Pharmacokinet. 2016; 55(4): ). The interpretation of clinical DDI 7/14

8 data related to the inhibition of OCT1 can be complicated by non-selective inhibition of other transporters (e.g. OCT2 and MATE1/2K). There is no example of a DDI known to be due to the inhibition of OCT1 in the literature. Therefore, evaluation of OCT1 inhibition should be removed from the routine screening list. We propose that Bile Salt Export Pump (BSEP) be deleted from the screening list considering the clinical translation of in vitro BSEP inhibition has not been clearly established and BSEP inhibition in vivo may not result in a direct translation to an increase in serum bile salts. We propose that the sponsor only study BSEP if there are liver safety signals. Please also refer to the comment on line 40 for additional information. Lines (Transporter inhibition screening: update of some cutoffs for determining in vivo relevance of in vitro inhibition) As different cut-off values are being used by EMA, PMDA and FDA to determine the in vivo relevance of transporter inhibition, we would strongly encourage the EMA to engage in cross-agency discussions and provide evidence based harmonized cut-off values for assessing transporter inhibition and translation to clinical impact. For example, different conclusions may be reached on potential OATP inhibition depending on whether you follow the FDA guidance (R-value determination) or EMA guidance (25*([I]u,inlet,max). We recommend that the EMA bases transporter in vitro inhibition assessment on IC50 values rather than Ki; IC50 is more readily determined and the majority of sponsors do not determine Ki values for transporters. In addition, IC50 values are similar to Ki when the probe substrate is at a concentration well below the Km, as per the Cheng-Prusoff equation (Ki = IC50/(1+[S]/Km) (Brouwer et al, Clin Pharmacol Ther. 2013;94(3):412). 8/14

9 Line (The need to know whether the (unbound) target concentration was maintained in an in vitro system during the incubations) We also propose the EMA consider updating the guidance to allow the use of measured fu values of <0.01 in DDI predictions. In recent years, improved sensitivity and accuracy have demonstrated the ability to provide an accurate measurement of plasma protein binding for such highly bound compounds (Riccardi et al., J Pharm Sci , ). The issue of ensuring that the concentration of added compound is maintained throughout the incubation period is also related to the issue of nominal concentration vs free concentration. The level of compound in the incubation is a function of the binding, both to proteins and non-specific binding to the apparatus and metabolism/degradation. Depletion of the compound during the incubation as a result of metabolism (or degradation) can be indicated through prior in vitro metabolism studies. Demonstration of stability in those systems would likely guarantee stability in most of the in vitro systems used for DDI assessment, e.g. plated hepatocytes are less metabolically competent than suspension or co-cultured hepatocytes and concentrations of liver microsomes used in inhibition and inactivation studies are often much lower than concentrations used for metabolic activity determinations. This latter approach is taken to minimize non-specific binding and also has the advantage of limiting loss of compound through metabolism. The current recommendation from regulators during induction studies is for determination of compound concentration at the end of the 24h treatment period (the last 24h of treatment since fresh application of compound is usually done every 24h). Attempts have been made to account for any loss of compound or to measure unbound intracellular compound levels (Sun et al., 2017; Zhang et al., 2014). These approaches are challenging and 9/14

10 are labour intensive. Additional data with more compounds will improve confidence in using this approach. Not accounting for intracellular concentrations can provide falsely low EC50 values in situations where uptake transporters elevate unbound intracellular concentrations. Particularly for DDI studies using HLM, fumic can be measured or estimated using available prediction methods (Austin et al., 2002 Drug Metab Dispos,30:1497; Hallifax and Houston 2006 Drug Metab Dispos, 34:724). It should be expected that the Ki values obtained from this system are unbound values; otherwise the DDI could be under-predicted. In addition, a sufficient percentage of the initial test inhibitor compound concentration should be present at the end of the incubation period to ensure appropriate exposure of the inhibitor. Further discussion on this important topic is encouraged. Experience within companies demonstrates that some NCEs are poorly soluble in in vitro assay buffers and/or have high levels of non-specific binding to the cells/cell fractions/assay plates. Measuring unbound concentrations may not always be feasible and could increase the complexity of in vitro data generation and interpretation. More research is needed before we can confidently define this topic adequately to include in guidelines. Line 40 (The use of Bile Salt Export Pump (BSEP) inhibition data) IQ is in agreement with recommendations by the International Transporter Consortium that measuring inhibition of BSEP by in vitro methods is useful for compounds that cause cholestasis (Hillgren et al. Clin Pharmacol Ther :52 63). However, while there is an association between drug-induced BSEP inhibition and liver injury in humans, causality has not been well established. For instance, it remains unclear whether BSEP inhibition alone can cause cholestasis or whether inhibition of 10/14

11 other mechanisms is needed to induce cholestatic liver injury (e.g. inhibition of basolateral efflux transporters such as MRP3/4 and OSTα/β, and FXR antagonism). Therefore, we recommend BSEP be deleted from the list of transporters to be investigated until such translation is well established and propose that the sponsor only study BSEP if there are liver safety signals. It should also be noted that an in vivo assessment of BSEP inhibitors remains challenging as confounding factors (e.g. inhibition of bile salt uptake or bile salt synthesis) make data interpretation difficult if increases in plasma levels of bile salts are found. Further, there is no consensus on whether animal models can help to understand the risk for BSEPmediated cholestasis nor is there an alignment on biomarkers to measure and how to translate the results obtained with these biomarkers to humans as there are species differences in bile salt composition and transporters (e.g. OSTa/B is expressed in human but not in rat liver). Therefore, if an in vitro result indicates that a NCE is a BSEP inhibitor, it is unclear what clinical study design should be used and which biomarkers should be measured in order to appropriately determine the clinical relevance of the in vitro result. Line 41 (How to calculate the unbound inlet concentration) We agree with the currently included calculation for the unbound inlet concentrations by Ito et al., (1998) Pharmacol Rev 50: (included below): II iiii,mmmmmm = ff uu (II mmmmmm + FF aaff gg DDDDDDDD kk aa QQ h ) The values for ka and FaFg in this equation should be based upon the measured or estimated ka and FaFg values. Only when an estimate is not available, should the default values of 0.1 min -1 and 1 be used for ka and FaFg, respectively. In 11/14

12 addition and as noted in comments for lines 34-35, the measured experimental fu values should be used to calculate the unbound liver inlet concentration for compounds with fu <0.01 as current and improved methods have demonstrated the ability to provide an accurate measurement of the plasma protein binding of highly bound compounds (Riccardi et al., J Pharm Sci , ). Line 42 (How to verify adequate sensitivity of the system for in vitro induction studies) The sensitivity of the in vitro induction study would be defined by the Emax of the positive control inducer for each isoform being tested. This forms part of the objectives currently being evaluated by the IQ Induction Working Group and will be shared once the team has completed their analysis. The current thinking is that the positive control inducer should induce mrna (and, optionally, activity) at least 5-fold to capture an induction response within 40% of the positive control (i.e. 2-fold change by the test compound when positive control is at 5-fold). It is recommended that the analysis be conducted with careful attention to cellular health and morphology together with inclusion of a positive control for cytotoxicity. Line (How to present the mass balance study results: adding a recommendation on how to illustrate the elimination of a drug schematically) The importance of clearly presented mass balance information for victim DDI assessments is acknowledged. While a schematic illustration of mass balance results may be beneficial for presentation in the dossier to assist in the review of the application, this may be overly prescriptive for the purposes of product labelling. Therefore, we prefer that the precise method of presentation of results in both the dossier and labelling be left to the discretion of individual Applicants. Proposed change (if any): Rather than a templated illustration(s) or other labelling specifications, in an effort to 12/14

13 foster harmonization of Global labelling and informative interpretation for health care providers, guidelines for the interpretation and communication of mass balance results for the purposes of application (dossier) and separately for labelling would be reasonable. An example illustration may be reasonable for general guidance; however, this should not be mandated with Applicants given the flexibility in the method of presentation. Line 46 (Discussing the text on interaction studies with oral contraceptives for potential teratogens) Currently the text pertaining to the necessity of in vivo evaluation for effects on contraceptive steroids if a potential teratogen is intended for use in fertile women, regardless of the in vitro induction study results is harmonized across the EMA (2012) and FDA DDI (2012) Guidance documents. Proposed change (if any): If any changes are proposed to the EMA DDI Guideline, these should be considered together with the expectations of the FDA PLLR to maintain harmonization of intent, as far as possible, across these Global Guidelines. Line 47 (Specification of the presently recommended duration of in vivo studies of CYP3A4 induction) For an NCE, the duration of treatment of a test inducer to measure CYP3A4 induction in vivo would be compound specific. Considerations should be made for the time the compound takes to reach steady-state, potency of the inducer, and the time for induction of the target enzyme (i.e. the synthesis rate and degradation rate constant, k deg for the specific enzyme being induced). Specifically for rifampin, steady-state levels of induction of CYP3A activity in humans occurred at 5-6 days of rifampin treatment (Tran et al., 1999 J Clin Pharmacol 39:487) 13/14

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