Metabolites In Safety Testing: When Are They Important and When Are They Not? - The PhRMA Perspective Lewis J. Klunk, Ph.D. Preclinical and Clinical Development Sciences Biogen Idec Chair, PhRMA Drug Metabolism Technical Group Toxicology Forum July 12, 2005 History of MIST • PhRMA develops and publishes position on Metabolites in Safety Testing (Toxicol. Appl. Pharmacol. 182, 188-196, 2002) • FDA commented on MIST in TAP (190, 91-92, 2003) • PhRMA responded to FDA comments in TAP (190, 9394, 2003) • FDA presentations at: • American College of Toxicology meeting (Fall 2004) • Position in SOT Regulatory Affairs subcommittee newsletter (Spring 2005) • Guidance for comment in June 2005 Task Force Goals Analysis of issues Survey of current best practices Present findings at joint PhRMA/FDA workshop (November, 2000) Prepare position paper Define practical and scientifically based approaches to use of metabolite data that address contemporary issues in the safety evaluation of drug candidates Position Paper Focus on metabolites in preclinical safety testing Aspects of metabolites in support of safety Restricted to small molecules Oral administration Emphasizes issues which may be ambiguous Provide basis for further discussion Metabolites Generally not considered in TK monitoring as index of systemic exposure Relevant properties should be considered when comparing tox species to humans Quantitative species differences common Species variation requires the need to address how different types of metabolites can contribute to interpretation of safety data major vs minor pharmacologically active vs inactive phase I vs phase II potentially formed via reactive intermediate Drug Discovery/Development Timeline LEADING UP TO FIRST HUMAN TRIALS FIM TO END OF PHASE II PHASE III TO REGISTRATION N O M I N A T E DRUG DISCOVERY HUMAN STUDY I N D P O P N D A 1 2 3 F I M DRUG DEVELOPMENT GUIDING SYNTHESIS EARLY INFORMATION HUMAN DATA Leading Up To FIM Trials Metabolism Studies Relevant To Safety Assessment Some information obtained on metabolic pathways in vitro animal/human in vivo animal Comparative biotransformation profile Identify major metabolites as feasible Test metabolites for activity/toxicity Leading Up To FIM Trials Implications of Metabolism Data for the Safety Program Help justify selection of toxicology species For GLP toxicology studies Customary to measure parent only Only preliminary metabolism data available No in vivo data on human plasma metabolites demonstrate dose related exposure calculate potential safety margins Start to generate data on potentially important metabolites which could be monitored in later pivotal studies. Consider potential for human unique metabolite want to ensure animals and humans are qualitatively exposed to same metabolites unique metabolites are rare if suspected from in vitro data, plan to look for in FIM and in vivo animal studies consider genetic toxicology assessment First Human Dose to End of Phase II Metabolism Studies Relevant to Safety Assessment Broad range of metabolism studies P450 inhibition of parent and possibly metabolites Identify P450 isoforms responsible for major metabolic pathways Synthesis and evaluation of significant metabolites as feasible Preclinical ADME studies (tissue distribution, routes of elimination, mass balance, metabolic profiles in plasma and urine) Human ADME Allows direct comparison of biotransformation pathways in humans and safety species qualitative similarity of metabolic profiles in plasma any human unique metabolites? First Human Dose to End of Phase II Metabolism Studies Relevant to Safety Assessment Determine which are the major circulating metabolites in human and toxicology species Implications on decision to monitor in subsequent toxicology and clinical studies Important active major known toxicity structural alert Recognize that contemporary analytical techniques permit detection at extremely low concentrations Quantitating metabolites that account for only a small percent of dose rarely results in data useful for interpretation of safety First Human Dose to End of Phase II Metabolism Studies Relevant to Safety Assessment Develop strategy for monitoring appropriate metabolites obtain PK information in limited number of Phase II and III clinical studies (sparse sampling) if important enough to monitor in humans, monitor in animals used for safety evaluation Major inactive metabolite need not be monitored on routine basis but should be identified in humans and tox species conjugates usually not monitored Timing of human ADME study Phase I-III current trend is earlier First Human Dose to End of Phase II Implications of Metabolism Data for the Safety Program For compounds with a high TI and no significant toxicity, the progression of this phase of safety assessment is relatively straightforward: an assurance of qualitatively similar metabolite profiles supports limiting TK support to parent However, for compounds with low TI, significant toxicity or dissimilar animal/human metabolite profiles consider careful investigation of role of metabolites in the drug safety profile determine if metabolites contribute to any observed preclinical toxicity First Human Dose to End of Phase II Implications of Metabolism Data for the Safety Program Similar metabolite profile among species adds assurance that exposure to drug related material in animals is meaningful in terms of clinical safety A major metabolite in animals not present in humans can help understand whether a preclinical toxicity may not be relevant to humans First Human Dose to End of Phase II Implications of Metabolism Data for the Safety Program A case in which a human circulating metabolite which is present in animals at very low concentrations could make conclusions about demonstrated safety in animals difficult to extrapolate to humans potential exposure issue consider use of alternative animal safety species consider further testing on metabolite If specific toxicological evaluation of the metabolite is warranted, consider: general toxicity testing genotoxicity (mutation and chromosome effects) testing reproductive toxicology studies carcinogenticity testing May be warranted only if there was evidence that metabolite caused lesions (not observed with parent) expected to progress to neoplasia Phase III to Registration Metabolism Studies Relevant to Safety Assessment If determined necessary to measure important human metabolites: validate assays for parent and metabolite(s) determine inter and intra subject variability in metabolite exposure determine alterations in metabolite AUC as function of age, gender, renal/hepatic insufficiency, target disease state, drug-drug interactions For drugs exhibiting high variability in PK or PD, consider generating genotype and phenotype data with respect to metabolite formation to fully understand behavior of drug in target patient population Human metabolite/pathway identification usually complete Phase III to Registration Implications of Metabolism Data for the Safety Program Drug metabolism probably has less impact in Phase III Consider establishing that major circulating metabolites are present in plasma from at least one animal species used for reproductive tox studies General Points to Consider Case-by-case approach is essential Approach should be practical and scientifically sound Emphasis on major circulating human metabolites Major metabolite accounts for at least 25% of the exposure (AUC) to circulating drug related material. Human ADME should be performed early to define major circulating metabolites Only major human metabolites should be considered for monitoring in selected toxicology studies for exposure assessment. Exclude monitoring conjugated metabolites unless reason to believe they may be chemically reactive (e.g. some acyl glucuronides). Exclude monitoring a metabolite that is major in animal but minor in human General Points to Consider “Major pharmacologically active metabolite” is defined as one that is deemed to make a significant contribution to the total pharmacological effect of a given dose of parent drug. Take into account systemic exposure and intrinsic activity of metabolite. If a major metabolite has no known target or non-target pharmacological activity, its PK should be defined at least once in humans and tox species following a single dose of parent drug. Metabolites defined as major in humans should be considered for monitoring in selected toxicology studies. A metabolite which is significant in human plasma, but very minor in all tox species should be considered for additional study to determine if it poses an unidentified risk to human safety. General Points to Consider Carc studies on an administered metabolite are not recommended unless there is evidence in separate metabolite toxicity studies that the metabolite caused novel lesions (i.e. different from parent) that might be expected to progress to neoplasia. Make effort to establish that all major circulating human metabolites are present in plasma of at least one animal species used for reproductive and developmental toxicology assessment. General Points to Consider Overriding consideration: the approach adopted should be based on sound scientific principles and practical considerations, and should be tailored to the specific issue at hand. It is the responsibility of the sponsor to demonstrate that an appropriate series of safety studies has been performed to adequately assess safety in humans at relevant exposure levels. New analytical techniques can not replace careful toxicology experiments and good scientific judgement. Comments on draft Guidance 1) Guidance focuses on…”human plasma metabolites which represent >10% of drug-related material which are not present at sufficient levels to permit adequate characterization in standard nonclinical animal studies.” Addresses human unique metabolites (rare) Addresses situations where a metabolite is more prevalent in humans than in the species used in standard toxicity testing”, guidance recommends that a battery of toxicology tests be performed on the metabolite in question Comments on draft Guidance while qualitative differences in metabolite profiles across species are rare, quantitative differences in metabolite exposure are the rule, rather than the exception. Therefore there will be many cases where dose escalation will provide safety margin for parent but not for metabolites Additional tox studies on synthetic metabolites would Have huge resource implications for drug development Be counter to the spirit of the FDA Critical Path Initiative Comments on draft Guidance 2) ..”nonclinical studies using direct administration of the unique human metabolite may be warranted.” May be necessary for a truly unique human metabolite Shown in literature that the disposition of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from the parent. Such a toxicology study could be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. Comments on draft Guidance 3) Definition for “…major metabolites primarily as those identified in human plasma that account for >10% of drug related material (administered dose or systemic exposure, whichever is less)”... guidance justifies this number using several examples of chemicals which undergo metabolism to toxic products which represent 10% or more of the administered dose. These are reactive intermediates which are not detected in plasma at any levels Comments on draft Guidance 4) „Decision Tree‟ focuses only the fraction of the dose that is represented by an individual metabolite, as opposed to the abundance of the metabolite in the systemic circulation. the Guidance is not internally consistent confuses plasma exposure with fraction metabolized. It is important that this ambiguity be resolved in the final form of the Guidance Guidance should indicate that the identification of certain stable end-products in excreta (e.g. thioether conjugates) is not necessarily reflective of the generation of reactive, potentially toxic intermediates in vivo. Conclusions MIST is a complex issue Good scientific rationale must prevail Approaches must be practical Should be tailored to specific issues Studies must allow for flexible design No single paradigm is applicable to all situations More dialog on the “first” draft of a guidance would help ensure the most useful outcome for all.