Prevalence of Non–Cytochrome P450–Mediated Metabolism in Food and Drug Administration–Approved Oral and Intravenous Drugs: 2006–2015 S

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1521-009X/44/8/1246–1252$25.00 http://dx.doi.org/10.1124/dmd.116.070763 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 44:1246–1252, August 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Special Section on Emerging Novel Enzyme Pathways in Drug Metabolism

Prevalence of Non–Cytochrome P450–Mediated Metabolism in Food and Drug Administration–Approved Oral and Intravenous Drugs: 2006–2015 s

Matthew A. Cerny

Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Inc., Groton, Connecticut

Received March 31, 2016; accepted April 14, 2016 Downloaded from

ABSTRACT In recent years, claims of increased involvement of non–cytochrome indicates that non-P450 enzymes contribute significantly to the metab- P450 (non-P450) enzymes in the metabolism of drugs have appeared olism of the 125 drugs analyzed. Approximately 30% of the metabolism in the literature. However, no temporal summaries of the contribu- of these drugs is carried out by non-P450 enzymes, with the predom- dmd.aspetjournals.org tion of non-P450 enzymes to the metabolism of drugs have been inant non-P450 enzymes identified being glucuronosyltransferases published. Using data from human radiolabeled absorption, distri- (11.7%), hydrolases (10.8%), carbonyl reductases (2.4%), and alde- bution, metabolism, and excretion studies available for a set of 125 hyde oxidase (1.1%). Although significant, the relative contribution orally or intravenously administered small-molecule drugs approved of non-P450 enzymes to drug metabolism does not appear to have by the United States Food and Drug Administration from 2006 to increased dramatically over the last 10 years. As the current eval- 2015, the contributions of P450 and non-P450 enzymes to the forma- uation involves drugs which emerged from the discovery phase ‡ > tion of major metabolites ( 10% of dose) were assessed and tabu- 10 years ago, this evaluation may not reflect the current or evolv- at ASPET Journals on September 29, 2021 lated. Over this time frame, the involvement of P450 versus non-P450 ing situation in some research organizations; therefore, additional enzymes in the formation of major metabolites is compared, and the monitoring and assessment of the involvement of non-P450 en- individual non-P450 enzymes responsible are described. This analysis zymes in the metabolism of drugs will be conducted in the future.

Introduction along with reaction phenotyping studies, result in a definitive assignment A major focus of drug discovery and development is to understand the of the fraction metabolized (fm) by enzymes contributing to the metab- metabolic biotransformations and enzymes which contribute to drug olism of the drug (Rodrigues et al., 2001; Zientek and Youdim, 2015). clearance (CL) and impact oral bioavailability (F). An appreciation of Cytochrome P450s (P450s) are a superfamily of membrane- these metabolic reactions and enzymes may impact the design of analogs associated heme-containing enzymes, for which the human genome with longer half-lives or higher F and may inform on the likelihood of contains 57 distinct P450 genes (Ortiz de Montellano, 1995; Guengerich drug-drug interactions (DDIs). Assays such as metabolic stability using and Cheng, 2011). P450 enzymes represent a well studied and relatively liver or other tissue subcellular fractions or hepatocytes, enzyme reaction well understood family of enzymes that have been reported as the most phenotyping using expressed enzymes or with selective inhibitors, me- important enzymes responsible for the majority of oxidative drug metabolite identification studies, as well as radiolabeled absorption, distri- tabolism. In humans, P450s 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and bution, metabolism, and excretion (ADME) studies in humans and other 3A5 are considered the major P450 isoforms involved in the metabolism preclinical species (Penner et al., 2012b; Beaumont et al., 2014) can of drugs (Walsky and Obach, 2004; Wienkers and Heath, 2005). provide screening and definitive data for these purposes. Data from these In recent years, claims have appeared in the literature indicating that assays and studies allow one to better understand the extent and rate of metabolism by P450 enzymes is no longer as prominent as it once was metabolism, identify metabolites, and define the individual enzymes (Pryde et al., 2010; Oda et al., 2015). These reports assert that other non- responsible for the CL of a drug. Furthermore, human ADME studies P450 enzymes play a more significant role in the metabolism of recent provide quantitative data for the amounts of metabolites formed and, drugs and drug candidates. Despite these claims, supporting data are sparse. Furthermore, no evaluation exists that looks at the changes in the dx.doi.org/10.1124/dmd.116.070763. contribution of P450 versus non-P450 enzymes to the metabolism of s This article has supplemental material available at dmd.aspetjournals.org. drugs over time. As such, one of the main goals of this manuscript is to

ABBREVIATIONS: ADME, absorption, distribution, metabolism, and excretion; AO, aldehyde oxidase; CL, clearance; DDI, drug-drug interaction; FDA, Food and Drug Administration; GDC-0834, N-[3-[6-[4-[(2R)-1,4-dimethyl-3-oxopiperazin-2-yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]- 4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide; P450, cytochrome P450; UGT, uridine 59-diphospho-glucuronosyltransferase.

1246 Non-P450 Metabolism of FDA-Approved Drugs: 2006–2015 1247 provide a starting data set which can be used to provide a temporal formation of major metabolites ($10% of dose) using data from human summary of the involvement of non-P450 enzymes in the metabolism of radiolabeled ADME studies available for small-molecule drugs ap- drugs. The current evaluation is intended to provide evidence to support proved by the United States Food and Drug Administration (FDA) from or refute claims of increased involvement of non-P450 enzymes versus 2006 to 2015. Additionally, data comparing the involvement of P450 P450 enzymes in the metabolism of drugs approved in the last 10 years. versus non-P450 metabolism for each year have been compiled to assess Additionally, future expansion of the current data set will provide an the change in involvement of P450 versus non-P450 over time. Last, the ongoing assessment of the involvement of P450 and non-P450 enzymes individual non-P450 enzymes that are involved in the formation of major in the metabolism of emerging drugs. metabolites of these drugs are also described. A goal of this analysis was The involvement of non-P450 enzymes in the metabolism of drugs to determine if there were perceptible trends in a changing role of non- and endogenous substances is well precedented (Penner et al., 2012a; P450 enzymes, and if so, which enzymes. Bohnert et al., 2016). The more commonly encountered enzymes As such, the results of this evaluation serve as a database for recurring involved in oxidation, reduction, and hydrolysis (phase I metabolism) analyses of the involvement of non-P450 enzymes in the metabolism of include molybdenum cofactor–containing enzymes [aldehyde oxidase emerging drugs. This work also affords specific examples of substrates (AO) (Hutzler et al., 2013) and xanthine oxidase (Pryde et al., 2010)], for non-P450 enzymes and may result in a better understanding and flavin-containing monooxygenases (Hines et al., 1994), monoamine oxi- appreciation of the contribution of non-450 enzymes to drug metabo- dase (Edmondson et al., 2009), reductases [carbonyl reductases (Forrest and lism. The data provided highlight specific non-P450 enzymes which Gonzalez, 2000) and aldo-keto reductases (Jin and Penning, 2007; require greater characterization. Greater knowledge of the involvement Downloaded from Oppermann, 2007; Penning, 2015)], dehydrogenases [alcohol dehydroge- and importance of non-P450 enzymes can result in consideration of nase (Bosron and Li, 1987; Jornvall et al., 2000) and aldehyde de- other factors for these enzymes, such as species differences, hepatic hydrogenase (Marchitti et al., 2008; Koppaka et al., 2012)], and hydrolytic versus extrahepatic expression and metabolism, enzyme polymorphisms enzymes (esterases, proteases/peptidases, amidases, etc.) (Testa and (Brian et al., 2016), likely DDIs, non-P450–mediated bioactivation Mayer, 2006; Uetrecht and Trager, 2007; Long and Cravatt, 2011; Yang (Grillo and Lyubimov, 2011; Hutzler and Cerny, 2012), as well as the et al., 2011; Bachovchin and Cravatt, 2012; Oda et al., 2015). Addition- development of in vitro assays to improve extrapolation to predict and ally, metabolites arising from conjugative enzymes (phase II metabo- understand in vivo CL for these non-P450 enzymes. Improving our dmd.aspetjournals.org lism), including uridine 59-diphospho-glucuronosyltransferases (UGT) understanding of these metabolic enzymes and biotransformations should (Tukey and Strassburg, 2000; Oda et al., 2015), N-acetyl transferases result in fewer surprises being encountered during the drug discovery and (Hein et al., 2006), glutathione S-transferases (Armstrong, 1997; Eaton development process, leading to safer drugs in the future. and Bammler, 1999; Salinas and Wong, 1999; Sheehan et al., 2001), sulfotransferases (Strott, 2002; Riches et al., 2009), and methyltrans- ferases (Petrossian and Clarke, 2011), are also frequently identified. Materials and Methods

An appreciation of the metabolic reactions and the totality of enzymes Sources of Data and Data Restriction Criteria. All medications considered at ASPET Journals on September 29, 2021 involved in the metabolism of a drug is important for a number of for evaluation were approved by the FDA between 2006 and 2015 (Supplemental reasons. Properly accounting for both P450 and non-P450 contributions Table 1). New Drug Application and Biologic License Application approval packages, including the drug labels, are available at the FDA website, Drugs@ to metabolism provides a more accurate assignment of the fm value for P450 enzymes and, therefore, results in a more accurate determination of FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/). The focus of this evaluation is the metabolism of small-molecule drugs. Drugs that fall outside of the drug’s likelihood of being a P450 DDI victim. Clinically relevant this category were removed, such as protein drugs (i.e., enzymes, antibodies, DDIs for a number of phase I and phase II non-P450 enzymes have also antibody drug conjugates), peptide drugs, antisense drugs, elemental/inorganic been reported. Non-P450 enzymes for which DDIs have been observed drugs, and botanical drugs (Table 1). For the subset of small-molecule drugs, only clinically include AO (Lake et al., 2002; Renwick et al., 2002), xanthine drugs administered intravenously or orally were considered for further evaluation. oxidase (Coffey et al., 1972; Zimm et al., 1983), monoamine oxidase For the remaining drugs, human radiolabeled ADME data were obtained from (Livingston and Livingston, 1996; Rolan, 1997; Van Haarst et al., 1999), sources which included the FDA New Drug Application approval package, alcohol dehydrogenase (Roine et al., 1990; Jacobsen et al., 1996), specifically the clinical pharmacology and biopharmaceutics reviews, pharma- carboxylesterases (Xiao et al., 2013; Wang et al., 2015), UGTs (Kiang cology reviews, and drug labels. Additionally, if data were available from the et al., 2005; Uchaipichat et al., 2006; Nivoix et al., 2008; Li et al., 2015), European Medicines Agency Application for Marketing Authorization (http:// sulfotransferases (Schwartz et al., 2009), and methyltransferase (Jorga www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search. jsp&mid=WC0b01ac058001d124) or from the scientific literature, these data et al., 1997; Lewis et al., 1997; Relling et al., 1999). Therefore, an early were also used for this evaluation. References describing the sources of data used understanding of the routes of metabolism and the contributing enzymes are presented in Supplemental Table 1. provides insights into potential DDIs as well as time for implementation For medications which are combination therapies, the metabolism of each of mitigation strategies. component (drug) was considered individually. For combination therapies where The major aim of this manuscript is to summarize and compare the one or more new chemical entities are combined with one or more previously contributions of P450 and non-P450 routes of metabolism to the approved drugs, only the newly approved drugs were included in the evaluation

TABLE 1 Compilation of metrics for FDA-approved drugs during 2006–2015

Year 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Totals Drug approvals 22 18 24 26 21 30 39 27 41 45 293 New active ingredient approvalsa 23 18 24 27 21 30 40 27 43 45 298 Proteins 4 2 3 6 7 6 9 2 11 12 62 Peptides 1 0 0 0 2 0 2 0 0 1 6 Other 2 1 0 0 0 0 1 3 1 1 9 Small molecules 16 15 21 21 12 24 28 22 31 31 221

aNumber of active ingredients contained within mono or combination small-molecule therapies approved for the designated year. 1248 Cerny

TABLE 2 Compilation of metrics for FDA-approved small-molecule drugs 2006–2015

Year 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Totals Active ingredients 16 15 21 21 12 24 28 22 31 31 221 Other route(s) 2 3 4 4 1 3 4 3 4 2 30 Intravenous 1 3 7 3 4 2 3 2 6 4 35 Imaging agents 0 0 4 0 0 2 2 2 1 0 11 Prodrugs 0 2 2 1 1 0 0 0 0 0 6 No ADME study 0 0 0 1 0 0 1 0 4 0 6 Insufficient data 0 0 1 0 1 0 0 0 0 1 3 Compounds evaluated 1 2 0 1 2 0 0 0 1 3 10 Oral 13 9 10a 14719211721a 25a 156 Prodrugs 0 0 1 1 2 3 0 2 1 6 16 No ADME study 1 1 1 2 0 2 3 0 3 3 16 Insufficient data 3 0 0 0 0 1 1 1 0 2 8 Compounds evaluated 9 7 8 11 5 13 17 14 17 14 115

aLacosamide, tedizolid phosphate, and isavuconazonium sulfate are administered either orally or intravenously. For simplicity, these drugs were only counted in the oral category. Downloaded from set. A summary of the total number of drug-substance approvals by year is by the enzyme systems involved in their metabolism without fractionation. More presented in Table 1. specifically, each drug was defined as having no major metabolites or as being For intravenous drugs, agents used as imaging agents, generally with extremely metabolized by P450 enzymes, non-P450 enzymes, or metabolized by both P450 short half-lives, were removed from the set. Last, prodrugs were also removed and non-P450 enzymes (mixed). A secondary assessment (method 2) used the from the main evaluation set. These drugs were compiled and evaluated as a fractional assignments for the contribution of P450 or non-P450 to each drug. The separate grouping. A summary of metrics for small-molecule drugs each year results of the method 2 assessment were summed for each year from 2006 to 2015, between 2006 and 2015 is presented in Table 2. for two 5-year periods (2006–2010 and 2011–2015), and for 2006–2015. dmd.aspetjournals.org For each small-molecule drug, a summary of the metabolites identified in Therefore, the relative contributions of P450 and non-P450 enzymes for drugs plasma, expired air, urine, and feces from the human ADME study was compiled. which fell into the mixed category for method 1 were assigned a fractional Metabolites that accounted for $10% of circulating radioactivity or $10% of assignment, thereby providing greater granularity to the data set. dose in expired air or excreta as a component of urine, feces, or a compilation of As a part of this secondary analysis, for metabolites whose primary bio- radioactivity in urine and feces were deemed “major” metabolites. For metabolites transformation was determined to be partially or entirely mediated by non-P450 that were reported at levels $10% in multiple matrices, the metabolite was enzymes, the enzyme(s) responsible were assigned and tabulated. Similar to what counted only once. The total number of major metabolites across matrices was is described earlier, if multiple enzymes were possibly responsible for a major summed, giving a total number of major metabolites per drug molecule. Drugs metabolite, then the metabolite was divided equally between the two enzymes. For at ASPET Journals on September 29, 2021 which showed sparse formation of metabolites or which produced multiple low- the sake of simplicity, esterases, amidases, or other hydrolytic enzymes that carried abundance (,10%) metabolites were specified as drugs with “no major metab- out hydrolytic biotransformations were combined and designated as “hydrolases.” olites” and were accounted for as such. Similarly, biotransformations resulting in reduction of a carbonyl are referred to as Data Analyses. The current evaluation is focused on defining the contribution “carbonyl reductases” and may be carried out by carbonyl reductase, aldo-keto of P450 and non-P450 enzymes to metabolism, not in terms of contribution to CL. reductases, or other enzymes which carry out similar biotransformations. The metabolism of the drugs included in the evaluation set focused on the primary Caveats of the Current Analyses. The primary goal of the current analyses biotransformation step, as this transformation and the enzyme system(s) re- was to evaluate the relative contribution of P450 versus non-P450 enzymes in the sponsible for the reaction(s) are of greatest interest due to their relationship to CL. metabolism of drugs. The current approach is also a consequence of certain Assignment of the contribution of a specific enzyme to CL of a drug is, of course, limitations of data availability. As such, there are some caveats worth describing: of utmost interest. However, this is not possible for the current evaluation for • For some drugs, only a portion of the mass balance data was reported or an several reasons. Human ADME metabolite data are reported as static percentages incomplete description or characterization of the metabolism was disclosed of circulating radioactivity or dose, not in terms of rates of formation. Again, by the sponsor. In these cases, only reported metabolite assignment and owing to the static nature of the data, other processes, such as reversible metabo- percentage data could be included. lism, reabsorption, and transporter-mediated uptake and efflux, are not accounted • Glucuronide conjugates are generally not stable in feces, and therefore, for. Additionally, for metabolites that are formed by multiple enzymes, the frac- their contribution to the total metabolism may be underappreciated. tional clearance through one particular enzyme cannot be defined using human • Multistep oxidations could involve both P450 and non-P450 enzymes, ADME data alone. Furthermore, an evaluation of metabolism after the initial e.g., conversion of a benzylic alcohol to a carboxylic acid. Additional biotransformation (subsequent metabolism) was considered. However, accounting for these transformations was complicated and, therefore, is not included in this evaluation. For drugs where one or more major metabolites were observed in plasma or excreta, each metabolite was assigned a designation of “P450” or “non-P450” and assigned 1 point based on the enzyme responsible for the primary step in its formation. For major metabolites where either a P450 or a non-P450 enzyme may be responsible for the primary biotransformation, the major metabolite was divided between P450 and non-P450 (i.e., 0.5 points each). The point totals for P450 and non-P450 were then divided by the total number of major metabolites so that the P450 and non-P450 reactions were fractions that would sum to 1.0. For example, if three major metabolites were determined for drug X, and two were P450-mediated and one was non-P450–mediated, the P450 component of drug X would be 0.67, whereas the non-P450 component would be 0.33, with the total of P450 and non-P450 equaling 1.00. Using the profile for each drug from the aforementioned analyses, the data were Fig. 1. Enzymes responsible for metabolic bioactivation of the 22 prodrugs examined in two ways. For the first method (method 1), the drugs were categorized approved by the FDA between 2006 and 2015. Non-P450 Metabolism of FDA-Approved Drugs: 2006–2015 1249

small-molecule approvals. The remainder of small-molecule drugs (30 drugs, 14%) fall under the category of “other routes” of administration, which includes inhalation/nasal spray, topical, subcutaneous, ophthalmic, or intramuscular. Drugs administered via these other routes of administration were removed from the analysis for a few reasons. The metabolism of these drugs is likely to involve a greater contribution of extrahepatic metabolism. Furthermore, concentrations of parent drug and metabolites in circulation and excreta are generally low because of the low doses administered and poor absorption encountered for drugs Fig. 2. Fractional assignment of FDA-approved intravenous and orally administered small-molecule drugs meeting acceptance criteria (2006–2015) which have no major administered by many of these routes. For several of the applications for metabolites or whose metabolites are formed by P450, non-P450, or a mix of both drugs in this subset, it is noted that levels of parent drug are extremely P450 and non-P450 enzymes. Categorization was carried out using method 1 as low or below the limit of quantitation. Although not included in this described in the Data Analyses section. evaluation, metabolism data for other routes of administration, where available, may be included in future analyses. characterization of non-P450 enzymes involved may not have been explored Because the main focus of this work is the metabolism of small- or reported. molecule drugs, the current evaluation focused on drugs administered • Multiple minor metabolites (,10%) formed by the same enzyme or via the two most prevalent routes of administration, intravenous and oral. enzyme group (i.e., P450 or non-P450) may additively contribute a major Downloaded from metabolic pathway and will not be appropriately accounted for. Similarly, Imaging agents were excluded from the set of intravenously administered multiple metabolites resulting from subsequent metabolism of a common drugs, as they generally have short half-lives and typically do not possess intermediate may not be properly attributed. “drug-like” properties. Additionally, prodrugs were removed from the • The contribution of enzymes to the formation of metabolites which are sets of intravenously and orally administered drugs, as these drugs possess derived from multiple enzymes may be underappreciated for one enzyme functionalities to improve ADME or physicochemical properties and and overstated for another. There is no correction factor for the contribution generally require metabolic bioactivation to generate the active drug. percentage of each enzyme (such as an fm value), and therefore, the Because ester and phosphate prodrugs are commonly used prodrug dmd.aspetjournals.org responsibility for the formation of the metabolite is divided equally between approaches (Clas et al., 2014; Wiemer and Wiemer, 2015), it was the enzymes (e.g., for an oxidative metabolite formed by four individual P450s and FMO1, the metabolite would be counted as 50% P450 and 50% non-P450). • The average development time for a drug is .10 years (DiMasi and Hanse, 2014). Thus, the drugs included in the evaluation represent chemical matter that was in the discovery setting 10–20 years prior. The chemical matter

currently being created and evaluated by medicinal chemists and drug- at ASPET Journals on September 29, 2021 metabolism scientists within the discovery setting may be significantly different in terms of the enzymes contributing to its metabolism. • The majority of ADME studies are carried out as single-dose studies, and therefore, do not represent steady-state levels of metabolites. Thus, the relative abundance of parent and metabolites may be different.

Results and Discussion As medicinal chemists and drug metabolism scientists more routinely mitigate P450-mediated metabolism, there is an expectation that drug metabolism will shift to non-P450 enzymes and processes (Pryde et al., 2010). Currently, only anecdotal data exist, indicating a movement away from P450-mediated metabolism. Evaluation of metabolism in the discovery phase is made difficult by a lack of access to data across the industry and a lack of definitive data. Additionally, metabolism in the discovery phase is often compound- or scaffold-dependent for a particular drug target. With these challenges in mind, attention was focused on data obtained from more definitive human radiolabeled ADME studies. Because human ADME data are commonly reported as part of drug applications, drugs approved by the U.S. FDA from 2006 to 2015 were used as the source of drugs included in the evaluation set. Over this time period, 293 medications were approved which, due to combination therapies, included 298 active ingredients (Table 1). The list of approved medications include 62 protein drugs, 6 peptide drugs, and 9 drugs that fall into a category of “other,” which comprises elemental/inorganic drugs, botanical drugs, and polymers. Drugs are by far the largest subset Fig. 3. Fraction of metabolism of approved intravenous and orally administered of approved drugs, tallying 221 drugs. Of the small molecule drugs small-molecule drugs meeting acceptance criteria by year characterized as having no approved, administration through the oral route (156 drugs, 71% major metabolites or metabolites which are formed by P450 or non-P450 enzymes. of small-molecule drugs) represents the largest subset of these drugs Data for drugs meeting acceptance criteria by year are presented as a percentage (A) or by number of drugs (B). Values presented on the top of each column (B) are the (Table 2). Intravenously administered drugs are the next largest cate- total number of drugs which meet acceptance criteria for that year. Categorization gory of small-molecule drugs, representing approximately 16% of all was carried out using method 2 as described in the Data Analyses section. 1250 Cerny

Fig. 4. Fractional assignment of approved intravenous and orally administered small-molecule drugs meeting acceptance criteria for 2006–2010 (A), 2011–2015 (B), and 2006-2015 (C) which have no major metabolites or whose metabolites are formed by P450 or non- P450 enzymes. Categorization was carried out using method 2 as described in the Data Analyses section. Downloaded from thought that the data set would be biased toward the enzymes involved in grouped and analyzed by year. Figure 3A presents the data for no major the bioactivation of the prodrugs (Fig. 1), and that these enzymes would metabolites, P450, and non-P450 by year for 2006–2015. The same data likely differ significantly from the majority of drugs evaluated. Despite are also presented in Fig. 3B in terms of number of drugs per year. The their removal from the larger set of drugs, data for the primary and P450 component for all but 3 years (2006, 2007, and 2008) remains at or subsequent metabolism of prodrugs were compiled. Due to the pre- above 50%. Non-P450 metabolism is also relatively consistent at ;20– viously stated reasons, the primary metabolism of prodrugs was 35%, with the exception of 2008 (64.6%) and 2010 (not present), where dmd.aspetjournals.org evaluated separately. Data for metabolites formed after or in addition a spike and dip, respectively, were seen in the non-P450 contribution. to the initial prodrug step are available and may be included in future The percentage of drugs with no major metabolites generally falls evaluations. As can be seen in Fig. 1, “hydrolase” enzymes represent between 10 and 25% for the majority of the years analyzed, which 86.4% (19 of 22 drugs) of the bioactivation reactions for prodrugs represents one to three compounds per year. approved between 2006 and 2015. Activation by kinases, glutathione, or Although the aforementioned assessment provides some chronolog- chemical transformation was found for one drug each. Clearly, ical data for categorization of the biotransformations for approved drugs combining prodrugs with non-prodrugs would significantly bias the which meet the assessment criteria, the number of drugs which meet the at ASPET Journals on September 29, 2021 larger data set toward hydrolytic enzymes. criteria for inclusion per year is generally small (7–18 drugs). The low After removal of drugs based on the aforementioned criteria, the numbers of drugs analyzed per year may result in a more easily biased resulting set of 125 drugs evaluated included 10 intravenously data set. For this reason, data sets over 5-year periods were also administered drugs and 115 drugs administered orally. The 96 small combined, which offers a larger and likely less variable data set for molecules not included in the set of drugs evaluated were removed analysis. Data for the 46 drugs approved between 2006 and 2010 which because they fell into the following categories: other routes of meet the acceptance criteria are presented in Fig. 4A. Likewise, data for administration (30), imaging agents (11), prodrugs (22), no ADME drugs approved between 2011 and 2015 (79 drugs) are presented in Fig. study performed (22), or insufficient data available (11). Using “major” 4B. A summary of all 125 drugs evaluated is presented in Fig. 4C. metabolites as indicators of route(s) of metabolism, the metabolism of Whether looking at 5-year time periods or the entire 10-year period, the 125 compounds can be divided into the following categories: no metabolism by P450 enzymes represents the largest percentage of major metabolites (22, 17.6%), P450 only (56, 44.8%), non-P450 only metabolism. Comparing the two 5-year groupings indicates that the non- (26, 20.8%), or a mixture of P450- and non-P450–mediated metabolism P450 component appears relatively similar at around 30%, and therefore, (21, 16.8%). Based on these values (Fig. 2), P450 enzymes account for the largest percentage of the metabolism of drugs receiving recent FDA approval. However, non-P450 enzymes, alone (20.8%) or in combination with compounds with mixed metabolism (37.6%), represent a substantial portion of the metabolism of these drugs. A closer examination of the ADME data for the 22 drugs which fell into the category of no major metabolites shows that, for these drugs, ;50% of the dose or greater is observed in the urine (8 drugs) or feces (12 drugs) as unchanged drug. Only two drugs (darunavir and ixabepilone) exhibited minor levels (,10%) of unchanged parent drug in the urine and feces. For both of these drugs, multiple, low-level metabolites were observed, indicating that metabolism is likely responsible for a significant portion of the CL of these drugs. Together, these data show that only a small portion of drugs in the “no major metabolites” category are significantly metabolized. In an effort to obtain more detailed data to describe the initial Fig. 5. Fractional assignment of FDA-approved intravenous and orally administered – metabolic step for these drugs, the initial biotransformations leading to small-molecule drugs meeting acceptance criteria for 2006 2015 which have no major metabolites or whose metabolites are formed by P450 by specific non-P450 major metabolites of these drugs were tabulated based on the relative enzymes. Categorization was carried out using method 2 as described in the Data contribution of P450 or non-P450 enzymes. Metabolism data were then Analyses section. Non-P450 Metabolism of FDA-Approved Drugs: 2006–2015 1251 the non-P450 contribution over the 10 years is also similar. However, the focused efforts on diminishing the involvement of P450-mediated percentage representing P450 metabolism and no major metabolites metabolism. All other non-P450 enzymes identified in this evaluation varies by .10% between the two 5-year spans of time. For the period of were relatively minor (,1%) and included sulfotransferases (0.8%), 2006–2010, P450 metabolism accounts for 43.1%, whereas it increases cytidine deaminase (0.8%), nucleotidases (0.8%), alcohol/aldehyde to 58.0% for 2011–2015. For the same two time periods, the no major dehydrogenase (0.4%), flavin-containing monooxygenases (0.3%), metabolites component decreases from 28.3 to 11.4%. glutathione conjugation (0.3%), gut microbes (0.3%), and undefined/ The current assessment of the metabolism of drugs approved by the unknown (0.3%). A number of these minor contributing enzymes fall FDA between 2006 and 2015 indicates that P450-mediated metabolism outside of the “usual” drug-metabolizing enzymes and may be the result is still the most common route of metabolism of the drugs evaluated of the drug targets and target space captured in the evaluation set. (52.5%). Regardless of the method of assessment, metabolism by non- The introduction of novel drug targets and drug-targeting approaches P450 enzymes contributes to a significant portion (;30%) of the to the drug-discovery environment will likely bring innovative ap- metabolism of these drugs. Although not as prominent as metabolism by proaches to small-molecule drugs. Whether this will result in an in- P450 and non-P450 enzymes, drugs which exhibit no major metabolites creased role in non-P450 metabolism for drugs of the future is yet to be represent a nontrivial, but more variable portion of the total. answered. Additionally, one may also question whether the introduction When looking at the contribution of non-P450 metabolism over time, of enzyme families which are not as well characterized or as commonly there is no apparent trend toward increasing contributions of non-P450 encountered in drug metabolism as P450 enzymes will provide benefits enzymes to the metabolism of these drugs. In actuality, the contribution or greater challenges to drug discovery and development. Remaining in Downloaded from of non-P450 enzymes remains relatively constant over time, with 2 of the area of P450-mediated metabolism may afford an easier discovery the 10 years displaying higher (2008) or lower (2010) involvement. As and development path, as the enzymes and methods for their evaluation stated earlier, based on current industry timelines for drug development are well developed and widely deployed. Whether medicinal chemists (DiMasi and Hansen, 2014), the current set of drugs likely emerged from and drug-metabolism scientists can exert sufficient control over the design drug discovery .10 years ago. Despite this fact, the current data set is of drug molecules which engage emerging drug targets and which remain the first to provide an evaluation of P450 versus non-P450 metabolism in this well characterized space of P450 metabolism will likely only be for drugs approved over a 10-year period. This evaluation also provides answered with more time and greater scrutiny of emerging drugs. dmd.aspetjournals.org a starting point for comparison for future evaluations. Because an assessment such as this is not possible in the research setting due to the Acknowledgments limitations in data type and access to data, future evaluation of this nature The author thanks Donald Tweedie for support, guidance, and thoughtful with an ever-increasing data set will be needed to determine if the suggestions throughout the compilation and writing of this manuscript. The author also thanks Melissa Kramer for helpful discussions and critical reading of this perceived changes are indeed occurring in the discovery space. manuscript. Therefore, the results of this evaluation will serve as a database for recurring analyses of the involvement of non-P450 enzymes in the Authorship Contributions at ASPET Journals on September 29, 2021 metabolism of emerging drugs. Based on a longer duration, a larger data Participated in research design: Cerny. set, and a greater appreciation of non-P450 reactions, it is expected that Performed data analysis: Cerny. future analyses will be more informative. Wrote or contributed to the writing of the manuscript: Cerny. Figure 5 depicts the individual enzymes and enzyme classes re- – sponsible for the non-P450 mediated metabolism. Interestingly, metab- References olism by non-P450 enzymes is carried out by a relatively limited set of Armstrong RN (1997) Structure, catalytic mechanism, and evolution of the glutathione transferases. enzymes, with UGTs and hydrolases being the most dominant, Chem Res Toxicol 10:2–18. representing 11.7 and 10.8%, respectively. Although the predominance Bachovchin DA and Cravatt BF (2012) The pharmacological landscape and therapeutic potential of serine hydrolases. Nat Rev Drug Discov 11:52–68. of UGT metabolism is not surprising based on a previous analysis Beaumont C, Young GC, Cavalier T, and Young MA (2014) Human absorption, distribution, (Williams et al., 2004), the high percentage of metabolism by hydrolases metabolism and excretion properties of drug molecules: a plethora of approaches. Br J Clin Pharmacol 78:1185–1200. is somewhat unanticipated, especially in light of the fact that prodrugs Bohnert T, Patel A, Templeton I, Chen Y, Lu C, Lai G, Leung L, Tse S, Einolf HJ, and Wang YH, have been removed from the evaluation set. The hydrolase-mediated et al. (2016) Evaluation of a new molecular entity as a victim of metabolic drug-drug interactions: an industry perspective. Drug Metab Dispos DOI: dmd.115.069096 [published ahead of print]. metabolism of 16 of the 19 drugs involves hydrolysis of an amide bond. 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DiMasi JAGH and Hansen RW(2014) Innovation in the pharmaceutical industry: new estimates of Dalvie and Zientek, 2015) indicates that non-P450 enzymes, such as R&D costs. Tufts Center for the Study of Drug Development, Boston, November 18, 2014 AO, may represent areas of emerging importance. Increased interest in (http://csdd.tufts.edu/news/complete_story/cost_study_press_event_webcast). ’ Dittrich Ch, Greim G, Borner M, Weigang-Köhler K, Huisman H, Amelsberg A, Ehret A, Wanders AO may be due, in part, to the enzyme s absence in some preclinical J, Hanauske A, and Fumoleau P (2002) Phase I and pharmacokinetic study of BIBX 1382 BS, an species, which has contributed to some well documented drug failures epidermal growth factor receptor (EGFR) inhibitor, given in a continuous daily oral administration. Eur J Cancer 38:1072–1080. 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INTRAVENOUS DRUGS: 2006 – 2015

Matthew A. Cerny

Drug Metabolism and Disposition

Supplemental Table 1. Complete list of FDA approved drugs 2006 – 2015

Approval Route of Drug Name Active Ingredients Drug Type Exclusion Criteria Reference Date Administration Savaysa edoxaban 1/8/2015 Small Molecule Oral N.A. 1-3 Cosentyx secukinumab 1/21/2015 Protein Subcutaneous Drug Type 4 Natpara parathyroid horomone 1/23/2015 Peptide IV Drug Type 5 Ibrance palbociclib 2/3/2015 Small Molecule Oral N.A. 6 Lenvima lenvatinib 2/13/2015 Small Molecule Oral N.A. 7-10 Farydak panobinostat 2/23/2015 Small Molecule Oral N.A. 11-14 ceftazidime (1989) Small Molecule Avycaz 2/25/2015 IV N.A. 15, 16 avibactam Combination Cresemba isavuconazonium sulfate 3/6/2015 Small Molecule Oral/IV Prodrug 17-19 Unituxin dinutuximab 3/10/2015 Protein IV Drug Type 20 Cholbam cholic acid 3/17/2015 Small Molecule Oral No ADME Study 21-23 Corlanor ivabradine 4/15/2015 Small Molecule Oral N.A. 24-26 Kybella deoxycholic acid 4/29/2015 Small Molecule Subcutaneous Route 27 Viberzi eluxadoline 5/27/2015 Small Molecule Oral Insufficient Data 28 Kengreal cangrelor 6/22/2015 Small Molecule IV N.A. 29, 30 lumacaftor Small Molecule Orkambi 7/2/2015 Oral N.A. 31, 32 ivacaftor (2012) Combination sacubitril Small Molecule Entresto 7/7/2015 Oral Prodrug 33, 34 valsartan (1996) Combination Rexulti brexpiprazole 7/10/2015 Small Molecule Oral N.A. 35 Praluent alirocumab 7/24/2015 Protein Subcutaneous Drug Type 36 Odomzo sonidegib 7/24/2015 Small Molecule Oral N.A. 37-39 Daklinza daclatasvir 7/24/2015 Small Molecule Oral N.A. 40, 41 Addyi flibanserin 8/18/2015 Small Molecule Oral N.A. 42 Repatha evolocumab 8/27/2015 Protein Subcutaneous Drug Type 43 Varubi rolapitant 9/2/2015 Small Molecule Oral N.A. 44 Xuriden uridine triacetate 9/4/2015 Small Molecule Oral Prodrug 45 Vraylar cariprazine 9/17/2015 Small Molecule Oral No ADME Study 46 trifluridine (1980) Small Molecule Lonsurf 9/22/2015 Oral No ADME Study 47 tipiracil Combination Tresiba insulin degludec 9/25/2015 Protein Subcutaneous Drug Type 48 Aristada aripiprazole lauroxil 10/6/2015 Small Molecule IM Route 49 Praxbind idarucizumab 10/16/2015 Protein IV Drug Type 50 Veltassa patiromer 10/21/2015 Polymer Oral Drug Type 51 Yondelis trabectedin 10/23/2015 Small Molecule IV Insufficient Data 52-56 Strensiq asfotase alfa 10/23/2015 Protein Subcutaneous Drug Type 57 Nucala mepolizumab 11/4/2015 Protein Subcutaneous Drug Type 58 elvitegravir (2014) cobicistat (2014) Small Molecule Genvoya 11/5/2015 Oral Prodrug 59-61 emtricitabine (2004) Combination tenofovir alafenamide Cotellic cobimetinib 11/10/2015 Small Molecule Oral N.A. 62-64 Tagrisso osimertinib 11/13/2015 Small Molecule Oral Insufficient Data 65 Darzalex daratumumab 11/16/2015 Protein IV Drug Type 66 Ninlaro ixazomib 11/20/2015 Small Molecule Oral Prodrug 67 Portrazza necitumumab 11/24/2015 Protein IV Drug Type 68 Empliciti elotuzumab 11/30/2015 Protein IV Drug Type 69 Kanuma sebelipase alfa 12/8/2015 Protein IV Drug Type 70 Alecensa alectinib 12/11/2015 Small Molecule Oral N.A. 71 Bridion sugammadex 12/11/2015 Small Molecule IV N.A. 72 Uptravi selexipag 12/22/2015 Small Molecule Oral Prodrug 73-76 Zurampic lesinurad 12/22/2015 Small Molecule Oral N.A. 77 Farxiga dapagliflozin 1/8/2014 Small Molecule Oral N.A. 78-80 Hetlioz tasimelteon 1/31/2014 Small Molecule Oral N.A. 81, 82 Vimizim elosulfase alfa 2/14/2014 Protein IV Drug Type 83 Northera droxidopa 2/18/2014 Small Molecule Oral No ADME Study 84 Myalept metreleptin 2/24/2014 Protein Subcutaneous Drug Type 85 Neuraceq florbetaben F 18 3/19/2014 Small Molecule IV Imaging Agent 86 Impavido miltefosine 3/19/2014 Small Molecule Oral No ADME Study 87 Otezla apremilast 3/21/2014 Small Molecule Oral N.A. 88-90 Tanzeum albiglutide 4/15/2014 Protein Subcutaneous Drug Type 91 Cyramza ramucirumab 4/21/2014 Protein IV Drug Type 92 Sylvant siltuximab 4/23/2014 Protein IV Drug Type 93 Zykadia ceritinib 4/29/2014 Small Molecule Oral N.A. 94, 95 Zontivity vorapaxar 5/8/2014 Small Molecule Oral N.A. 96-98 Entyvio vedolizumab 5/20/2014 Protein IV Drug Type 99 Dalvance dalbavancin 5/23/2014 Small Molecule IV No ADME Study 100, 101 Jublia efinaconazole 6/6/2014 Small Molecule Topical Route 102 Sivextro tedizolid phosphate 6/20/2014 Small Molecule Oral/IV Prodrug 103-106 Beleodaq belinostat 7/3/2014 Small Molecule IV No ADME Study 107 Kerydin tavaborole 7/7/2014 Small Molecule Topical Route 108 Zydelig idelalisib 7/23/2014 Small Molecule Oral N.A. 109-111 Striverdi Respimat olodaterol 7/31/2014 Small Molecule Inhalation Route 112 Jardiance empagliflozin 8/1/2104 Small Molecule Oral N.A. 113-117 Orbactiv oritavancin 8/6/2014 Small Molecule IV No ADME Study. 118, 119 Belsomra suvorexant 8/13/2014 Small Molecule Oral N.A. 120 Plegridy peginterferon beta-1a 8/15/2014 Protein Subcutaneous Drug Type 121 Cerdelga eliglustat 8/19/2014 Small Molecule Oral N.A. 122, 123 Keytruda pembrolizumab 9/4/2014 Protein IV Drug Type 124 Movantik naloxegol 9/16/2014 Small Molecule Oral N.A. 125-127 Trulicity dulaglutide 9/18/2014 Protein Subcutaneous Drug Type 128 129, 130 ledipasvir Small Molecule N.A. Harvoni 10/10/2014 Oral sofosbuvir (2013) Combination

netupitant Small Molecule Akynzeo 10/10/2014 Oral N.A. 131-133 palonosetron (2003) Combination Lumason sulfur hexafluoride lipid microsphere 10/10/2014 Inorganic IV Drug Type 134 Ofev nintedanib 10/15/2014 Small Molecule Oral N.A. 135-138 Esbriet pirfenidone 10/15/2014 Small Molecule Oral No ADME Study 139, 140 Blincyto blinatumomab 12/3/2014 Protein IV Drug Type 141 Xtoro finafloxacin 12/17/2014 Small Molecule Topical (Otic) Route 142 Lynparza olaparib 12/19/2014 Small Molecule Oral N.A. 143, 144 paritaprevir ritonavir (1996) Small Molecule Viekira Pak 12/19/2014 Oral N.A. 145, 146 dasabuvir Combination ombitasvir ceftolozane Small Molecule Zerbaxa 12/19/2014 IV N.A. 147, 148 tazobactam (1993) Combination Rapivab peramivir 12/19/2014 Small Molecule IV No ADME Study 149 Opdivo nivolumab 12/22/2014 Protein IV Drug Type 150 Nesina alogliptin 1/25/2013 Small Molecule Oral N.A. 151, 152 Kynamro mipomersen sodium 1/29/2013 Antisense Drug Subcutaneous Drug Type 153 Pomalyst pomalidomide 2/8/2013 Small Molecule Oral N.A. 154-157 Kadcyla ado-trastuzumab emtansine 2/22/2013 Protein (ADC) IV Drug Type 158 Osphena ospemifene 2/26/2013 Small Molecule Oral Insufficient Data 159-162 Subcutaneous Intradermal Lymphoseek technetium Tc 99m tilmanocept 3/13/2013 Elemental Drug Type 163 Subareolar Peritumoral Dotarem gadoterate meglumine 3/20/2013 Small Molecule IV Imaging Agent 164 Tecfidera dimethyl fumarate 3/27/2013 Small Molecule Oral N.A. 165-167 Invokana canagliflozin 3/29/2013 Small Molecule Oral N.A. 168-171 fluticasone furoate (2007) Small Molecule Breo Ellipta 5/10/2013 Inhalation Route 172 vilanterol Combination Xofigo radium Ra 223 dichloride 5/15/2013 Elemental IV Drug Type 173 Tafinlar dabrafenib 5/29/2013 Small Molecule Oral N.A. 174-177 Mekinist trametinib 5/29/2013 Small Molecule Oral N.A. 178-180 Gilotrif afatinib 7/12/2013 Small Molecule Oral N.A. 181-183 Tivicay dolutegravir 8/12/2013 Small Molecule Oral N.A. 184-187 Brintellix vortioxetine 9/30/2013 Small Molecule Oral N.A. 188-191 conjugated estrogens (1942) Small Molecule Duavee 10/3/2013 Oral N.A. 192-196 bazedoxifene Combination Adempas riociguat 10/8/2013 Small Molecule Oral N.A. 197, 198 Opsumit macitentan 10/18/2013 Small Molecule Oral N.A. 199-201 Vizamyl flutemetamol F 18 10/25/2013 Small Molecule IV Imaging Agent 202 Gazyva obinutuzumab 11/1/2013 Protein IV Drug Type 203 Aptiom eslicarbazepine acetate 11/8/2013 Small Molecule Oral Prodrug 204-207 Imbruvica ibrutinib 11/13/2013 Small Molecule Oral N.A. 208-210 Luzu luliconozole 11/14/2013 Small Molecule Topical Route 211 Olysio simeprevir 11/22/2013 Small Molecule Oral N.A. 212, 213 Sovaldi sofosbuvir 12/6/2013 Small Molecule Oral Prodrug 214-218 umeclidinium Small Molecule Anoro Ellipta 12/18/2013 Inhalation Route 219 vilanterol (5/10/2013) Combination Voraxaze glucarpidase 1/17/2012 Protein IV Drug Type 220 Picato ingenol mebutate 1/23/2012 Small Molecule Topical Route 221 Inlyta axitinib 1/27/2012 Small Molecule Oral N.A. 222-225 Erivedge vismodegib 1/30/2012 Small Molecule Oral N.A. 226-229 Kalydeco ivacaftor 1/31/2012 Small Molecule Oral N.A. 230, 231 Zioptan tafluprost 2/10/2012 Small Molecule Opthalmic Route 232 Lucinactant (sinapultide, 1,2-dipalmitoyl-sn- Protein Small Surfaxin glycero-3-phosphocholine, 1- 3/6/2012 Molecule Intratracheal Drug Type 233 palmitoyl-2-oleoyl-sn-glycero-3- Combination phosphoglycerol, and palmitic acid) IV Omontys peginesatide 3/27/2012 Protein Drug Type 234 Subcutaneous Amyvid florbetapir F18 4/6/2012 Small Molecule IV Imaging Agent 235 Stendra avanafil 4/27/2012 Small Molecule Oral N.A. 236, 237 Elelyso taliglucerase alfa 5/1/2012 Protein IV Drug Type 238 Perjeta pertuzumab 6/8/2012 Protein IV Drug Type 239 Belviq lorcaserin hydrochloride 6/27/2012 Small Molecule Oral N.A. 240-243 Myrbetriq mirabegron 6/28/2012 Small Molecule Oral N.A. 244-246 sodium picosulfate Small Molecule Prepopik magnesium oxide 7/16/2012 Oral No ADME Study 247 Combination citric acid Kyprolis carfilzomib 7/20/2012 Small Molecule IV No ADME Study 248, 249 Tudorza Pressair aclidinium bromide 7/23/2012 Small Molecule Inhalation Route 250 Zaltrap ziv-aflibercept 8/3/2012 Protein IV Drug Type 251 elvitegravir cobicistat Small Molecule Stribild 8/27/2012 Oral N.A. 252-256 emtricitabine (2006) Combination tenofovir disoproxil fumarate (2001) Neutroval tbo-filgrastim 8/29/2012 Protein Subcutaneous Drug Type 257 Linzess linaclotide 8/30/2012 Peptide Oral Drug Type 258, 259 Xtandi enzalutamide 8/31/2012 Small Molecule Oral N.A. 260-262 Bosulif bosutinib 9/4/2012 Small Molecule Oral N.A. 263, 264 Aubagio teriflunomide 9/12/2012 Small Molecule Oral N.A. 265-268 Choline C 11 choline C 11 9/12/2012 Small Molecule IV Imaging Agent 269 Stivarga regorafenib 9/27/2012 Small Molecule Oral N.A. 270-272 Jetrea ocriplasmin 10/17/2012 Protein Intravitreal Drug Type 273 Fycompa perampanel 10/22/2012 Small Molecule Oral Insufficient Data 274, 275 Synribo omacetaxine mepesuccinate 10/26/2012 Small Molecule Subcutaneous Route 276 Xeljanz tofacitinib 11/6/2012 Small Molecule Oral N.A. 277-279 Cometriq cabozantinib 11/29/2012 Small Molecule Oral N.A. 280-282 Iclusig ponatinib 12/14/2012 Small Molecule Oral N.A. 283, 284 Raxibacumab raxibacumab 12/14/2012 Protein IV Drug Type 285 Signifor pasireotide 12/14/2012 Peptide IV Drug Type 286 Gattex teduglutide 12/21/2012 Peptide IV Drug Type 287 Juxtapid lomitapide 12/21/2012 Small Molecule Oral N.A. 288, 289 Sirturo bedaquiline 12/28/2012 Small Molecule Oral No ADME Study 290, 291 Eliquis apixaban 12/28/2012 Small Molecule Oral N.A. 292-295 Fulyzaq crofelemer 12/31/2012 Botanical Drug Oral Drug Type 296 DaTSCAN ioflupane (123I) 1/14/2011 Small Molecule IV Imaging Agent 297 Spinosad Small Molecule Natroba 1/18/2011 Topical Route 298 (~17:3 spinosyn A:spinosyn D) Mixture Viibryd vilazodone 1/21/2011 Small Molecule Oral N.A. 299 Edarbi azilsartan medoxomil 2/25/2011 Small Molecule Oral Prodrug 300-302 Daliresp roflumilast 2/28/2011 Small Molecule Oral N.A. 303-306 Benlysta belimumab 3/9/2011 Protein IV Drug Type 307 Gadavist gadobutrol 3/14/2011 Small Molecule IV Imaging Agent 308 Yervoy ipilimumab 3/25/2011 Protein IV Drug Type 309 Caprelsa vandetanib 4/6/2011 Small Molecule Oral Insufficient Data 310, 311 Horizant gabapentin enacarbil 4/6/2011 Small Molecule Oral Prodrug 312-314 Zytiga abiraterone acetate 4/28/2011 Small Molecule Oral Prodrug 315-317 Tradjenta linagliptin 5/2/2011 Small Molecule Oral N.A. 318-320 Victrelis boceprevir 5/13/2011 Small Molecule Oral N.A. 321-323 Edurant rilpivirine 5/20/2011 Small Molecule Oral N.A. 324-326 Incivek telaprevir 5/23/2011 Small Molecule Oral N.A. 327-330 Dificid fidaxomicin 5/27/2011 Small Molecule Oral No ADME Study 331, 332 Potiga ezogabine 6/10/2011 Small Molecule Oral N.A. 333-335 Nulojix belatacept 6/15/2011 Protein IV Drug Type 336 Arcapta Neohaler indacaterol maleate 7/1/2011 Small Molecule Inhalation Route 337 Xarelto rivaroxaban 7/1/2011 Small Molecule Oral N.A. 338-341 Brilinta ticagrelor 7/20/2011 Small Molecule Oral N.A. 342-345 Zelboraf vemurafenib 8/17/2011 Small Molecule Oral N.A. 346-348 Adcetris brentuximab vedotin 8/19/2011 Protein IV Drug Type 349 Firazyr icatibant acetate 8/25/2011 Small Molecule Subcutaneous Route 350 Xalkori crizotinib 8/26/2011 Small Molecule Oral N.A. 351, 352 Ferriprox deferiprone 10/14/2011 Small Molecule Oral No ADME Study 353-355 Onfi clobazam 10/21/2011 Small Molecule Oral N.A. 356-358 Jakafi ruxolitinib 11/16/2011 Small Molecule Oral N.A. 359-361 Erwinaze asparaginase erwinia chrysanthemi 11/18/2011 Protein IM Drug Type 362 Eylea aflibercept 11/18/2011 Protein IV Drug Type 363 IV Actemra tocilizumab 1/8/2010 Protein Drug Type 364 Subcutaneous Ampyra dalfampridine 1/22/2010 Small Molecule Oral N.A. 365-367 Victoza liraglutide 1/25/2010 Peptide Subcutaneous Drug Type 368 Xiaflex clostridial collagenase 2/2/2010 Protein Intralesional Drug Type 369 VPRIV velaglucerase alfa 2/26/2010 Protein IV Drug Type 370 Carbaglu carglumic acid 3/18/2010 Small Molecule Oral N.A. 371, 372 Asclera polidocanol 3/30/2010 Small Molecule IV No ADME Study 373 estradiol valerate(1954) Small Molecule Natazia 5/6/2010 Oral N.A. 374 dienogest Combination Lumizyme alglucosidase alfa 5/24/2010 Protein IV Drug Type 375 Prolia denosumab 6/1/2010 Protein Subcutaneous Drug Type 376 Jevtana cabazitaxel 6/17/2010 Small Molecule IV N.A. 377-379 Lastacaft alcaftadine 7/28/2010 Small Molecule Topical Route 380 Xeomin incobotulinum toxin A 7/30/2010 Protein IM Drug Type 381 Ella ulipristal acetate 8/13/2010 Small Molecule Oral N.A. 382-384 Krystexxa pegloticase 9/14/2010 Protein IV Drug Type 385 Gilenya fingolimod 9/21/2010 Small Molecule Oral Prodrug 386-389 Pradax dabigatran etexilate mesylate 10/19/2010 Small Molecule Oral Prodrug 390-395 Latuda lurasidone 10/28/2010 Small Molecule Oral N.A. 396, 397 Teflaro ceftaroline fosamil 10/29/2010 Small Molecule IV Prodrug 398, 399 Egrifta tesamorelin 11/10/2010 Peptide Subcutaneous Drug Type 400 Halaven eribulin mesylate 11/15/2010 Small Molecule IV N.A. 401, 402 Savella milnacipran 1/14/2009 Small Molecule Oral N.A. 403, 404 Uloric febuxostat 2/13/2009 Small Molecule Oral N.A. 405-407 Afinitor everolimus 3/30/2009 Small Molecule Oral N.A. 408-411 artemether Small Molecule Coartem 4/7/2009 Oral No ADME Study 412 lumefantrine Combination Ulesfia benzyl alcohol 4/9/2009 Small Molecule Topical Route 413 Simponi golimumab 4/24/2009 Protein Subcutaneous Drug Type 414 Dysport abobotulinum toxin A 4/29/2009 Protein IM Drug Type 415 Fanapt iloperidone 5/6/2009 Small Molecule Oral N.A. 409, 410, 416 Samsca tolvaptan 5/19/2009 Small Molecule Oral N.A. 417-419 Besivance besifloxacin 5/28/2009 Small Molecule Topical Route 420 Ilaris canakinumab 6/17/2009 Protein Subcutaneous Drug Type 421 Multaq dronedarone 7/1/2009 Small Molecule Oral N.A. 422-424 Effient prasugrel 7/10/2009 Small Molecule Oral Prodrug 425-429 Onglyza saxagliptin 7/31/2009 Small Molecule Oral N.A. 430-434 Livalo pitavastatin 8/3/2009 Small Molecule Oral N.A. 431-433, 435 Saphris asenapine 8/13/2009 Small Molecule Oral N.A. 436-438 Sabril vigabatrin 8/21/2009 Small Molecule Oral N.A. 439, 440 Bepreve bepotastine besilate 9/8/2009 Small Molecule Opthalmic Route 441 Vibativ telavancin 9/11/2009 Small Molecule IV N.A. 442, 443 Folotyn pralatrexate 9/24/2009 Small Molecule IV No ADME Study 444 Stelara ustekinumab 9/25/2009 Protein Subcutaneous Drug Type 445 Votrient pazopanib 10/19/2009 Small Molecule Oral N.A. 446-448 Arzerra ofatumumab 10/26/2009 Protein IV Drug Type 449 Istodax romidepsin 11/5/2009 Small Molecule IV Prodrug 450 Qutenza capsaicin 11/16/2009 Small Molecule Topical Route 451 Kalbitor ecallantide 12/1/2009 Protein Subcutaneous Drug Type 452 Intelence etravirine 1/18/2008 Small Molecule Oral N.A. 453-455 Arcalyst rilonacept 2/27/2008 Protein Subcutaneous Drug Type 456 Pristiq desvenlafaxine succinate 2/29/2008 Small Molecule Oral Insufficient Data 457, 458 Treanda bendamustine 3/20/2008 Small Molecule IV Insufficient data 459 Lexiscan regadenoson 4/10/2008 Small Molecule IV Imaging Agent 460, 461 Cimzia certolizumab pegol 4/22/2008 Protein Subcutaneous Drug Type 462 Relistor methylnaltrexone bromide 4/24/2008 Small Molecule Subcutaneous Route 463 Entereg alvimopan 5/20/2008 Small Molecule Oral N.A. 464, 465 Durezol difluprednate 6/23/2008 Small Molecule Topical Route 466 Eovist gadoxetate disodium 7/3/2008 Small Molecule IV Imaging Agent 467 Cleviprex clevidipine butyrate 8/1/2008 Small Molecule IV Prodrug 468 Xenazine tetrabenazine 8/15/2008 Small Molecule Oral N.A. 469-471 Nplate romiplostim 8/22/2008 Protein Subcutaneous Drug Type 472 AdreView iobenguane sulfate I-123 9/19/2008 Small Molecule IV Imaging Agent 473 Rapaflo silodosin 10/8/2008 Small Molecule Oral N.A. 474-477 Vimpat lacosamide 10/28/2008 Small Molecule Oral/IV N.A. 478-482 Toviaz fesoterodine fumarate 10/31/2008 Small Molecule Oral Prodrug 483, 484 Banzel rufinamide 11/14/2008 Small Molecule Oral N.A. 485-487 Promacta eltrombopag olamine 11/20/2008 Small Molecule Oral N.A. 488-490 Nucynta tapentadol 11/20/2008 Small Molecule Oral N.A. 491, 492 Lusedra fospropofol disodium 12/12/2008 Small Molecule IV Prodrug 493 Mozobil plerixafor 12/15/2008 Small Molecule Subcutaneous Route 494 Ablavar gadofosveset trisodium 12/22/2008 Small Molecule IV Imaging Agent 495 Firmagon degarelix acetate 12/24/2008 Small Molecule Subcutaneous Route 496 Vyvance lisdexamfetamine dimesylate 2/23/2007 Small Molecule Oral Prodrug 497 Tekturna aliskiren 3/5/2007 Small Molecule Oral N.A. 498-500 Tykerb lapatinib 3/13/2007 Small Molecule Oral N.A. 501-505 Soliris eculizumab 3/16/2007 Protein IV Drug Type 506 Altabax retapamulin 4/12/2007 Small Molecule Topical Route 507 Topical Neupro rotigotine 5/9/2007 Small Molecule Route 508 Transdermal Torisel temsirolimus 5/30/2007 Small Molecule IV Prodrug 509-511 Letairis ambrisentan 6/15/2007 Small Molecule Oral N.A. 512, 513 Selzentry maraviroc 8/6/2007 Small Molecule Oral N.A. 514-516 Ammonia N13 ammonia N-13 8/23/2007 Inorganic IV Drug Type 517 IM Somatuline Depot lanreotide 8/30/2007 Small Molecule Route 518 Subcutaneous Doribax doripenem 10/12/2007 Small Molecule IV N.A. 519-521 Isentress raltegravir 10/12/2007 Small Molecule Oral N.A. 522-524 Ixempra ixabepilone 10/16/2007 Small Molecule IV N.A. 525, 526 Tasigna nilotinib 10/29/2007 Small Molecule Oral N.A. 527, 528 methoxy polyethylene glycol-epoetin IV Mircera 11/14/2007 Protein Drug Type 529 beta Subcutaneous Kuvan sapropterin 12/13/2007 Small Molecule Oral No ADME Study 530, 531 Bystolic nebivolol 12/17/2007 Small Molecule Oral N.A. 532 Sutent sunitinib 1/26/2006 Small Molecule Oral N.A. 533-535 Ranexa ranolazine 1/27/2006 Small Molecule Oral N.A. 536-538 Amitiza lubiprostone 1/31/2006 Small Molecule Oral Insufficient Data 539 Eraxis anidulafungin 2/17/2006 Peptide IV Drug Type 540 Myozyme alglucosidase alfa 4/28/2006 Protein IV Drug Type 541 Dacogen decitabine 5/2/2006 Small Molecule IV N.A. 542, 543 Chantix varenicline 5/10/2006 Small Molecule Oral N.A. 544-546 Azilect rasagiline 5/16/2006 Small Molecule Oral Insufficient Data 547, 548 Prezista darunavir 6/23/2006 Small Molecule Oral N.A. 549-551 Sprycel dasatinib 6/28/2006 Small Molecule Oral N.A. 552-556 Lucentis ranibizumab 6/30/2006 Protein Intravitreal Drug Type 557 avobenzone (1992) Small Molecule Anthelios SX ecamsule 7/21/2006 Topical Route 558 Combination octocrylene Elaprase idursulfase 7/24/2006 Protein IV Drug Type 559 Noxafil posaconazole 9/15/2006 Small Molecule Oral N.A. 560-563 Vectibix panitumumab 9/27/2006 Protein IV Drug Type 564 bismuth subcitrate potassium Small Molecule Pylera metronidazole (1959) 9/28/2006 Oral No ADME Study 565 Combination tetracycline (1953) Zolinza vorinostat 10/6/2006 Small Molecule Oral Insufficient Data 566 Januvia sitagliptin 10/16/2006 Small Molecule Oral N.A. 567-569 Omnaris ciclesonide 10/20/2006 Small Molecule Nasal Spray Route 570 Tyzeka telbivudine 10/25/2006 Small Molecule Oral N.A. 571-573 Veregen sinecatechins 10/31/2006 Botanical Drug Topical Drug Type 574 Invega paliperidone 12/19/2006 Small Molecule Oral N.A. 575-577 N.A. – Not Applicable

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