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PREVALENCE OF NON-CYTOCHROME P450-MEDIATED IN FDA

APPROVED ORAL AND INTRAVENOUS DRUGS: 2006 – 2015

Downloaded from Matthew A. Cerny

dmd.aspetjournals.org

Pharmacokinetics, Pharmacodynamics, and , Pfizer, Inc., Groton, CT

at ASPET Journals on September 27, 2021

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Running Title: Non-P450 Metabolism of FDA Approved Drugs: 2006 – 2015

Corresponding Author: Matthew A. Cerny, Pfizer, Inc., Groton, CT, 06340 [email protected]

Number of:

Text Pages: 20

Tables: 2

Figures: 5 Downloaded from

References: 72

Number of Words in: dmd.aspetjournals.org Abstract: 242

Introduction: 1182 (942 with reference citations removed)

Results and Discussion: 2115 at ASPET Journals on September 27, 2021

Abbreviations: CL, clearance; F, oral ; ADME, absorption, distribution, metabolism, and excretion; FDA, Food and Drug Administration; EMA; European Medicines

Agency; P450, cytochrome P450; UGT, 5'-diphospho-glucuronosyltransferase; FMO,

Flavin-containing monooxygenase; AO, aldehyde oxidase, XO, oxidase; MAO, monoamine oxidase; CBR, carbonyl reductase; AKR, aldo-keto reductase; ALDH, aldehyde dehydrogenase; ADH, dehydrogenase; NAT, N-acetyl transferase; GST, glutathione S- transferase; SULT, sulfotransferase; MT, methyltransferase; CES, carboxylesterase; NDA, New

Drug Application; BLA, Biological License Application; ADC, antibody drug conjugate; DDI, drug-drug interaction.

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Abstract

In recent years, claims of increased involvement of non-cytochrome P450 (non-P450) in the metabolism of drugs have appeared in the literature. However, no temporal summaries of the contribution of non-P450 enzymes to the metabolism of drugs have been published. Using data from human radiolabeled ADME studies available for a set of 125 orally or intravenously administered small molecule drugs approved by the United States Food and Drug Administration Downloaded from from 2006 – 2015, the contributions of P450 and non-P450 enzymes to the formation of major metabolites (≥10% of dose) were assessed and tabulated. Over this time frame, the involvement

of P450 versus non-P450 enzymes in the formation of major metabolites is compared, and the dmd.aspetjournals.org individual non-P450 enzymes responsible are described. This analysis indicates that non-P450 enzymes contribute significantly to the metabolism of the 125 drugs analyzed. Approximately

30% of the metabolism of these drugs is carried out by non-P450 enzymes with the predominant at ASPET Journals on September 27, 2021 non-P450 enzymes identified being: glucuronosyltransferases (11.7%), hydrolases (10.8%), carbonyl reductases (2.4%), and aldehyde oxidase (1.1%). Though significant, the relative contribution of non-P450 enzymes to drug metabolism does not appear to have increased dramatically over the last 10 years. As the current evaluation involves drugs which emerged from the discovery phase >10 years ago, this evaluation may not reflect the current or evolving situation in some research organizations, and, therefore, additional monitoring and assessment of the involvement of non-P450 enzymes to the metabolism of drugs will be conducted in the future.

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Introduction

A major focus of drug discovery and development is to understand the metabolic biotransformations and enzymes which contribute to drug clearance (CL) and impact oral bioavailability (F). An appreciation of these metabolic reactions and enzymes may impact the design of analogs with longer half-lives or higher F and may inform on the likelihood of drug- drug interactions (DDIs). Assays such as metabolic stability using liver or other tissue Downloaded from subcellular fractions or hepatocytes, reaction phenotyping using expressed enzymes or with selective inhibitors, metabolite identification studies, as well as radiolabeled absorption,

distribution, metabolism, and excretion (ADME) studies in humans and other preclinical species dmd.aspetjournals.org

(Penner et al., 2012b; Beaumont et al., 2014) can provide screening and definitive data for these purposes. Data from these assays and studies allow one to understand better the extent and rate of metabolism, identify metabolites, as well as define the individual enzymes responsible for the at ASPET Journals on September 27, 2021

CL of a drug. Furthermore, human ADME studies provide quantitative data for the amounts of metabolites formed and, along with reaction phenotyping studies, result in a definitive assignment of the fraction metabolized (fm) by enzymes contributing to the metabolism of the drug (Rodrigues et al., 2001; Zientek and Youdim, 2015).

Cytochromes P450 (P450) are a superfamily of membrane-associated heme-containing enzymes, for which the human genome contains 57 distinct P450 genes (Ortiz de Montellano, 1995;

Guengerich and Cheng, 2011). P450 enzymes represent a well-studied and relatively well- understood family of enzymes that have been reported as the most important enzymes responsible for the majority of oxidative drug metabolism. In humans P450s 1A2, 2B6, 2C8,

2C9, 2C19, 2D6, 3A4, and 3A5 are considered the major P450 isoforms involved in the metabolism of drugs (Walsky and Obach, 2004; Wienkers and Heath, 2005).

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In recent years, claims have appeared in the literature indicating that metabolism by P450 enzymes is no longer as prominent as it once was. (Pryde et al., 2010; Oda et al., 2015) These reports assert that other non-cytochrome P450 (non-P450) enzymes are playing a more significant role in the metabolism of recent drugs and drug candidates. Despite these claims, supporting data are sparse. Furthermore, no evaluation exists looking at the changes in the contribution of P450 versus non-P450 enzymes to the metabolism of drugs over time. As such, one of the main goals of this manuscript is to provide a starting data set which can be utilized to Downloaded from provide a temporal summary of the involvement of non-P450 enzymes in the metabolism of drugs. The current evaluation is intended to provide evidence to support or refute claims of dmd.aspetjournals.org increased involvement of non-P450 enzymes versus P450 enzymes in the metabolism of drugs approved in the last 10 years. Additionally, future expansion of the current data set will provide an ongoing assessment of the involvement of P450 and non-P450 enzymes in the metabolism of at ASPET Journals on September 27, 2021 emerging drugs.

The involvement of non-P450 enzymes in the metabolism of drugs and endogenous substances is well-precedented (Penner et al., 2012a; Bohnert et al., 2016). The more commonly encountered enzymes involved in oxidation, reduction, and hydrolysis (phase I metabolism) include molybdenum cofactor-containing enzymes (aldehyde oxidase (AO (Hutzler et al., 2013)) and xanthine oxidase (XO (Pryde et al., 2010))), flavin-containing monooxygenases (FMO (Hines et al., 1994)), monoamine oxidase (MAO (Edmondson et al., 2009)), reductases (carbonyl reductases (CBR (Forrest and Gonzalez, 2000)) and aldo-keto reductases (AKR (Jin and

Penning, 2007; Oppermann, 2007; Penning, 2015))), dehydrogenases (alcohol dehydrogenase

(ADH (Bosron and Li, 1987; Jornvall et al., 2000)) and aldehyde dehydrogenase (ALDH

(Marchitti et al., 2008; Koppaka et al., 2012))), and hydrolytic enzymes (esterases,

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proteases/peptidases, amidases, etc. (Testa and Mayer, 2006; Uetrecht and Trager, 2007; Long and Cravatt, 2011; Yang et al., 2011; Bachovchin and Cravatt, 2012; Oda et al., 2015)).

Additionally, metabolites arising from conjugative enzymes (phase II metabolism), including glucuronosyl transferases (UGT (Tukey and Strassburg, 2000; Oda et al.,

2015)), N-acetyl transferases (NAT (Hein et al., 2006)), glutathione S-transferases (GST

(Armstrong, 1997; Eaton and Bammler, 1999; Salinas and Wong, 1999; Sheehan et al., 2001)), sulfotransferases (SULT (Strott, 2002; Riches et al., 2009)), and methyltransferases (MT Downloaded from

(Petrossian and Clarke, 2011)) are also frequently identified.

An appreciation of the metabolic reactions and the totality of enzymes involved in the dmd.aspetjournals.org metabolism of a drug is important for a number of reasons. Proper accounting for both P450 and non-P450 contributions to metabolism provide a more accurate assignment of the fm value for

P450 enzymes and, therefore, result in a more accurate determination of the drug’s likelihood of at ASPET Journals on September 27, 2021 being a P450 DDI victim. Clinically relevant DDIs for a number of phase I and phase II non-

P450 enzymes have also been reported. Non-P450 enzymes for which DDIs have been observed clinically include AO (Lake et al., 2002; Renwick et al., 2002), XO (Coffey et al., 1972; Zimm et al., 1983) MAO (Livingston and Livingston, 1996; Rolan, 1997; Van Haarst et al., 1999), ADH

(Roine et al., 1990; Jacobsen et al., 1996), carboxylesterases (CES, (Xiao et al., 2013; Wang et al., 2015)), UGTs (Kiang et al., 2005; Uchaipichat et al., 2006; Nivoix et al., 2008; Li et al.,

2015), SULTs (Schwartz et al., 2009), and MT (Jorga et al., 1997; Lewis et al., 1997; Relling et al., 1999). Therefore, an early understanding of the routes of metabolism and the contributing enzymes provides insights into potential DDIs as well as provides time for implementation of mitigation strategies.

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The major aim of this manuscript is to summarize and compare the contributions of P450 and non-P450 routes of metabolism to the formation of major metabolites (≥10% of dose) using data from human radiolabeled ADME studies available for small molecule drugs approved by the

United States Food and Drug Administration (FDA) from 2006 – 2015. Additionally, data comparing the involvement of P450 versus non-P450 metabolism for each year have been compiled so as to assess the change in involvement of P450 versus non-P450 over time. Lastly, the individual non-P450 enzymes that are involved in the formation of major metabolites of these Downloaded from drugs are also described. A goal of this analysis was to determine if there were perceptible trends in a changing role of non-P450 enzymes, and, if so, which enzymes. dmd.aspetjournals.org

As such, the results of this evaluation serve as a data base for recurring analyses of the involvement of non-P450 enzymes in the metabolism of emerging drugs. This work also affords specific examples of substrates for non-P450 enzymes and may result in a better understanding at ASPET Journals on September 27, 2021 and appreciation of the contribution of non-450 enzymes to drug metabolism. The data provided highlight specific non-P450 enzymes which require greater characterization. Greater knowledge of the involvement and importance of non-P450 enzymes can result in consideration of other factors for these enzymes such as: species differences, hepatic versus extrahepatic expression and metabolism, enzyme polymorphisms (Brian et al., 2016), likely DDIs, non-P450-mediated bioactivation (Grillo and Lyubimov, 2011; Hutzler and Cerny, 2012), as well as the development of in vitro assays to improve extrapolation to predict and understand in vivo CL for these non-

P450 enzymes. Improving our understanding of these metabolic enzymes and biotransformations should result in fewer surprises being encountered during the drug discovery and development process, leading to safer drugs in the future.

Materials and Methods

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Sources of Data and Data Restriction Criteria

All considered for evaluation were approved by the FDA between 2006 and 2015

(Supplemental Table 1). New Drug Application (NDA) and Biological License Application

(BLA) approval packages, including the drug labels, are available at the FDA website,

Drugs@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 this category Downloaded from were removed, such as protein drugs (i.e. enzymes, antibodies, antibody drug conjugates

(ADCs)), peptide drugs, antisense drugs, elemental/inorganic drugs, and botanical drugs

(Table 1). For the subset of small molecule drugs, only drugs administered intravenously or dmd.aspetjournals.org orally were considered for further evaluation. For the remaining drugs, human radiolabeled

ADME data were obtained from sources which included the FDA NDA approval package, specifically the clinical pharmacology and biopharmaceutics reviews, pharmacology reviews, at ASPET Journals on September 27, 2021 and drug labels. Additionally, if data were available from the European Medicines Agency

(EMA) Application for Marketing Authorization

(http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=

WC0b01ac058001d124) or from the scientific literature, these data were also used for this evaluation. References describing the sources of data used are presented in Supplemental

Table 1.

For medications which are combination therapies, the metabolism of each component (drug) was considered individually. For combination therapies where one or more new chemical entities are combined with one or more previously approved drugs, only the newly approved drugs were included in the evaluation set. A summary of the total number of drug substance approvals by year is presented in Table 1.

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For intravenous drugs, agents used as imaging agents, generally with extremely short half-lives, were removed from the set. Lastly, were also removed from the main evaluation set.

These drugs were compiled and evaluated as a separate grouping. A summary of metrics for small molecule drugs each year between 2006 and 2015 are presented in Table 2.

For each small molecule drug, a summary of the metabolites identified in plasma, expired air, urine, and feces from the human ADME study was compiled. Metabolites that accounted for Downloaded from ≥10% of circulating radioactivity or ≥10% of dose in expired air or excreta as a component of urine, feces, or a compilation of radioactivity in urine and feces were deemed “major”

metabolites. For metabolites that were reported at levels ≥10% in multiple matrices, the dmd.aspetjournals.org metabolite was counted only once. The total number of major metabolites across matrices was summed giving a total number of major metabolites per drug molecule. For drugs which showed sparse formation of metabolites or which produced multiple low (<10%) abundance metabolites, at ASPET Journals on September 27, 2021 these drugs were specified as drugs with “no major metabolites” and were accounted for as such.

Data Analyses

The current evaluation is focused on defining the contribution of P450 and non-P450 enzymes to metabolism, not in terms of contribution to CL. The metabolism of the drugs included in the evaluation set focused on the primary biotransformation step as this transformation, and the enzyme system(s) responsible for the reaction(s) are of greatest interest due to their relationship to CL. Assignment of the contribution of a specific enzyme to CL of a drug is, of course, of utmost interest. However, this is not possible for the current evaluation for several reasons.

Human ADME metabolite data are reported as static percentages of circulating radioactivity or dose, not in terms of rates of formation. Again, owing to the static nature of the data, other

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processes such as reversible metabolism, reabsorption, and transporter-mediated uptake and efflux are not accounted for. Additionally, for metabolites that are formed by multiple enzymes, the fractional clearance through one particular enzyme cannot be defined using human ADME data alone. Furthermore, an evaluation of metabolism after the initial biotransformation

(subsequent metabolism) was considered. However, accounting for these transformations was complicated and, therefore, is not included in this evaluation. Downloaded from 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 dmd.aspetjournals.org 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 total for

P450 and non-P450 were then divided by the total number of major metabolites so that the P450 at ASPET Journals on September 27, 2021 and non-P450 reaction 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 while 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 above analyses, the data were examined in two ways.

For the first method (Method 1) the drugs were categorized by the enzyme systems involved in their metabolism without fractionation. More specifically each drug was defined as having no major metabolites or as being metabolized by P450 enzymes, non-P450 enzymes, or metabolized by both P450 and non-P450 enzymes (mixed). A secondary assessment (Method 2) utilized the fractional assignments for the contribution of P450 or non-P450 to each drug. The results of the

Method 2 assessment were summed for each year from 2006 to 2015, for two five year periods

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(2006 – 2010 and 2011 – 2015), and for 2006 – 2015. Therefore, the relative contributions of

P450 and non-P450 enzymes for drugs which fell into the mixed category for Method 1 were assigned a fractional assignment, thereby providing greater granularity to the data set.

As a part of this secondary analysis, for metabolites whose primary biotransformation was determined to be partially or entirely mediated by non-P450 enzymes, the enzyme(s) responsible were assigned and tabulated. Similar to what is described above, if multiple enzymes were Downloaded from possibly responsible for a major metabolite, then the metabolite was divided equally between the two enzymes. For the sake of simplicity, hydrolytic biotransformation carried out by esterases,

amidases, or other hydrolytic enzymes are combined and designated as “hydrolases.” Similarly, dmd.aspetjournals.org biotransformations resulting in reduction of a carbonyl are referred to as “carbonyl reductases” and may be carried out by CBR, AKRs, or other enzymes which carry out similar biotransformations. at ASPET Journals on September 27, 2021

Caveats of the Current Analyses

The primary goal of the current analyses was to evaluate the relative contribution of P450 versus non-P450 enzymes in the metabolism of drugs. The current approach is also a consequence of certain limitations of data availability. As such, there are some caveats worth describing.

• Access to only a portion of the mass balance data or incomplete description or

characterization of the metabolism from the sponsors. In these cases, only reported

metabolite assignment and percentage data could be included.

• Glucuronide conjugates are generally not stable in feces, and, therefore, their contribution to

the total metabolism may be underappreciated.

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• Multistep oxidations could involve both P450 and non-P450 enzymes, e.g. conversion of a

benzylic alcohol to a carboxylic acid. Additional characterization of non-P450 enzymes

involved may not have been explored or reported.

• Multiple minor metabolites (<10%) formed by the same enzyme or enzyme group (i.e. P450

or non-P450) may additively contribute a major metabolic pathway and will not be

appropriately accounted for. Similarly, multiple metabolites resulting from subsequent

metabolism of a common intermediate may not be properly attributed. Downloaded from

• The contribution of enzymes to the formation of metabolites which are derived from multiple

enzymes may be underappreciated for one enzyme and overstated for another. There is no dmd.aspetjournals.org

correction factor for the percent contribution of each enzyme (such as an fm value) and,

therefore, the responsibility for the formation of the metabolite is divided equally between

the enzymes (e.g. an oxidative metabolite formed by 4 individual P450s and FMO1, the at ASPET Journals on September 27, 2021

metabolite would be counted as 50% P450 and 50% non-P450).

• The average development time for a drug is >10 years (DiMasi JA, 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 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

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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 exists 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 the 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 Downloaded from from more definitive human radiolabeled ADME studies.

Because human ADME data are commonly reported as part of drug applications, drugs approved dmd.aspetjournals.org by the United States FDA from 2006 – 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 at ASPET Journals on September 27, 2021

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. Small molecule drugs are by far the largest subset of approved drugs tallying 221 drugs. Of the small molecule drugs approved, administration through the oral route represents the largest subset of these drugs

(Table 2, 156 drugs, 71% of small molecule drugs). Intravenously administered drugs are the next largest category of small molecule drugs representing approximately 16% of all small molecule approvals. The remainder of small molecule drugs (30 drugs, 14%) falls 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,

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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 administered by many of these routes. For several of the applications for drugs in this subset, it is noted that levels of parent drug are extremely low or below the limit of quantitation. Though not included in this evaluation, metabolism data for other routes of administration, where available, may be included in future analyses. Downloaded from As the main focus of this work is the metabolism of small molecule drugs, the current evaluation has focused on drugs administered via the two most prevalent routes of administration,

intravenous and oral. Imaging agents were excluded from the set of intravenously administered dmd.aspetjournals.org drugs as they generally have short half-lives, and typically do not possess “drug-like” properties.

Additionally, prodrugs were removed from the sets of intravenously and orally administered drugs as these drugs possess functionalities to improve ADME or physicochemical properties at ASPET Journals on September 27, 2021 and generally require metabolic bioactivation to generate the active drug.

As ester and prodrugs are commonly employed approaches (Clas et al., 2014;

Wiemer and Wiemer, 2015), it was thought that the data set would be biased toward the enzymes involved in the bioactivation of the prodrugs (Figure 1) and that these enzymes would likely differ significantly from the majority of drugs evaluated. Despite their removal from the larger set of drugs, data for the primary and subsequent metabolism of prodrugs were compiled. Due to the reasons stated above, the primary metabolism of prodrugs was evaluated separately. Data for metabolites formed after or in addition to the initial prodrug step are available and may be included in future evaluations. As can be seen in Figure 1, “hydrolase” enzymes represent

86.4% (19 of 22 drugs) of the bioactivation reactions for prodrugs approved between 2006 and

2015. Activation by kinases, glutathione, or chemical transformation were found for one drug

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each. Clearly, combining prodrugs with non-prodrugs would significantly bias the larger data set towards hydrolytic enzymes.

After removal of drugs based on the above criteria, the resulting set of 125 drugs evaluated included 10 intravenously administered drugs and 115 drugs administered orally. The 96 small molecules not included in the set of drugs evaluated were removed because they fell into the following categories: other routes of administration (30), imaging agents (11), prodrugs (22), no Downloaded from ADME study performed (22), or insufficient data available (11). Using “major” metabolites as indicators of route(s) of metabolism, the metabolism of the 125 compounds can be divided into

the following categories: no major metabolites (22, 17.6%), P450 only (56, 44.8%), non-P450 dmd.aspetjournals.org only (26, 20.8%), or a mixture of P450- and non-P450-mediated metabolism (21, 16.8%). Based on these values (Figure 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 at ASPET Journals on September 27, 2021 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.

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In an effort to obtain more detailed data to describe the initial metabolic step for these drugs, the initial biotransformations leading to major metabolites of these drugs were tabulated based on the relative contribution of P450 or non-P450 enzymes. Metabolism data were then grouped and analyzed by year. Figure 3A presents the data for no major metabolites, P450, and non-P450 by year for 2006 – 2015. The same data are also presented in Figure 3B in terms of number of drugs per year. The P450 component for all but three years (2006, 2007, and 2008), remains at or above 50%. Non-P450 metabolism is also relatively consistent at ~20 – 35%, with the Downloaded from exception of 2008 (64.6%) and 2010 (not present), where a spike and dip, respectively, were seen in the non-P450 contribution. The percentage of drugs with no major metabolites generally dmd.aspetjournals.org falls between 10 and 25% for the majority of the years analyzed, which represents 1 – 3 compounds per year.

Though the above assessment provides some chronological data for categorization of the at ASPET Journals on September 27, 2021 biotransformations for approved drugs which meet the assessment criteria, the number of drugs which meet the criteria for inclusion per year are generally small (7 – 18 drugs). The low numbers of drugs analyzed per year may result in a more easily biased data set. For this reason, data sets over 5 year periods were also combined, which offers a larger and likely less variable data set for analysis. Data for the 46 drugs approved between 2006 – 2010 which meet the acceptance criteria, are presented in Figure 4A. Likewise, data for drugs approved between 2011

– 2015 (79 drugs) are presented in Figure 4B. A summary of all 125 drugs evaluated is presented in Figure 4C. Whether looking at 5 year time periods or the entire ten year period, metabolism by P450 enzymes represents the largest percentage of metabolism. Comparing the two 5 year groupings indicates that the non-P450 component appears relatively similar at around

30%, and, therefore, the non-P450 contribution over the ten years is also similar. However, the

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percentage representing P450 metabolism and no major metabolites vary by >10% between the two 5 year spans of time. For the period of 2006 – 2010, P450 metabolism accounts for 43.1% while it increases to 58.0% for 2011 – 2015. For the same two time periods the no major metabolites component decreases from 28.3% to 11.4%.

The current assessment of the metabolism of FDA approved drugs between 2006 – 2015 indicates that P450-mediated metabolism still is the most common route of metabolism of the Downloaded from drugs evaluated (52.5%). Regardless of the method of assessment, metabolism by non-P450 enzymes contributes to a significant portion (~30%) of the metabolism of these drugs. Though

not as prominent as metabolism by P450 and non-P450 enzymes, drugs which exhibit no major dmd.aspetjournals.org metabolites represent a non-trivial, but more variable portion of the total.

When looking at the contribution of non-P450 metabolism over time, there is no apparent trend at ASPET Journals on September 27, 2021 towards increasing contributions of non-P450 enzymes to the metabolism of these drugs. In actuality the contribution of non-P450 enzymes remains relatively constant over time with two of the ten years displaying higher (2008) or lower (2010) involvement. As stated above, based on current industry timelines for drug development (DiMasi JA, 2014), the current set of drugs likely emerged from drug discovery >10 years ago. Despite this fact, the current data set provides for the first time an evaluation of P450 versus non-P450 metabolism for drugs approved over a 10 year period. This evaluation also provides a starting point for comparison for future evaluations. Being that an assessment such as this is not possible in the research setting due to the limitations in data type and access to data, future evaluation of this nature with an ever increasing data set will be needed to determine if the perceived changes are indeed occurring in the discovery space. Therefore, the results of this evaluation will serve as a data base for reoccurring analyses of the involvement of non-P450 enzymes in the metabolism of emerging

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drugs. Based on a longer duration, a larger data set, and a greater appreciation of non-P450 reactions, it is expected that future analyses will be more informative.

Figure 5 depicts the individual enzymes and enzyme classes responsible for the non-P450- mediated metabolism. Interestingly, metabolism by non-P450 enzymes is carried out by a relatively limited set of enzymes, with UGTs and hydrolases being most dominant, representing

11.7 and 10.8%, respectively. While the predominance of UGT metabolism is not surprising Downloaded from based on a previous analysis (Williams et al., 2004), the high percentage of metabolism by hydrolases is somewhat unanticipated, especially in light of the fact that prodrugs have been

removed from the evaluation set. The hydrolase-mediated metabolism of 16 of the 19 drugs dmd.aspetjournals.org involves hydrolysis of an amide bond. Therefore, hydrolytic metabolism, specifically of amide bonds, and the enzymes capable of this metabolism may represent underappreciated metabolic routes in need of greater characterization (Testa and Mayer, 2006). This point has been recently at ASPET Journals on September 27, 2021 illustrated by the report of the unappreciated ability of AO to catalyze amide hydrolysis of GDC-

0834 resulting in no measureable levels of the parent compound in human circulation (Liu et al.,

2011; Sodhi et al., 2015).

Recent literature (Pryde et al., 2010; Hutzler et al., 2012; Hutzler et al., 2013; Hutzler et al.,

2014b; Dalvie and Zientek, 2015) would indicate that non-P450 enzymes such as AO may represent areas of emerging importance. Increased interest in AO may be due, in part, to the enzyme’s absence in some preclinical species which has contributed to some well-documented drug failures (Dittrich et al., 2002; Diamond et al., 2010; Hutzler et al., 2014a; Lolkema et al.,

2015). However, the current evaluation indicates that the contribution of AO to the metabolism of drugs in the set is minor at 1.1%. For other enzymes, increased awareness may be the result of focused efforts on diminishing the involvement of P450-mediated metabolism. All other non-

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P450 enzymes identified in this evaluation were relatively minor (<1%) and included sulfotransferases (0.8%), deaminase (0.8%), nucleotidases (0.8%), alcohol/aldehyde dehydrogenase (0.4%), flavin-containing monooxygenases (0.3%), glutathione conjugation

(0.3%), gut microbes (0.3%), undefined/unknown (0.3%). A number of these minor contributing enzymes fall outside of the “usual” drug metabolizing enzymes and may be the result of the drug targets and target space captured in the evaluation set. Downloaded from The introduction of novel drug targets and drug targeting approaches to the drug discovery environment will likely bring with it innovative approaches to small molecule drugs. Whether

this will result in an increased role in non-P450 metabolism for drugs of the future is yet to be dmd.aspetjournals.org answered. Additionally, one may also question whether the introduction of enzyme families which are not as well characterized or commonly encountered in drug metabolism as P450 enzymes will provide benefits or greater challenges to drug discovery and development. at ASPET Journals on September 27, 2021

Remaining in the area of P450-mediated metabolism may afford an easier discovery and development path, as the enzymes and methods for their evaluation are well-developed and widely deployed. Whether medicinal chemists and drug metabolism scientists can exert sufficient control over the design of drug molecules which engage emerging drug targets and which remain in this well-characterized space of P450 metabolism, will likely only be answered with more time and greater scrutiny of emerging drugs.

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Acknowledgements

Thanks to Donald Tweedie for support, guidance, and thoughtful suggestions throughout the compilation and writing of this manuscript. Thanks also to Melissa Kramer for helpful discussions and critical reading of this manuscript.

Authorship Contributions Downloaded from

Participated in research design: Cerny

Performed data analysis: Cerny dmd.aspetjournals.org

Wrote or contributed to the writing of the manuscript: Cerny

at ASPET Journals on September 27, 2021

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Legends for Figures

Figure 1. Enzymes responsible for metabolic bioactivation of the twenty-two prodrugs approved by the FDA between 2006 – 2015.

Figure 2. Fractional assignment of FDA approved intravenous and orally administered small molecule drugs meeting acceptance criteria (2006 – 2015) which have no major metabolites or whose metabolites are formed by P450, non-P450, or a mix of both P450 and non-P450 Downloaded from enzymes. Categorization was carried out using ‘Method 1’ as described in the Data Analyses section. dmd.aspetjournals.org

Figure 3. Fraction of metabolism of approved intravenous and orally administered small molecule drugs meeting acceptance criteria by year characterized as having no major metabolites or metabolites which are formed by P450 or non-P450 enzymes. Data for drugs meeting at ASPET Journals on September 27, 2021 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 total number of drugs which meet acceptance criteria for that year. Categorization was carried out using ‘Method 2’ as described in the Data

Analyses section.

Figure 4. Fractional assignment of approved intravenous and orally administered small molecule drugs meeting acceptance criteria for 2006 – 2010 (A), 2011 – 2015 (B), 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.

Figure 5. Fractional assignment of FDA approved intravenous and orally administered small molecule drugs meeting acceptance criteria for 2006 – 2015 which have no major metabolites or

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whose metabolites are formed by P450 by specific non-P450 enzymes. Categorization was carried out using ‘Method 2’ as described in the Data Analyses section.

Downloaded from dmd.aspetjournals.org at ASPET Journals on September 27, 2021

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Tables

Table 1. Compilation of metrics for FDA approved drugs 2006 – 2015 This articlehasnotbeencopyeditedandformatted.Thefinalversionmaydifferfromthisversion.

Year 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Totals DMD FastForward.PublishedonApril15,2016asDOI:10.1124/dmd.116.070763

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

a – number of active ingredients contained within mono or combination small molecule therapies approved for the designated year

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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 This articlehasnotbeencopyeditedandformatted.Thefinalversionmaydifferfromthisversion. Active Ingredients 16 15 21 21 12 24 28 22 31 31 221 DMD FastForward.PublishedonApril15,2016asDOI:10.1124/dmd.116.070763 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 14 7 19 21 17 21a 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

a Lacosamide, phosphate, and sulfate are administered either orally or intravenously. For simplicity, these drugs were only

counted in the Oral category 33

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DMD Fast Forward. Published on April 15, 2016 as DOI: 10.1124/dmd.116.070763 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from dmd.aspetjournals.org at ASPET Journals on September 27, 2021 DMD Fast Forward. Published on April 15, 2016 as DOI: 10.1124/dmd.116.070763 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from dmd.aspetjournals.org at ASPET Journals on September 27, 2021 DMD Fast Forward. Published on April 15, 2016 as DOI: 10.1124/dmd.116.070763 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from dmd.aspetjournals.org at ASPET Journals on September 27, 2021 DMD Fast Forward. Published on April 15, 2016 as DOI: 10.1124/dmd.116.070763 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from dmd.aspetjournals.org at ASPET Journals on September 27, 2021 DMD Fast Forward. Published on April 15, 2016 as DOI: 10.1124/dmd.116.070763 This article has not been copyedited and formatted. The final version may differ from this version. Downloaded from dmd.aspetjournals.org at ASPET Journals on September 27, 2021 PREVALENCE OF NON-CYTOCHROME P450-MEDIATED METABOLISM IN FDA APPROVED ORAL AND

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 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 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 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 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 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 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 2/24/2014 Protein Subcutaneous Drug Type 85 Neuraceq florbetaben F 18 3/19/2014 Small Molecule IV Imaging Agent 86 Impavido 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 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 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 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 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 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 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 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 (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 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 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 2/26/2010 Protein IV Drug Type 370 Carbaglu 3/18/2010 Small Molecule Oral N.A. 371, 372 Asclera polidocanol 3/30/2010 Small Molecule IV No ADME Study 373 valerate(1954) Small Molecule Natazia 5/6/2010 Oral N.A. 374 dienogest Combination Lumizyme 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 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 1/14/2009 Small Molecule Oral N.A. 403, 404 Uloric 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 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 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 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 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 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 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 7/24/2006 Protein IV Drug Type 559 Noxafil 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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W., Williams, D., Peng, B., Schubert, E., Gorycki, F., Levy, M., and Gorycki, P. D. (2011) Metabolism and disposition of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, in healthy human subjects, Drug metabolism and disposition: the biological fate of chemicals 39, 1734-1746. [490] EMA. (2010) Human medicines: Revolade (eltrombopag) Agency product number: EMEA/H/C/001110. London, UK. [491] FDA. (2008) Drug approval package: Nucynta (tapentadol). FDA application NDA 022304. FDA Silver Springs, MD. [492] Terlinden, R., Ossig, J., Fliegert, F., Lange, C., and Gohler, K. (2007) Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects, European journal of drug metabolism and pharmacokinetics 32, 163-169. [493] FDA. (2008) Drug approval package: Lusedra (fopropofol). FDA application NDA 022244. FDA Silver Springs, MD. [494] FDA. (2008) Drug approval package: Mozobil (plerixafor). FDA application NDA 022311. FDA Silver Springs, MD. 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M., Chao, G. C., Brown, N. A., and Lai, C.-L. (2006) Pharmacokinetics of Telbivudine following Oral Administration of Escalating Single and Multiple Doses in Patients with Chronic Hepatitis B Virus Infection: Pharmacodynamic Implications, Antimicrobial agents and chemotherapy 50, 874-879. [573] EMA. (2007) Human medicines: Sebivo (telbivudine) Agency product number: EMEA/H/C/000713. London, UK. [574] FDA. (2006) Drug approval package: Veregen (sinecatechins). FDA application NDA 021902. FDA Silver Springs, MD. [575] FDA. (2006) Drug approval package: Invega (paliperidone). FDA application NDA 021999. FDA Silver Springs, MD. [576] Vermeir, M., Naessens, I., Remmerie, B., Mannens, G., Hendrickx, J., Sterkens, P., Talluri, K., Boom, S., Eerdekens, M., van Osselaer, N., and Cleton, A. (2008) Absorption, metabolism, and excretion of paliperidone, a new monoaminergic antagonist, in humans, Drug metabolism and disposition: the biological fate of chemicals 36, 769-779. [577] EMA. 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