1. MATERIALS AND METHODS Sex-Differences in Exposure for FDA Approved New Molecular Entities (NMEs) 2007-2010: Exposure Based Dosing in Subgroup Populations Vanessa Copeland B.S., Chandrahas Sahajwalla, Ph.D. Ameeta Parekh, Ph. D. Food and Drug Administration, Silver Spring, MD CONCLUSION RESULTS OBJECTIVES A list of new molecular entities (NMEs) for drugs (NDAs) and biologics (BLAs) approved from September 2007 to August 2010 was obtained from the Center for Drug Evaluation and Research website Approved labels of these NMEs were accessed from the Drugs @ FDA website- www.accessdata.fda.gov/scripts/cder/drugsatfda NMEs for sex-specific indications and those without systemic exposure were excluded from further analysis. Sex based PK information in the label was evaluated by 1. assessing sex- differences in PK parameters: AUC, Cmax, CL, t1/2 (exposure) 2. assessing exposure- based dosage adjustments, if any. The same approach was used to collect data on other demographic subgroups: renal impairment, hepatic impairment, elderly, and race i.e. assessing exposure differences and the corresponding dosage adjustments, if any. If sex-based PK information was unavailable in the label, then the Clinical Pharmacology Review was accessed via Drugs @ FDA to determine if PK subgroup analysis based on sex was performed. This sex-based exposure data was compared to the other demographic subgroups to assess how exposure differences in women to other subgroups where dosage adjustments were recommended based on exposure differences. Information on metabolic pathways and excretion pathways were accessed from the Clinical Pharmacology Review via Drugs @ FDA Only exposure differences >20% were considered potentially clinically relevant, and were further analyzed for trends in elimination pathways RESULTS 69 total NMEs, both NDAs and BLAs, were approved from September 2007-August 2010 12 were excluded from further analysis- 6 sex-specific, 6 no systemic exposure Sex specific NMEs (6): Estradial valerate& Estradiol valerate/dienogest; Cabazitaxel; Ulipristal Acetate; Silodosin; Degarilex; Ixabepilone No systemic exposure NMEs (6): Polidocanol; Collagenase Clostridium Histolyticum; Incobotulinumtoxinia; Benzyl Alcohol; Abotulinumtoxinia; Difluprednate Next, the NMEs with exposure based dosage adjustments in other subgroups were compared to exposures in women. This was to assess if the criteria of dosage adjustment based on exposure differences were consistent for all subgroup populations. Although several NME drugs and biologics exhibited sex-based exposure differences in women, no dosage adjustments for women based on exposure were recommended in the labels. These PK differences were described in the label as not clinically relevant. For subgroups that had dosage adjustments, the PK differences were greater than the sex-based PK differences. As demonstrated in the elderly population, pharmacodynamic differences and increased adverse events can also warrant dosage adjustments For NMEs that showed sex-based exposure differences, no clear trend was elucidated between sex-differences in PK and pathways of elimination (metabolism and excretion), as described in the labels. When safety or efficacy outcomes are different in women compared to men, even at similar exposures, other intrinsic and extrinsic factors may be involved to explain these differences. Note: The Clinical Pharmacology Review was accessed only when sex-specific information was not found in the label. NMEs with no sex-related PK information available (6): Carglumic acid, Iloperidone, Besifloxacin Hydrochloride, Bepotasine Besilate, Iobenuane, Romiplostim Carglumic acid, Iobenuane, and Romiplostim have an orphan designation for rare disease so these NMEs have small patient populations Besifloxacin hydrochloride and bepotasine besilate are both eye drops with very minimal systemic exposure; it is unlikely there would be gender differences in exposure Iloperidone is indicated for schizophrenia, no sex-related PK analysis was found NME PK Parameter Difference Liraglutide34% decrease CL Febuxostat 14% increase in AUC 30% increase in Cmax Dronedarone30% increase in AUC Saxagliptin25% increase AUC Pitavastatin 54% increase in AUC 60% increase in Cmax PK Exposure for Women PK Exposure for Women vs. Other Subgroups Ofatumumab14-25% decrease in CL Desvenlafaxine Succinate 10% increase in AUC 25% increase in Cmax Gadoxetate Disodium22% decrease CL Clevidipine Butyrate25% decrease CL Eltrombopag Olamine23% increase AUC NME PK Parameter Difference Green= No dosage adjustment Red= Dosage adjustment Pink= Contraindication *= CL was reported for women in the label; converted to AUC by (dose/AUC=CL) PK Differences in Exposure for Women The 6 NMEs with no sex-based PK information available were excluded from further analysis. Figure 2- The number of NMEs that reported sex-specific differences in exposure. The majority (73%) had no exposure difference observed between men and women. 8% had a PK parameter difference less than 20% and 20% had an exposure difference greater than 20%. Figure3 shows all subgroups that were examined for dosage adjustments based on exposure and/or response. Women had exposure differences, but no dosage adjustments. Renal impairment was the subgroup with the largest number of dosage adjustments followed by hepatic impairment. The elderly subgroup had a dosage adjustment for fosopropofol disodium based on an increase in the frequency of hypoxemia (PD difference) rather than an exposure difference (PK). Pathways of Metabolism and Excretion for NMEs with Sex-Based PK Difference ABSTRACT Poster# 1.To evaluate exposure differences for women compared to men and sex-based exposure dosing recommendations. 2. To compare women’s exposures and dosing compared to exposures and dosing for other demographic subgroups—elderly, race, hepatic impairment, and renal impairment. 3. For NMES with sex-based PK differences >20%, to examine trends in elimination pathways as an explanation for observed exposure differences Introduction: Subgroup population differences in drug exposure are now routinely examined during drug development and regulatory review. This study investigates FDA approved drugs and biologics new molecular entities (NMEs) from September 2007-August 2010 for sex-based and sub- population-based exposure differences mentioned in the labeling. Exposure differences have been documented for intrinsic and extrinsic factors. Consistency of exposure changes due to elimination pathways and exposure-based dosage adjustments for subgroup populations (renal and hepatic impairment, elderly, and race) are examined in this study. Methods: The labels of approved NMEs from September 2007-August 2010 were accessed from the Drugs @ FDA website and were evaluated for sex- specific indications, sex-based PK information, exposures, and dosing adjustments in subgroup populations. NMEs with sex-specific indications or no systemic exposure were excluded from further analysis. NMEs that had sex-based PK differences >20% were examined for consistency of dosing adjustment across subgroup populations with similar exposures and whether there were any trends for elimination pathways. Results: Of the 69 approved NMEs, 12 were excluded (6 sex-specific indications; 6 no systemic exposure). 6 had no sex-related PK reported. 37 had no sex-based PK differences observed. 4 had PK differences for all parameters (AUC, Cmax, or CL) ≤20%. 10 had at least one sex-based PK parameter difference >20%. Women’s exposures were not as high as other subgroup populations with dosage adjustments. Although there were no sex-based dosage adjustments, these 10 NMEs were further explored for routes of elimination (% renally cleared, % hepatically cleared, and major metabolic pathways of elimination). The elimination pathways for drugs with PK differences >20% were compared to the drug pathways that showed no PK differences. The comparison showed no specific trends between metabolic pathways and sex-specific exposure differences. Discussion: Exposure based dosing is consistent across subgroup populations. Since there was no clear trend between sex-differences in PK and pathways of elimination, there may be other factors that contribute to these sex differences and warrant further investigation. NMEMajor Metabolic Pathway Liraglutide fully cleaved by sequential peptide cleavage Febuxostat conjugation and oxidative pathways; conjugation via UGT1A1, UGT1A9, UGT2B7; oxidation via CYP1A2, 2C8, 2C9 & non P450 enzymes DronedaroneCYP3A Pitavastatin marginally metabolized by CYP2C9 and to a lesser extent CYP2C8; principally metabolized by glucorondination: UGT1A3&2B7 Desvenlafaxine succinate metabolized by conjugation mediated through UGT enzymes; CYP3A4 is a minor pathway for oxidative metabolism Gadoxetate disodiumnot metabolized Clevidipine Butyrate rapidly metabolized by hydrolyis of ester linkage; carboxylic acid metabolims further metabolized by glucorondination or oxidation Eltromobpag Olamine CYP1A2 &2C8 responsible for oxidative metabolism, UGT1A1&1A3 for glucorondination SaxagliptinCYP3A4/5 OfatumumabB-cell mediated elimination NME % renal excreted % hepatic excreted Liraglutideminimal Febuxostat49.1 +/- 9.8 44.9 +/- 10.1 Dronedarone684 Pitavastatin1579 Desvenlafaxine succinate45 Gadoxetate disodium50 Clevidipine Butyrate63-747 to 22 Eltromobpag Olamine3159 Saxagliptin7522 Ofatumumabn/a Discussion of Results 12 NME NDAs and 2 NME BLAs have PK differences for women; 9 NME NDAs and 1 NME BLA had exposures >20% None of the NDAs had dosage adjustments for women Women’s exposures were not higher than subgroups with dosage adjustments PK Differences for women were considered “not clinically relevant” in the label Desvenlafaxine Succinate shows similar exposure between elderly and renal impairment; the label states that age alone should not warrant a dosage adjustment but that the renal function of the elderly person should be considered to determine potential dosage changes Pitavastatin had the highest sex-based exposure difference in the NMEs analyzed This NME had the only contraindication for a specific subgroup– hepatic impairment Asian men was the racial subgroup that had the highest exposure for both Eltrombopag Olamine and Dronedarone There was a dosage adjustment for Asians in Eltrombopag Olamine (70% increase AUC) but not for Dronedarone (200% increase AUC) Dronedarone label states that PK differences related to race were not formally assessed and that the exposure was based following a single dose in Asian men vs. Caucasian men 5 of the 10 NMEs with sex-based PK differences >20% undergo glucorondination via UGT enzymes, all are mixed metabolism Oxidation is another common metabolic process 1of the 10 NMEs oxidized primairly viaCYP3A, 2 mixed metabolism via CYP3A 3 of the 10 NMES undergo mixed metabolism oxidized via CYP2C8 and CYP2C9 2 of the 10 NMES oxidized via CYP1A2, mixed metabolism Many NMEs undergo mixed metabolic processes, so it is difficult to determine each enzyme’s specific role in the sex- based exposure difference No trend in excretory pathway amongst NMEs with sex-based exposure differences When compared to NMEs with sex-based exposure differences, there were no specific trends observed between metabolic pathways or pathways of excretion and sex-specific exposure differences