MATERIALS AND METHODS

1. FDA Approved Drug Labels 2007-2010: Dose Adjustments for Women Based on Exposure Vanessa Copeland B.S., Ameeta Parekh, Ph. D. Food and Drug Administration, Silver Spring, MD INTRODUCTION RESULTS RESULTS There has been an increased awareness of subgroup population differences in drug exposures and/or responses since the 1980s. Demographic factors such as age, race, and sex as well as genetic factors and concomitant disease- hepatic and renal dysfunction for instance, are factors contributing to exposure and/or response differences. This has generated considerable interest in studying subgroup populations throughout drug development. The U.S. Food and Drug Administration (FDA) has developed guidances that address the importance of including and analyzing outcome differences in subgroups due to underlying biological factors. 1 Early phase clinical pharmacology studies typically generate information on pharmacokinetics (PK) and pharmacodynamics (PD) of drugs in subgroup populations. Women are reported to have more adverse events than men. 2 Frequently when women have higher exposure than men, body weight differences are the justification for the observation. However, drugs are often dosed in milligrams, not milligrams/kilogram, lending women towards higher exposures worth further investigation. The focus of this poster is to evaluate sex-based exposure differences and their respective dosing recommendations as compared to exposures and dosing for other demographic subgroups-elderly, race, hepatic impairment, and renal impairment. PK 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). Green = No dosage adjustment Red= Dosage adjustment *= CL was reported for women in the label; converted to AUC by (dose/AUC=CL) MATERIALS AND METHODS • 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. Discussion of Results PK Differences in Exposure for Women • 12 NME NDAs and 2 NME BLAs have PK differences for women • 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-difference in exposure for the NMEs analyzed • This NME had the only contraindication for a specific subgroup-hepatic impairment • Asian men was the racial subgroup that had highest exposure for both Eltrombopag Olamine and Dronedarone • There was a dosage adjustment for Asians in Eltrombopag Olamine (70% increase in AUC) but not for Dronedarone (200% increase in 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 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. PK Exposure for Women vs. Other Subgroups RESULTS CONCLUSION • 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 • Although several drugs showed exposure differences in women, no dosage adjustments based on exposure were recommended in the labels. • Renal impairment was the subgroup with the largest number of dosage adjustments, followed by hepatic impairment • When safety or efficacy outcomes are different in women compared to men, even at similar exposures, other factors may be involved to explain these differences. REFERENCES • http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072044.pdf • Anderson GD, Gender Differences in Pharmacological Response. Int Rev Nerobiol 2008; 83:1-10 Note: The Clinical Pharmacology Review was accessed only when sex-specific information was not found in the label. Green= No dosage adjustment Red= Dosage adjustment Pink= Contraindication *= CL was reported for women in the label; converted to AUC by (dose/AUC=CL) • 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 DISCLOSURES Vanessa Copeland: Nothing to Disclose Ameeta Parekh: Nothing to Disclose