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1 w wz 21«1y Kor. J. Clin. Pharm., Vol. 21, No Physician's Desk Reference ùkù x Á½ Á Á½x Á½ Á Á Á y Á x y w w w w y w w w ( Á Á ) Analysis of Gender Differences in Physician s Desk Reference Jung Sun Heo 2, Kyung Hee Kim 1, In Kyung Yoon 1, Hyun Ju Kim 1, You Jin Kim 1, Jong Min Choi 1, Hwa Jeong Lee 1 *, and Hye Sun Gwak 1,2 * 1 College of Pharmacy and Division of Life & Pharmaceutical Sciences, Ewha Womans University 2 Graduate School of Clinical Health Sciences, Ewha Womans University (Received October 1, 2010ÁRevised December 26, 2010ÁAccepted January 2, 2011) Purpose: This study aims to investigate how gender-based differences are actually reflected on drug approval. Methods: Data on gender-based differences of drugs were analyzed by searching PDR (Physician s Desk Reference) with the keyword, GENDER. Results: There were descriptions related to gender in product directions of 361 drugs in 2009 PDR, out of which 63 items actually showed gender-related differences. Drug categories showing comparatively high gender-based differences were nervous system, cardiovascular system, and alimentary tract and metabolism. Pharmacokinetic differences between genders were observed most frequently; compared to men, 32 drugs showed higher absorption while 18 drugs revealed lower clearance in women. There were 2 drugs which gender should be considered before prescribing, and 5 drugs which showed different severity of adverse effects according to gender. Conclusions: It is necessary to establish domestic policies for drug approval and use which reflects gender-based differences through sufficient researches. Key words - Gender-based differences, Physician's Desk Reference, Drug approval û j,,, p š š w w, y x x ùký.,,, ƒ w x š, 1) û y x šx,, ƒ š x ƒ û š š. 2) 500,000 w û w 50,000 Correspondence to : x y w w w/ w / w w p x 11-1 Tel: , Fax: hsgwak@ewha.ac.kr y y w w w/ w p x 11-1 Tel: , Fax: hwalee@ewha.ac.kr, 1 ü û. û serotonin w ƒ û 2~3 wš, ƒ» œ y 80%ƒ š. û x w öe œ ûš w ö ùkû. 3) ù ƒ» t» x ww w š. x w w k»x w w. z w û w l w., û w k t,, š û w š. ƒ û w k, 22

2 Physician's Desk Reference ùkù 23 w û w. w» Seldane (terfenadine) p ³ew w e x, 1998 w z n. Torsades de pointes š Seldane w û š û y l m l l yw w w» w. 4) Torsade de pointes w x j QT interval m û QT interval ¼ r, p QT interval g û e x ƒ k. 5) FDA (Food and Drug Administration) 1994l 2000 ¾ FDA 300 t k e w w swwš š, 20% û k ƒ š. 4) p û w w w j Cytochrome P450 (CYP)3A z û š CYP3A4 y û 20-50% j. z y ƒ j t ù 6),7) t w w z k. z y j w ü û j y ú. 4) ù w j 1993 z x NIH (National Institutes of Health)» w ƒ sw w w. 8) w 1993 FDA t w x s w sƒw ƒ w z œw» w Guideline for the Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs ww. 9) ù ƒ 1994» w FDA ü OWH (Office of Women's Health) w w w,, w wš. OWH t»» e w w w» w w w w t k w w š. 8) EMEA (European Medicines Agency) e ICH (International Conference on Harmonisation) x w y z e y w «šw x w š. 10) w k e w w öe š wš ù wš t w w. PDR (Pysicians' Desk Reference) 11) mw, t ƒ x ƒ w ƒ wš t z w mw ü w t xƒ» wš ª w t wš w. t xƒ w ƒ š, t xƒ w» w PDR GENDER j w t w w, ƒƒ t w PDR 2400 t FDA w t ƒ. 11) t xƒ w ùkù w š, 2009 PDR ü 2009 PDR CD-ROM GENDER j. ƒƒ t l GENDER ü, w, ƒƒ t w w ƒ ùkù w. w ƒ ƒ ùkù t w. w w z t, w. w w ƒƒ w m w t ( 1055t ) w 2009 PDR 11) t GENDER j w, 361 t t GENDER w x w. ƒƒ t l GENDER w ü w, ƒ ùkù w. 63 t ƒ ùkù ƒ w. ƒ w ATCg (Anatomical Therapeutic Chemical Classification System)» z w. z ƒ ùkü, (Nervous system) 21, x (Cardiovascular system) 9, y» m (Alimentary tract and

3 24 Kor. J. Clin. Pharm., Vol. 21, No. 1, 2011 Table 1. Drug list showing gender-based differences in PDR ƒ ùkù p Amphetamine Frovatriptan Pantoprazole Aprepitant Gemcitabine Pioglitazone Aripiprazole Indinavir Pramipexole Atorvastatin Irbesartan Propranolol Bevacizumab Lamotrigine Repaglinide Carisoprodol Levetiracetam Riluzole Caspofungin Levocetirizine Rituximab Cetuximab Levodopa Rizatriptan Citalopram Linezolid Rosiglitazone Clopidogrel Losartan Sibutramine Darifenacin Meloxicam Sirolimus Deferasirox Metaxalone Telithromycin Desloratadine Mirtazapine Telmisartan Desvenlafaxine Nevirapine Temozolomide Dexmethylphenidate Niacin Teriparatide (rdna origin) Enoxaparin Olanzapine Theophylline Esomeprazole Olmesartan Tipranavir Ezetimibe Olopatadine Topotecan Fentanyl Ondansetron Tramadol Fluvastatin Oxycodone Trospium Fluvoxamine Oxymorphone Zolmitriptan metabolism) 9 (Table 1). l ü w ƒ ùkù ü w w ü, ù kü ql AUC(x - š w ) C max (n z š x )ƒ ùkù 32. AUCƒ 30 š, C max ƒ 27. AUC C max w ƒ ùkû š 3. x ƒ ùkù 13 x ƒ ùkù 3. û ƒ ùkù 1 ùkû. jƒ û ùkù ü 18 ùkû.» ¼ 2 4. w w, š w ƒ š w 8. wr, zù ƒ ùkù» v w 2., w wù, w y e š w w. z ƒ 8, z ùkù 3, ùkù 5. Table 2. Nervous system agents Amphetamine Aripiprazole Citalopram Desvenlafaxine Dexmethylphenidate Fentanyl Fluvoxamine Frovatriptan Lamotrigine Levetiracetam Levodopa Metaxalone» w mg/kg n, amphetamine ƒ. ù w w C max AUC. aripiprazole y dehydro-aripiprazole C max AUCƒ û w. j ƒ û ù ùkù. citalopram AUCƒ 1.5 ~2 š ù w ƒ ùkù. C max AUCƒ ùkû.» n šx sww x ƒ š w ù. C max AUCƒ ùkû. AUC C max ƒ û w. ù ƒ ùkù. ù ƒ 2 ƒ¾. valproic acid lamotrigine, û w lamotrigine x ƒ 24~45% ùk û. šƒ w ùký. C max, AUCƒ 20%. Levodopa AUC C max ƒ w ùkû. Metaxalone C max AUC w š,» ¼ ùkû.» s û ù, w.

4 Physician's Desk Reference ùkù 25 Table 2. Nervous system agents (continued) Mirtazapine Olanzapine Oxycodone Oxymorphone Pramipexole Riluzole Rizatriptan Tramadol Zolmitriptan»ƒ w ¼ ùkû. Olanzapine jƒ 30% û. p w û v j ƒ 3 ùkú. ù š w v w. s³ x oxycodone ƒ 25%. Oxymorphone x x AUC, C max ƒ. ù Pramipexole jƒ 30% û ùkû. Riluzole AUCƒ 45% ƒw š s³ j 30% û. Rizatriptan s³ AUC C max ƒ. Tramadol AUCƒ. s³ x ƒ 1.5 ¾ ùkû. ƒ z t ùkù w ü 55 GENDER w š, 21 w w ƒ ùkù. ƒ ùkù w ü ƒ û w ùkù ü w ql AUC C max ƒ ùkù x ƒ 14 (Table 2). p olanzapine jƒ w û v 3 ùkú» ù š w v w š wš. GENDER w 32 x, û ƒ ùkù 9 Table 3. x ƒ ƒ ùkù ü x ƒ û w ü. Niacin, û j z ( w) ùküš, v w š ùkù ù w. GENDER w 36 y» m 9 w ƒ ùkû (Table 4). ƒ w ü ql C max AUCƒ ùkù ü 6 š. Rosiglitazone û w jƒ û ùkû BMI (Body mass index) rosiglitazone peroxisome proliferator-activated receptor-gammaƒ x» j ùkü w. pioglitazone, rosiglitazone e z ƒ j ùkû ù, š w x e y ww x e ƒ v w š wš. GENDER w 47 w (Antineoplastic and immumomodulating agents) t 7 ƒ ùkû. jƒ û ùkù ü 6 Table 3. Cardiovascular system agents Atorvastatin Ezetimibe Fluvastatin Irbesartan Losartan Niacin Olmesartan Propranolol Telmisartan C max ƒ 20% š, AUCƒ 10% û. LDL-C ƒ. x ƒ (<20%) ùkû z fluvastatin ƒ ù ƒ w. šx y»ù ƒ ù irbesartan x ƒ (11~44%) ùkû 65~75 losartan x ƒ û šx y w šx y 2 ùkû. ù y û w. z niacin k x ƒ û w ùkû. û w j w š û w û ùký. AUC C max ƒ 10~15%. j 15% û. s³ AUC C max ƒ ùkû.» ¼ ùkû. x ƒ 2~3. x w z ù» x ƒ.

5 26 Kor. J. Clin. Pharm., Vol. 21, No. 1, 2011 Table 4. Alimentary tract and metabolism agents Aprepitant 125 mg z n AUC 0-24h. C max 16%.» 25% û. Esomeprazole k AUC C max ƒ û w 13%. Ondansetron j. j û š» s. Pantoprazole û w AUC C max ƒ. w j w. Pioglitazone s³ C max, AUCƒ 20~60%. x HbA 1c ƒ j ùkû. Repaglinide 0.5~4 mg, 2x AUCƒ 15~70% ùkû. ù x ù»k w. Rosiglitazone w rosiglitazone jƒ w y û y w 6% û. j e z ƒ. ù ƒ ùkû. Rosiglitazone sulfonylureas n j e z ƒ. Sibutramine Trospium w w x C max 1 2 AUCƒ. k x ùkû. w w x û ùkû. ùkû. Gemcitabine jƒ û ùkû, û w,, p w w š, grade 3/4 y x q xw. Temozolomide jƒ û ùkû, w f grade 4 y x q (Table 5). GENDER w 38 w 5 ƒ ùkû. Telithromycin kw 3 x e w ƒ 40 w ƒ (Table 6). Nevirapine t š (Box Warning) t. y» 16 GENDER w. 3 ƒ ùkû (Table 7). Levocetrizine»ƒ w ùkû ù, j w š, š. Desloratadine desloratadine, C max AUCƒ ùkû. y» š w w ù, p w l w w. 10 GENDER š, 2 ƒ ùkû. Meloxicam x ƒ û ùk ûš, z n». 7.5 mg meloxicam z n s³»ƒ 19.5, û 23.4 ùkûš, k ( 17.9, û 21.4 )w. Carisoprodol ƒ ùkû ƒ 30-50% ùkû. Table 5. Antineoplastic and immumomodulating agents Bevacizumab û j s. Cetuximab ü jƒ 25% û. rs s y w j ƒ. w v. jƒ û ùkû. Gemcitabine û wù,, p Gemcitabine w w š, grade 3/4 y x q xw. p ƒ y û w 37% û j ùký. z Rituximab w. Sirolimus û w jƒ 12% û. û w»ƒ ƒ w. t jƒ 5% û. wf grade 4 y x q Temozolomide. Topotecan s³ x jƒ t û 24%.

6 Physician's Desk Reference ùkù 27 Table 6. General anti-infectious system agents Caspofungin Indinavir Linezolid Nevirapine Telithromycin Table 7. Respiratory system agents Desloratadine Levocetirizine Theophylline w 70 mg z n x w. 50 mg 13 n z caspofungin x. HIV û w AUC, C max x ƒ û. s û. x. 600 mg n z j 38% û. y 13.8% jƒ û. ùkû. w. e w w ƒ 40 w ƒ ƒ. Cmax AUCƒ. 3-hydroxydesloratadine Cmax AUC ƒƒ.» ùkû. j û w. j ù û. ù» 20 ú 3» j ƒ w ùkû. x x 8 GENDER w š, 2 ƒ ùkû. Clopidogrel ³ x q z ƒ ùk. ù x û ƒ š, ³ w ƒ š. Enoxaparin û j x ƒ ùkû.,» w. ƒ» 6 GENDER w š, 1 w ƒ ùkû. Olopatadine y n z C max ƒ 40%, AUC 27% ùkû. y 10 GENDER w š 1 ƒ ùkû. Teriparatide û 20~30% ƒ û ù, (20 µg/day) ƒ. ATCg» 18 GENDER w š 3 ƒ ü. Tipranavir, k x ƒ ùkû. Darifenacin k AUC C max ƒ ƒƒ 57-79% 61-73% ùkû. Deferasirox jƒ 17.5% û ùkû. ù û w l w ƒ š w. š 10 ƒwš p e w, w w w ƒ w. 12) y û y w x 1.5~1.7 š. 13),14) w ƒ x kw» w, z w» w, û n š ù, mg/kg y n w w ƒ w š. 12) û j»,, s,,, kw ùkü. j» û j.» x s w w s j ƒ. û» (kg) x ùkü. y w (kg) n 93% û 83% w w ù kû. 15) ¼ j w. 16) s û w û s j ùkù. û. s ƒ k. s j ùkù. 1, 2 z û ƒ š. 17) CYP3A z û

7 28 Kor. J. Clin. Pharm., Vol. 21, No. 1, 2011 CYP3Az» z y ƒ j t z z ƒ j ùkù. 4),, w w û j ùkù. y w jƒ x ƒ. ù ù š w, û w 10% û ùkù. 18) û kw w ùkù û w» w Long QT syndrome x ùkù w š š. 19) w 2/3ƒ ùkù. w w š û (rash) š. 13),14) w ƒ w ƒ y 75%ƒ š. w w, w ƒw ü. 20) w û k w w, 2009 PDR 11) w, 361 x w w. 63 t ƒ ùkù ü. kw qlƒ 69 š w ƒ ù kù 8. ƒ š w š 2 ùkû. t ùkù w» x» q z x ù y ƒ ùkù ƒ. ƒ w w. l PDRü wš w w ü w l w t l. t wš, e w» û t e wš, y mw e ù ƒ» w š wš w. ü w w t z ùkù w mw, w t xƒ v w š tt ( ) w w. š x 1. Yang X, Schadt EE, Wang S, et al., Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res 2006; 16: Pepine CJ, Kerensky RA, Lambert CR, et al., Some thoughts on the vasculopathy of women with ischemic heart disease. J Am Coll Cardiol 2006; 47: S Society for Women's Health Research. ( womenshealthresearch.org/site/pageserver?pagename =hs_sbb_10diff) 4. enotealone. ( 5. Ebert SN. Liu XK, Woosley RL. Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence. J Womens Health 1998; 7: Kim HJ, Choi JM, Kim YJ, et al., Review of gender differences in medicine and primary factors resulting in gender differences. Kor J Clin Pharm 2010; 20: Cummins CL, Wu CY, Benet LZ. Sex-related differences in the clearance of cytochrome P450 3A4 substrates may be caused by P-glycoprotein. Clin Pharmacol Ther 2002; 72: Protecting and Advancing Women's Health: The FDA Office of Women's Health Æ Progress Peport 10 years and Beyond, Mar report0306.pdf) 9. Guideline for Study and Evaluation of Gender Differences in the Clinical Evaluation of Drugs, Jul ( Reflection Paper on Gender Differences in Cardiovascular Diseases, Dec ( 11. PDR 63edition Gail D. Gender differences in pharmacological response. Int Rev Neuro 2008; 83: Fattinger K, Roos M, Vergeres P, et al., Epidemiology of drug exposure and adverse drug reactions in two Swiss departments of internal medicine. Br J Clin Pharmacol 2000; 49: Tran C, Knowles S, R Liu, et al., Gender difference in

8 Physician's Desk Reference ùkù 29 adverse drug reactions. J Clin Pharmacol 1998; 38: Domecq C, Naranjo C, Ruiz I et al., Sex-related variations in the frequency and characteristics of adverse drug reactions. Int J Clin Pharmacol Ther 1980; 18: Mojaverian P, Rocci M, Vlasses P et al., Effect of Food on the absorption of enteric coated aspirin: Correlation with gastric residence time. Clin Pharmacol Ther 1987; 41: Anderson G. Sex and racial differences in pharmacological response: Where is the evidence? Pharmacogenetics, and pharmacokinetics, and pharmacodynamics. J Womens Health 2005; 14: Gross J, Friedman R, Azevedo M, et al., Effect of age and sex on glomerular filtration rate measured by 51Cr-EDTA. Braz J Med Biol Res 1992; 25: Drici M, Clement N. Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome. Drug Saf 2001; 24: Buckwalter J, Lappin D. The disproportionate impact of chronic arthralgia and arthritis among women. Clin Orthop Relat Res 2000; 372:

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16(2)-7(p ).fm w wz 16«2y Kor. J. Clin. Pharm., Vol. 16, No. 2. 2006 ü t xy y w tœ ½ BÁ x BC B y w w w C y w w w Current Status and Expectations of Orphan Drugs in Korea -In point of supplying medicines for the rare