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1 ±SD C max ±SD -21

2 t max ±SD AUC±SD -23

3 t 1/2 ±SD CL±SD -25

4 PK PK 4-2recFSH 7 75 IU IU IU D F 7 3 O R S recfsh recfsh -15 m kg BMI kg/m 2 FSH 1) IU/L -2 B 2) / 1.9 E 2) /.54 D 2) /.52 F / /.63 SD / / / O /.87 P / 1.1 Q /.42 R / 1.15 S /.19 T /.16 U ) /.5 3) /.56 SD / ) /.5 3) / ) : rec FSH / 432 2) B B E E D D 3).5 IU/L FSH FSH 2 B F FSH 2 FSH -19 FSH -111

5 A 3 B 3 FSHIU/L) FSHIU/L) A-4B FSH C FSH (IU/L) D FSH (IU/L) ( ) -19-2C-4D FSH ( ) PK C ss,min t ½ -17 recfsh C ss,min 4 recfsh 4 9% FSH t ½ B -112

6 PK -16 (kg) C ss,min (IU/L) 1 t ½ (h) 2 75 IU 15 IU 225 IU 75 IU 15 IU 225 IU B F E R U O D T Q S P SD *PK [-1] 3 Appendix 1 1) FSH 2) FSH FSH C ss,min -2 FSH C ss,min -21 A B -2AB C ss,min IU (n=4)15 IU (n=3)225 IU (n=3) 75 IU (n=7)15 IU (n=7)225 IU (n=4) -113

7 C D -21CD C ss,min IU (n=4)15 IU (n=3)225 IU (n=3) 75 IU (n=7)15 IU (n=7)225 IU (n=4) PK PK/PD IU 6 kg -23 AUC AUC -1-2 FSH PK C max C max -25 t max -5 t max t max FSH 136 FSH

8 -18 PK/PD -17 () ,-6 x x x x x x x x x x x x x (x) x x x x -2, -1 x x x x x x x x x x x -3, -8 x x x x x x x x x x (x) x x x x x -5, -9 x x x x x x x x x x x x -12 x x x x x x x x x x x x x (x) 7 6 FSH (IU/L) (h) IU 5 FSH t 1/ FSH t 1/2-115

9 AUC (IU.h/L) 25 2 AUC (IU.h/L) , 15, SC 1 IM SC IM SC IM IM , 15, SC IM SC IM SC IM IM -8 9* * PK AUC-3 * () C max (IU/L) 8 6 C max (IU/L) , 15, , 15, SC IM SC IM SC IM IM SC1 IM 2 SC 3IM SC 4 IM5 6IM 7-8 9* * PK C max -31 * () -116

10 t max (h) 3 t max (h) , 15, IM SC IM SC IM IM -8 9* , 15, SC1 IM 2 SC 3IM SC 4 5IM 6IM 7-8 9* PK t max -32 * () t ½ (h) 5 4 t ½ (h) , 15, SC IM SC IM IM -9* # -1-11# 75, 15, SC IM SC IM IM -9* # -1-11# -26PK t 1/2-33 * #75, 15, 225 IU1 () -117

11 2.2.4 PK PK/PD recfsh PK PK IU PK/PD PK FSH Lyndiol FSH Lyndiol PK -9-1hCG FSH hcg FSH FSH FSH hcg FSH 24 FSH C ss,min FSH kg kg FSH C ss,min hcg FSH hcg FSH C ss,min -27 PK FSH PK PK FSH ART PK PK -118

12 A B -27 hcg FSH hcg FSH -35 n=149n= PD -2-4 FSH mm FSH FSH FSH mm FSH FSH (IU/L) B FSH IU 15.7 D FSH IU 8.6 F FSH IU 2.2 / 23. 1) O FSH 1 15 IU 7.25 Q FSH IU 11.8 R FSH IU 1.1 S FSH 4 75 IU 1.64 / ) 1) 19 / ) 3 / 5-5 FSH IU IU 7 81 mm 112 mm 15 IU IU 15 IU 16 mm -119

13 IU (n=12) 15IU (n=11) 225IU (n=1) 5 < (mm) -28 Org ART FSH -29 hcg FSH 1 mm FSH FSH -3 FSH FSH USS recfsh USS E 2 FSH OHSS FSH -12

14 FSH FSH PD FSH high responder FSH poor responder IU IU IU IU IU/21.5 IU/ PK FSH SD-31A FSH -31B 17 mm 3 FSH OHSS FSH -31AB OHSS FSH -121

15 -29Org32489 PK/PD: hcg FSH n=149n=12-122

16 -3Org32489 PK/PD: hcg FSH n=149n=12-31 OHSS -4 5 SD A 4.1±.75 IU/kg (n=153)ohss 3.39±.79 IU/kg (n=9) 3.35±1.1 IU/kg (n=11)ohss 3.21±.71 IU/kg (n=7) B 35.2±12.2 IU/kg (n=153)ohss 27.4±8.5 IU/kg (n=9) 33.3±12.9 IU/kg (n=11)ohss 28.±2.7 IU/kg (n=7) FSH ufsh FSH

17 OHSS PD PD FSH Mannaerts, BMJL et al.: Clinical profiling of recombinant follicle stimulating hormone (rfsh; Puregon): relationship between serum FSH and efficacy. Human Reproduction Update, 2, (1996) 7 Duijkers, IJM et al.: Pharmacodynamics and pharmacokinetics after repeated subcutaneous administration of three gonadotrophin preparations. Human Reproduction, 12, (1997) 8 Baird, DT: A model for follicular selection and ovulation: lessons from superovulation. J. Steroid Biochem. 27, (1987) 9 Ben-Rafael, Z et al.: Pharmacokinetics of follicle-stimulating hormone: clinical significance. Fertil. Steril., 63, (1995) 1 Scheele, F and Schoemaker, J: The role of follicle-stimulating hormone in the selection of follicles in human ovaries: a survey of the literature and a proposed model. Gyn. Endocrinol., 1, (1996) 11 Macklon, NS and Fauser, BCJM: Follicle development during the normal menstrual cycle. Maturitas, 3, (1998) 12 Schipper, I et al.: Lack of correlation between maximum early follicular phase serum follicle stimulating hormone concentrations and menstrual cycle characteristics in women under the age of 35 years. Human Reproduction, 13, (1998) 13 Schipper, I et al.: The follicle-stimulating hormone (FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration rather than magnitude, of FSH increase affects follicle development. J. Clin. Endocrinol. Metab., 83, (1998) -124

18 2.3 PK PD 672 C D recfsh C C PD recfsh FSH FSH recfsh FSH FSH recfsh ufsh in vitro 14 ufsh recfsh FSHLH hmg 4 15 hmg FSH/LH 1 ufsh-hp FSH/LH 6 ufsh-hp LH FSH DNA recfsh recfsh hmg 16 FSH FSH USS USS IVF-ET 17 FSH USS ART FSH 2. recfsh ufsh -11 PK -125

19 t max FSH t max C max t max ufsh recfsh n-c max IU/L 1% C max C max FSH C max n-c max IU/L 3 ufsh 1 recfsh t max n-auc IUh/L AUC ufshrecfsh t 1/ le Cotonnec 18 ufsh recfsh PK t 1/ ) FSH t 1/2 t 1/2 19 2) le Cotonnec FSH GnRHa GnRHa FSH FSH PK n-c max, n- AUC t 1/2 recfsh ufsh PK recfsh ufsh ufsh ufsh PK recfsh ufsh -126

20 -11 Org FSH PK N C max 3) n-c max t max AUC 4) n-auc 3) t ½ (IU) 2) (IU/L) (h) (IUh/L) (h) Org s.d./i.m ± ± ± ± ± ± ufsh-hp 3 s.d./i.m ± ± ± ± ± ± 9.3 Org32489 Org32489 (cake) 15 s.d./s.c ± ± ± ± ± ± PK Org32489 (pen) 15 s.d./s.c ±.7.23 ± ± ± ± ± 4.2 recfshα ufsh-hp 15 s.d./i.v ± ±.33 NR 319 ± ± ± 3 18 ufsh-hp PK recfsh 1) 15 s.d./i.v ± ±.67 NR 274 ± ± ± 7 recfsh 1) 3 s.d./i.v ± ±.6 NR 598 ± ± ± 3 Org s.d./i.v ± ±.13 NR 588 ± ±.68 ND 22 Org s.d./i.m ± ± ± ± ±.45 ND Org s.d./s.c ±.7.18 ± ± ± ±.47 ND PK/PD Org m.d./s.c ±.6.57 ± ± ± ± ± Org m.d./s.c ± ± ± ± ± ± 4.6 Org m.d./s.c ± ± ± ± ± ± 2.9 Org m.d./i.m ± ± ± ± ± ± 4.6 PK/PD hmg(3/1) 15 m.d./s.c ± ± ± ± ± ± hmg(6/1) 15 m.d./s.c ± ± ± ± ± ± 3. ufsh-hp 15 m.d./s.c ± ± ± ± ± ± 4.7 1) α 2) s.d. ; m.d. ; i.v. ; i.m. ; s.c. 3) n-c max n-auc (=/) 4) s.d. AUC - m.d. AUC -24h NR ND

21 2.3.2 D D 1. PK 2. PD , 8-5 n-c max n- AUC PK ,

22 , IU USS , Kupffer N- 33 7% 34,35 ufsh FSH , 14, 15 FSH 3 3 IU -3 FSH C max t max AUC -312h FSH FSH Org32489 IV, IM, SC PK IV 5 IM 5 SC 5 C max (IU/L) t max (h) AUC -312h (IUh/L) F (%)95% C.I.) ± 3.89 n.a ± 22.7 n.a ± ± ± ( ) 5.41 ± ± ± ( ) n.a. C.I.F FSH AUC 77% C max t max t max -129

23 FSH recfsh , 17 FSH FSH recfsh recfsh 35 kd in vitro FSH FSH LH GnRH FSH 2 FSH hcg FSH 22.5 FSH hcg recfsh FSH recfsh GnRH -13

24 Org PK PD PK PK FSH PD FSH recfsh -131

25 de Leeuw, R et al.: Structure-function relationship of recombinant follicle stimulating hormone (Puregon). Molecular Human Reproduction, 2, (1996) 15 Lunenfeld, B et al.: Clinical effects of a human postmenopausal gonadotropin. Rass. Clin. Therap. 59, (196) 16 Out HJ, et al.: A prospective, randomized, assessor-blind, multicentre study comparing recombinant and urinary follicle stimulating hormone (Puregon versus Metrodin) in in-vitro fertilization. Human Reproduction 1, (1995) 17 IVF-ET le Cotonnec, J-Y et al.: Clinical pharmacology of recombinant human follicle-stimulating hormone (FSH). I. Comparative pharmacokinetics with urinary human FSH. Fertil. Steril., 61, (1994) 19 le Cotonnec, J-Y et al.: Clinical pharmacology of recombinant human follicle-stimulating hormone. II. Single doses and steady state pharmacokinetics. Fertil. Steril., 61, (1994) 2 Mannaerts, BMJL et al.: Clinical profiling of recombinant follicle stimulating hormone (rfsh; Puregon): relationship between serum FSH and efficacy. Human Reproduction Update, 2, (1996) 21 Voortman, G et al.: Bioequivalence of subcutaneous injections of recombinant human follicle stimulating hormone (Puregon ) by Pen-injector and syringe. Human Reproduction, 14, (1999) 22 Absolute bioavailability study. Protocol 37614, SDG RR 3692 (1994) 23 Voortman, G et al.: A dose proportionality study of subcutaneously and intramuscularly administered recombinant human follicle stimulating hormone (Follistim/Puregon) in healthy female volunteers. Fertil. Steril., 73, (2) 24 Duijkers, IJM et al.: Pharmacodynamics and pharmacokinetics after repeated subcutaneous administration of three gonadotrophin preparations. Human Reproduction, 12, (1997) 25 Baird, DT: A model for follicular selection and ovulation: lessons from superovulation. J. Steroid Biochem., 27, (1987) 26 Ben-Rafael, Z et al.: Pharmacokinetics of follicle-stimulating hormone: clinical significance. Fertil. Steril., 63, (1995) 27 Scheele, F and Schoemaker, J: The role of follicle-stimulating hormone in the selection of follicles in human ovaries: a survey of the literature and a proposed model. Gyn. Endocrinol., 1, (1996) 28 Macklon, NS and Fauser, BCJM: Follicle development during the normal menstrual cycle. Maturitas, 3, (1998) 29 Schipper, I et al.: Lack of correlation between maximum early follicular phase serum follicle stimulating hormone concentrations and menstrual cycle characteristics in women under the age of 35 years. Human Reproduction, 13, (1998) 3 Schipper, I et al.: The follicle-stimulating hormone (FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration rather than magnitude, of FSH increase affects follicle development. J. Clin. Endocrinol. Metab., 83, (1998) 31 Boer, de JAM et al.: Growth hormone (GH) substitution in hypogonadotropic, GH-deficient women decreases the follicle-stimulating hormone threshold for monofollicular growth. J. Clin. Endocrinol. Metab., 84, (1999) 32 Drickamer, K: Clearing up glycoprotein hormones. Cell, 67, (1991) 33 Nisula, BC et al.: Metabolic fate of human choriogonadotropin. J Steroid Biochem., 33, (1989) 34 Lefort, GP et al.: Evidence that desialylation and uptake by hepatic receptors for galactose-terminated Glycoproteins are immaterial to the metabolism of human choriogonadotropin in the rat. Endocrinology 115, (1984) 35 Morell, AG et al.: The role of sialic acid in determining the survival of glycoproteins in the circulation. J Biol. Chem., 246, (1971) -132

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