Single and multidose pharmacokinetic study of a vaginal micronized progesterone insert (Endometrin)

Transcription

1 Sigle ad multidose pharmacokietic study of a vagial microized progesteroe isert (Edometri) 按一下以編輯母片副標題樣式 compared with vagial gel i healthy reproductive-aged E m ily J. B la ke, M.D., Fertility a d S terility V ol. 94, N o. 4, S eptem ber 2010 P res eter: R 孫怡虹

2 Itroductio IVF / ART -- exogeous luteal phase support Edometrial preparatio (edo- or exogeously) Estroge Edometrial proliferatio Progesteroe Secretory trasformatio Available exogeous optios: oral, IM, vagial formulatios

3 oral admiistratio Coveiet rapidly cleared by 1st-pass hepatic metabolism low systemic bioavailability requires high doses associated with systemic adverse effects (drowsiess, flushig, ad ausea) P ha rm a c okietic ifluec ed by food ita ke Lim ited effic a c y i iduc ig a ipha s e s ec retory edom etrium

4 IM admiistratio Rapidly absorbed, 2 hrs -- High plasma cocetratios, 8 hrs -- Peak cocetratios Extremely ucomfortable (oil-based product) D a ily ijectios maitai adequate [progesteroe]s Placetal autoomy: 10~12 ws protracted use of daily IM ijectios Iflammatory reactios at the ijectio

5 Vagial route Avoids the variable absorptio, high first-pass hepatic metabolism, ucomfortable (ofte paiful), Result i sustaied plasma cocetratios Sigificat levels of progesteroe to the edometrial tissue, iducig secretory trasformatio

6 Progesteroe Available for vagial admiistratio More reliable delivery of progesteroe tha oral Favorable Pharmacokietics Greater bio-availability Less variability i serum cocetratios Equivalet edometrial developmet ad pregacy rates comparig with IM (cohort observatioal study)

7 Edometri A ovel vagial microized progesteroe isert àluteal support i the Tx of ifertile wome udergoig ART The comparative pha rm a c okietic pa ra m eters of this ew vagial isert ad a previously marketed Va g ia l g el prog es teroe

8 Purpose of this study Compare Pharmacokietic & safety profiles 2 dosage regimes of the Microized progesteroe 100 mg vagial isert (twice a day & three times a day) 8% vagial gel (90 mg every day) I Normal, reproductive-aged females with a itact uterus

9 Pricipal pharmacokietic objective [1] Obtai s ig le-da y ad s tea dys tate progesteroe pharmacokietics for the 3 treatmet groups [2] Describe progesteroe s tea dys ta te pharmacokietics [3] Compare progesteroe pharmacokietics amog the three treatmet groups.

10 MATERIALS AND METHODS Guidelies of the Uiversity of Miami Huma Subjects Research Committee (istitutioal review board Good Cliical Practices ad Iteratioal Coucil o Harmoizatio guidelies Persoel iformed coset before etry ito the study Phase I Cliical Research Uit of the Divisio of Cliical Pharmacology of the Uiversity of Miami

11 Study Desig Sigle-ceter, radomized, ope-label, parallel desig pharmacokietic study Normally cyclig female, 18 ~ 40 y/o, itact uterus 18 x subjects (6/ Tx group), radomly assiged to receive 1 of 2 differet dosig regimes 100 mg vagial isert (2 or 3 times a day) (E dometri, Ferrig Pharmaceuticals, Ic., P arsippay, NJ) 8% gel (90 mg every day)

12 4-Phases Screeig Sigle-day (Sigle day of dosig, 24hr) Washout (7-day) separated the sigle- & multiple-day Multiple day (5 days of dosig)

13 subjects Geeral good health (by medical Hx & PE) Regular mestrual cycles (24 ~ 35 days) BMI: 18 ~ 28 kg/m2 Negative Pap smear Negative urie pregacy test Radomly assiged to 1 of 3 Tx arms of study medicatio

14 Iitiated after mestrual flow ceased Betwee cycle days 5 & 8 of the subject s MC S igle-day phase Drug admiistered for 1 day Sigle dose Every day treatmet 2 doses, Q12H 2 times a day Tx 3 doses, Q8H 3 times a day Tx Blood samples for pharmacokietic aalysis Pre-dose (0 hour) 2, 4, 8, 12, 16, 24, 36, ad 48 hours

15 à à à 7-day washout phase Retured to the phase-i i-patiet uit Stay of approximately 6 overights Received 5 days of treatmet durig the Multiple-day phase O day 5 of medicatio, Blood samples Pre-dose (0 hour), at 2, 4, 8, 12, 16, 24, 36, ad 48 hours after first dosig

16 Safety parameters Adverse evets (AEs) Serious AEs (SAEs) Cliical laboratory evaluatios (hematology ad serum chemistry) Vital sigs (blood pressure, heart rate, ad body temperature) Electrocardiogram

17 Aalytical Methods Validated, sesitive, & specific ra dioim m uoa s s a y 125-I labeled progesteroe derivative àquatify progesteroe cocetratios i huma serum Coefficiets of variatio for quality cotrol samples Itra-assay/Iter-assay: 2~8%/5~10%

18 Statistical Methods ad Pharmacokietic Aalysis Tx group comparisos for demographic ad baselie characteristics Fisher s exact test qualitative variables ad aalysis of variace Kruskal-Wallis test quatitative variables

19 Pharmacokietic parameters (Sigle-day & multipledose, multiple-day, Tx day 5) Max observed serum cocetratio (Cmax) Time to Max observed serum cocetratio (Tmax) A rea uder the serum cocetratio (systemic exposure) Time curve over the dosig iterval (AUC0 T)

20 Pharmacokietic parameters Trough (pre-dose) cocetratios assess the oset of s tea dy s tate Fluc tuatio Idex over a 24-hour period : (Cmax-Cmi)/(AUC0 24/24) Cmi was determied by ispectio

21 RESULTS Compliace

22 Pharmacokietic Results Sigle-day Treatmet M ea C m a x (g / m L) / A U C 0 24(g h/m L): 17/217 (2x/D is ert) 19.8/284 (3x/D is ert)

23 Approach to Steady State Trough (predose) cocetratios oce per day Durig the multiple days Is erted g roup: 24~32 hours

24 Multiple-day Treatmet: day 24-hr period of D5: Progesteroe threshold associated with the midluteal phase 5

25 2 x 30% higher Less tha dose proportioal respose Radom variability across most treatmets i a previous study with Edometri slow approach to

26 variability Betwee-subject variability i day 5 pharmacokietic parameters => Vagial gel: Greatest Vagial isert 3x/D: Least Coefficiet of variatio for Cmax o day 5 => gel group: 39.7% Vagial isert 3x/D: 23.2% Vagial isert 2x/D: 29.9% (itermediate)

27 Decay phases 2 & 3 times daily idetical at 24 ad 48 hours postdose The gel group: Prologed (cocetratios decreased by oly about a factor of four durig the 48- hour observatio period) Slowed eve further with repeated dosig àby the ed of the 5-day period àno decay i serum progesteroe cocetratio over the 36-hour widow from 12 hours to 48 hours postdose

28 Safety Results Serious AE ecompass the followig evets Death, Life-threateig (i.e., at immediate risk of death), I-patiet hospitalizatio or prologatio of existig hospitalizatio, Persistet or sigificat disability/icapacity, Cogeital aomaly/birth defect

29 Safety Results Total AES : 7 (o SAEs, mild i itesity) 1x headache (vagial gel every day) 3x mild vagial, durig the washout phase (3 times a day), subsided after persisted progesteroe use Normal withdrawal bleedig, rather tha breakthrough bleedig Abdomial pai, back pai, ad rash All resolved without treatmet withi 3 to 4 days

30 DISCUSSION Pharmacokietic profile of both dosage regimes of the vagial isert formulatio of progesteroe compares favorably with the vagial gel formulatio Limitatios small sample size cosiderable variability of plasma cocetratios amog the study subjects. Variables such as Mestrual cycle/phase

31 Coclusio 2 dosage regimes of a ovel vagial isert formulatio of progesteroe ca à achieve relatively high serum progesteroe cocetratios à reach steady state withi 24 to 32 hours à maitai mea cocetratios above 10 g/ml.

32 à à à à Edometri vagial isert formulatios Reached higher Cmax Produced greater systemic exposure (AUC0 24) Achieved steady state more rapidly Leared more rapidly after termiatio of therapy tha the comparator

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