Pharmacokinetics of a triphasic oral contraceptive containing desogestrel and ethinyl estradiol*

FERTILITY AND STERILITY Copyright

©

Vol. 61, No, 4, April 1994

1994 The American Fertility Society

Printed on acid-free paper in U

s. A.

Pharmacokinetics of a triphasic oral contraceptive containing desogestrel and ethinyl estradiol*

David F. Archer, M.D.t Cees J. Timmer, M.Sc.:\: Paul Lammers, M.D. § The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia; Organon International B. V" Oss, The Netherlands; and Organon Inc" West Orange, New Jersey

Objective: To demonstrate that pharmacokinetic measurements were made at steady state, Subsequently, dose proportionality for desogestrel and ethinyl E2 kinetics were demonstrated, Design: Open-label, noncomparative study, Setting: Healthy volunteers in an academic research environment, Participants: Twenty white women who were 19 to 32 years old were solicited via an advertisement, Nineteen of the 20 women completed the study, Interventions: Study medication consisted of three cycles of a triphasic oral contraceptive containing desogestrel and ethinyl E 2, Blood samples were taken at baseline and during cycle 3 between -48 and 24 hours on days 1, 7, 14, and 21, with additional sampling times on day 21 at 48, 60, and 72 hours. Main Outcome Measures: Serum concentrations of 3-keto-desogestrel and ethinyl E 2. Results: Evaluation of the trough serum levels indicated that a steady state of 3-keto-desogestrel had been reached. Statistical analysis on the C max , area under the curve (AUC), and C••.min indicated dose proportionality for the administered desogestrel. Ethinyl E2 serum levels obtained at the same time points also reflected steady state levels and showed minimal variability. The statistical analysis on Cmax , AUC, C ..,min' and T max indicated that the pharmacokinetics of ethinyl E2 on days 7, 14, and 21 were not statistically significantly different, indicating dose equivalency. Conclusions: Steady state of 3-keto-desogestrel is reached after each ofthe three phases and the pharmacokinetics are dose proportional. After reaching steady state, the pharmacokinetics of ethinyl E2 remain constant over time, Fertil Steril 1994;61:645-51. Key Words: Desogestrel, ethinyl E 2, pharmacokinetics, steady state, triphasic oral contraceptives

Oral contraceptives (OCs) contain both an estrogen and a progestogen, and their contraceptive efficacy is dependent upon the pharmacokinetics of

Received July 26, 1993; revised and accepted November 29, 1993. * Supported by Organon, Inc., West Orange, New Jersey. t Reprint requests: David F. Archer, M.D., The Jones Institute for Reproductive Medicine, 601 Colley Avenue, Norfolk, Virginia 23507-1912. :I: Drug Metabolism and Kinetics, Organon International B.V. § Professional Services Department, Organon, Inc. Vol. 61, No, 4, April 1994

these two steroids. Numerous factors can influence the absorption, distribution, metabolism, and excretion of these steroids. In addition, there is a considerable interindividual variability in these parameters because of environmental, genetic, dietary, and other factors. Desogestrel is an orally active progestin that is metabolized rapidly and extensively by the liver to 3-keto-desogestrel (1). 3-Keto-desogestrel has a high progestational activity based on receptorbinding studies and is considered to be the biologically active metabolite of desogestrel (2). Therefore, Archer et al.

Pharmacokinetics of desogestrel

645

;

the pharmacokinetic profile of desogestrel is best characterized by the serum levels of 3-keto-desogestrel. Desogestrel is one of a new generation of more selective progestogens to be used in OCs (which means that the compound has a high affinity for the P receptor and a low affinity for the androgen receptor). A monophasic OC preparation containing desogestrel was introduced first in most European countries starting in 1981 under the trade name Marvelon (Organon International, The Oss, The Netherlands) and recently also in the United States under the trade names Desogen and ORTHOCEPT (Organon Inc., West Orange, NJ and Ortho Pharmaceutical Corp., Raritan, NJ, respectively). Previous pharmacokinetic studies using this monophasic preparation containing 150 Jlg/d desogestrel and 30 Jlg/d ethinyl E2 have shown a rapid absorption and a high bioavailability of both 3 -keto-desogestrel and ethinyl E2 (3-6). The current study was designed to evaluate the pharmacokinetics of three different combinations of desogestrel and ethinyl E2 in a new triphasic OC preparation during steady state conditions in healthy volunteers. MATERIALS AND METHODS Volunteers

All 20 subjects in this study were volunteers who were solicited via an advertisement. The protocol, informed consent, and advertisement copy all had been approved by the Institutional Review Board for Human Subjects at the Eastern Virginia Medical School before any recruitment. Each volunteer was required to be between the ages of 18 and 35 years, in good health without any medical condition that would preclude the use of an OC, and not taking any concurrent medication. An explanation of the study and the signing of an informed consent took place before the performance of a complete history and physical examination. During this examination, a Papanicolaou smear was obtained, along with venous blood samples for hematologic and biochemical evaluation. A urine analysis was performed. All laboratory results were required to be within the normal range for each parameter to enroll the volunteer into the study. Nineteen of 20 volunteers completed the entire study.

blister strips. The dosage schedule was 7/7/7, that is, three times 7 days of a different dose, followed by a 7-day tablet-free period to reflect a 28-day cycle. The tablets in sequence contained 50/35 Jlg desogestreljethinyl E 2; 100/30 Jlg desogestreljethinyl E 2 ; and 150/30 Jlg desogestreljethinyl E2 and were supplied by Organon Inc. (West Orange, NJ). Study Protocol

In this open-label, noncomparative study, each volunteer initiated the study medication on the first Sunday after the onset of menses and took one tablet each day thereafter for 3 consecutive weeks followed by a tablet-free period of 7 consecutive days. The tablets were to be taken at a consistent time of day at 24-hour intervals. During the third cycle of use of the medication, subjects were instructed to take their pills at 8.00 A.M. to maintain consistency with dosing for pharmacokinetic assessments. Venous blood samples were obtained on days 1, 7, 14, and 21 of active pill use. Each volunteer underwent multiple venous blood sampling at -48, -24, 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, and 24 hours on medication days 1, 7, 14, and 21, with additional sampling times on day 21 at 48, 60, and 72 hours. Each serum sample was then analyzed for 3 -keto-desogestrel, ethiny1 E 2 , and sex hormonebinding globulin (SHBG) as described in the section on Analysis of 3-keto desogestrel, ethinyl E 2 , and SHBG. After completion of the three study cycles, each volunteer was offered the opportunity to continue with the study medication in an ongoing evaluation of the safety and efficacy of this triphasic OC preparation. Blood Sampling

All peripheral venous blood samples were obtained by venipuncture except during the pharmacokinetic phase, when an indwelling venous intracatheter was placed. Patency was' maintained with a dilute heparin solution. All venous samples were allowed to clot at room temperature for 10 minutes and then centrifuged at 5,000 rpm for 10 minutes. After this, the serum was decanted into vials and stored at -20°C until analysis.

Preparations

Analysis of 3-keto-desogestrel, ethinyl E 2 • and SHBG

The study medication consisted of oral tablets containing desogestrel and ethinyl E2 in 21-day

All serum samples from the same volunteer were run in the same assay. Hazelton Laboratories

646

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Pharmacokinetics of desogestrel

Fertility and Sterility

(Vienna, VA) performed all the 3-keto-desogestrel, ethinyl E 2, and SHBG assays. 3-keto-desogestrel was estimated using a specific RIA. The following procedure was used: the serum samples were extracted with anhydrous diethyl ether followed by chromatography of the organic phase extract. 3-Keto-desogestrel was isolated by step-gradient elution with ethyl acetate: isooctane through celite-supported ethylene glycol. The 3keto-desogestrel-containing eluent was then dried and reconstituted in an aqueous buffer. The celite chromatography isolated 3-keto-desogestrel from a metabolite, 3-keto-5a-H-desogestrel, which was found to cross-react substantially with the 3-ketodesogestrel antibody. The concentration of 3-ketodesogestrel was then estimated in an RIA using rabbit-anti -3-keto-desogestrel-3 -carboxymethyloxine-bovine serum albumin (BSA) at a final dilution of 1:150,000. This antibody cross-reacted for 32.8 % with 3-keto-5a-H -desogestrel. This antibody was evaluated against other metabolites of desogestrel with the following results: cross-reactivity with 3iJ-OH-desogestrel, 3.8%; 3iJ-OH-5a-H-desogestrel, 1.6%; 3a-OH-5a-H-desogestrel, 1.2%; and desogestrel, 0.5%. Cross-reactivity with other endogenous steroids was <0.001 %. Ethinyl E2 initially was extracted with the same technique as described above for 3-keto-desogestrel followed by isolation on the celite column. The ethinyl E2 content of the eluted fraction was estimated using an RIA where the antibody was a rabbit antibody raised against ethinyl E2-7-(3-thiopropanic acid)-BSA. The cross-reactivity of the antibody with 17iJ-E2 was 1.1 %, with 2-0H-ethinyl E 2, 1.6%, with desogestrel, 0.5%; with mestranol, 0.9%, with 16-0H-ethinyl E 2, 0.1%; and with 3-keto-desogestrel < 0.01 %. Blood samples from the O-hour blood draw of days 1, 7, 14, and 21 were also used for SHBG determinations by immunoradiometric assay (IRMA) (Farmos Spectria, Turku, Finland). Data Analysis

The following pharmacokinetic parameters were calculated from the 3-keto-desogestrel and ethinyl E2 serum levels: 1. Minimum steady state serum concentration (C ••,min); C•• , min was characterized by serum levels measured at -48, -24,0, and 24 hours of days 7, 14, and 21. 2. Peak serum concentration (C max ) and peak Vol. 61, No.4, April 1994

serum time (T max); C max and T max were taken from the measured serum level data. 3. Area-under-the-curve (AUC); the AUC was calculated over the 24-hour dosing interval of the last dose of each 7-day dosing period by means of the trapezoidal rule. 4. Elimination half-life (Tl/2elim); Tl/2elim was calculated by means of the individual plots of the log concentration versus time for the last dose of the last 7-day dosing period (day 21). It was estimated from which time onward, up to the last data point at 72 hours, the curve was approximately log linear. Using log-linear regression on these terminal data points, the Tl/2elim for each individual subject was estimated. To verify the attainment of steady state both for 3-keto-desogestrel and ethinyl E 2 , a one-way analysis of variance (ANOVA) with repeated-measures design was used for C••,mins' If the means of the serum concentrations at -48, -24, 0, and 24 hours on days 7, 14, and 21 were not significantly different (P> 0.05), then steady state was assumed. Dose proportionality was tested for 3-keto-desogestrel with dose levels of 50, 100, and 150 ILg desogestrel at steady state. For ethinyl E 2, dose proportionality cannot be tested, because only the dose during the first 7 days of treatment (35 ILgjd) was slightly higher than that on the remaining 14 days (30 ILgjd). Therefore, comparison of ethinyl E2 parameters on days 7, 14, and 21 can be referred to more accurately as dose equivalence. To verify dose proportionality (3-keto-desogestrel) anddoseequivalence (ethinyl E 2), an AN OVA with repeated-measures design was used. For the parameters known to be dose dependent (C max , C••,min, and AUC), the analysis included also polynomial contrasts to evaluate the relationship with the dose level in the case of 3-keto-desogestrel. For ethinyl E 2, the serum concentrations on day 7 were normalized to a 30-lLg dose by multiplication with a factor obtained by dividing 30 ILg by 35 ILg. Mean SHBG serum levels were measured from the O-hour blood draw on days 1, 7, 14, and 21 of cycle 3 and the mean values were tabulated. Analysis of variance with repeated-measures was used. Mean data are presented as mean ± SD. RESULTS Study Population

Twenty subjects were enrolled in the study, 19 of whom completed all study assignments according Archer et al.

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647

Table 1 Minimum Steady State Serum Concentrations of 3-Keto-Desogestrel on Days 7, 14, and 21

Table 2 Minimum Steady State Serum Concentrations of Ethinyl E2 on Days 7, 14, and 21

Cs8,min * 50 ILg Desogestrel (day 7) n

Time

100 ILg Desogestrel (day 14) n

h

pg/mLt

pg/mLt

-48

227.8 ± 98.9 19 253.6 ± 96.8 19 276.4 ± 80.6 271.3 ± 106.1 18

589.0 ± 272.4 19 653.1 ± 214.9 19 670.7 ± 231.4 641.3 ± 265.9 19

-24 0 24

Css,min

150 ILg Desogestrel (day 21) n

Time

pg/mLt

1,021.6 ± 19 1,089.6 ± 18 981.5 ± 1,008.3 ± 18

35 ILg Ethinyl E2t (day 7) n

h

pg/mL*

562.7

-48

559.6

-24

501.9 501.5

0 24

23.3 ± 19 24.3 ± 18 25.3 ± 17 24.0 ± 15

9.2 6.8 7.0 5.8

30 ILg EthinylE2 (day 14) n pg/mq

27.8 ± 17 27.6 ± 16 25.4 ± 16 23.0 ± 17

30/Lg Ethinyl E2 (day 21) n pg/mq

7.8 9.2 9.2 7.8

22.3 ± 17 24.0 ± 17 25.7 ± 14 21.9 ± 16

6.2 9.1 8.2 5.2

* Values

are means ± SD. t Conversion factor to SI units (nmol/L) is 3.22 X 10-3 •

to the study protocol. One subject was discontinued prematurely from the study after day 1 of the pharmacokinetic evaluation because of loss of contact. The ages of the subjects varied between 19 and 32 years, with a mean age of 25.1 years. The mean body weight was 143.0 pounds (64.9 kilograms), with a range of 115.0 to 182.0 pounds (52.2 to 82.6 kilograms). The mean height was 65.5 inches (166 centimeters), with a range of 62.0 to 71.0 inches (157 to 180 centimeters). All subjects were white. 3-Keto-Desogestrel Steady State

Evaluation of the trough serum levels indicated that a steady state of 3-keto-desogestrel had been reached. The predose (minimum) serum concentrations of 3-keto-desogestrel at days 7, 14, and 21 were 276 ± 81 pgjmL (0.9 ± 0.3 nmoljL) after 50 J-Lg of desogestrel, 671 ± 231 pgjmL (2.2 ± 0.7 nmoljL) after 100 J-Lg of desogestrel, and 982 ± 502 pgjmL (3.2 ± 1.6 nmoljL) after 150 J-Lg of desogestrel, respectively (Table 1).

± SD. t Dose normalized by multiplying serum concentrations by the factor 30 ILg divided by 35 ILg. :I: Conversion factor to SI units (pmol/L) is 3.37. * Values are means

3-Keto-desogestrel Dose Proportionality and Elimination

The Cmax of 3-keto-desogestrel was 1,551 ± 397 pgjmL (5.0 ± 1.3 nmoljL), 3,233 ± 1,029 pgjmL (10.4 ± 3.3 nmoljL), and 4,909 ± 1,577 pgjmL (15.8 ± 5.1 nmoljL) after 50,100, and 150 J-Lg desogestrel, respectively (Table 3). The AUC for 3-keto-desogestrel was 12,105 ± 3,661 pgjmL per hour (39.0 ± 11.8 nmoljL per hour), 28,158 ± 8,372 pgjmL per hour (90.7 ± 27.0 nmoljL per hour), and 41,844 ± 15,763 pgjmL per hour (134.8 ± 50.8 nmoljL per hour) after 50, 100, and 150 J-Lg desogestrel, respectively. The Css,min levels are described under Steady State, Statistical analysis on the Cmax , AUC, and

Table 3 3-Keto-Desogestrel Dose Proportionality and Elimination Parameters on Days 7, 14, and 21 Dose*

Ethinyl E2 Steady State

Ethinyl E2 serum levels obtained at the same time points as above also reflected steady state levels. The mean ethinyl E2 predose (minimum) serum concentrations on days 7,14, and 21 were 25.3 ± 7.0 pgjmL (85.4 ± 23.6 pmoljL; normalized to a dose of 30 J-Lg), 25.4 ± 9.2 pgjmL (85.7 ± 31.0 pmoljL), and 25.7 ± 8.2 pgjmL (86.7 ± 27.7 pmoljL), respectively. The ethinyl E2 trough serum concentrations before and after these days showed minimal variability (Table 2). 648

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Pharmacokinetics of desogestrel

Parameter C_ (pg/mL)t n T_/h n AVC (pg/mL/h)t n Tl/2.,mJh n

50 I'g Desogestrel (day 7)

100 l'g Desogestrel (day 14)

150 l'g Desogestrel (day 21)

1,551 ± 397 19 1.8 ± 1.3 19 12,105 ± 3,661 19

3,233 ± 1,029 19 1.9 ± 0.9 19 28,158 ± 8,372 19

4,909 ± 1,577 19 1.6 ± 0.9 19 41,844 ± 15,763 19 30.1 ± 13.2 18

* Values are means ± SD. t Conversion factor to S1 units (nmoljL) and (nmoljL per hour) is 3.22 X

10-'.

Fertility and Sterility

Table 4 Ethinyl E2 Dose Equivalence and Elimination Parameters on Days 7, 14, and 21 Dose' 35 jig Ethinyl E2t Parameter

(day 7)

30 jig Ethinyl E2t (day 14)

C ma• (pg/mL):j: n Tmaxlh n AUC (pg/mL/hlt n T , /2e1bn/h n

151.9 ± 34.9 19 1.7 ± 1.3 19 1,085 ± 278 18

153.6 ± 40.1 19 1.5 ± 0.4 19 1,136 ± 347 18

30 jig Ethinyl E2t (day 21) 162.8 ± 19 1.4 ± 19 1,091 ± 18 32.8 ± 7

39.7 0.9 335 10.1

• Values are means ± SD. t Dose normalized for comparison purposes by multiplying serum concentrations by the factor 30/35. :j: Conversion factor to SI units (pmol/L) and (pmol/L per hour) is 3.37.

Css,min indicated dose proportionality for the administered desogestrel. The T max was reached after 1.8 ± 0.3, 1.9 ± 0.2, and 1.6 ± 0.2 hours, respectively, for the three doses and was thus independent of the dose. During the study, the elimination half-life (T 1/2min) of 3-ketodesogestrel could only be estimated on the last dose of desogestreljethinyl E2 (150/30 J.Lg) administered on day 21. This was because a 72-hour drug-free period is required for the estimation of the T 1/2elim' The terminal log-linear part of the plot began after 24 hours based on the serum concentration versus time profile of 3-keto-desogestrel. The mean T 1/2elim of 3-keto-desogestrel based on these calculations was 30.1 ± 3.1 hours. Ethinyl E2 Dose Equivalence and Elimination

The C max for ethinyl E2 was 151.9 ± 34.7 pg/mL (512 ± 117 pmol/L; normalized to a dose of 30 J.Lg), 153.6 ± 40.1 pg/mL (518 ± 135 pmoljL), and 162.8 ± 39.7pg/mL (549 ± 134pmoljL) on days 7,14, and 21, respectively. The AUC for ethinyl E2 was 1,085 ± 278 pg/mL per hour (3,661 ± 938 pmoljL per hour), 1,136 ± 347 pg/mL per hour (3,833 ± 1,171 pmoljL per hour), and 1,091 ± 335 pg/mL per hour (3,681 ± 1,130 pmoljL per hour) on days 7, 14, and 21, respectively (Table 4). The Css,min levels are described under Steady State. The T max of ethinyl E2 varied between 1.7 ± 0.3 hours on day 7 and 1.4 ± 0.2 hours on day 21. The statistical analysis on C max , AUC, C•• ,min, and T max indicated that the pharmacokinetics of ethinyl E2 on days 7, 14, and 21 Vol. 61, No.4, April 1994

were not significantly different. During the study the elimination half-life (Tl/2elim) could only be estimated on the last dose of desogestreljethinyl E2 (150/30 J.Lg) administered on day 21. This was because a 72-hour drug-free period is required for the estimation of the Tl/2elim' The terminal log-linear part of the plot began after 16 hours based on the serum concentration versus time profile of ethinyl E 2. The mean T 1/2elim for ethinyl E2 based on these calculations was 32.8 ± 3.8 hours. Sex Hormone-binding Globulin

Sex hormone-binding globulin was not measured before the first dose of the preparation. Therefore, it is not possible to determine the extent of SHBG increase after two cycles of exposure to the preparation. During cycle 3 SHBG levels determined on days 1, 7, 14, and 21 were 153.1 ± 38.6,185.5 ± 32.1, 202.3 ± 26.5, and 205.6 ± 21.9 mmoljL, respectively. The values on days 7, 14, and 21 were significantly different from day 1 (P < 0.05). There were no significant differences in SHBG between days 7, 14, and 21.

DISCUSSION

The pharmacokinetic parameters on day 21 for the 150/30 J.Lg desogestreljethinyl E2 dose of this triphasic preparation can be adequately compared with those on day 21 of monophasic desogestrelj ethinyl E 2, which contains 150/30 J.Lg/d desogestreljethinyl E2 for 21 days. Absorption of both desogestrel and ethinyl E2 was rapid with a mean T max for 3-keto-desogestrel being reached within 1.6 to 1.9 hours and for ethinyl E2 within 1.4 to 1. 7 hours, which is comparable to the findings in studies with monophasic desogestreljethinyl E2 (3, 7-13). The mean Cmax during steady state as found in this study for 3-keto-desogestrel in the 150/30 phase is comparable with what has been reported in the literature for monophasic desogestreljethinyl E 2: 4.9 ± 1.6 ng/mL (15.8 ± 5.1 nmoljL) in this study versus a range of 3.7 to 6.4 ng/mL (11.9 to 20.6 nmoljL) in the literature for monophasic desogestreljethinyl E2 (3, 7, 8, 11). The steady state Cmax of 162.8 ± 39.7 pg/mL (549 ± 134 pmoljL) reported for ethinyl E2 in this study also falls within the range of steady state C max values of 102 to 739 pg/mL (344 to 2,490 pmoljL) that has been reported earlier during use of monophasic desogestreljethinyl E2 (7-10, 12, 13). Archer et al.

Pharmacokinetics of desogestrel

649

The AUe during steady state appeared in the present study to be in good agreement with that found in other studies with monophasic desogestreljethinyl E 2. For example, for 3-keto-desogestrel, during use of monophasic desogestreljethinyl E 2, steady-state AUe values in the range of 22.0 to 55.1 ng/mL per hour (70.8 to 177.4 nmoljL per hour) have been reported (3, 7,8,11) compared with 41.8 ± 15.8 ng/mL per hour (134.6 ± 50.9 nmoljL per hour) in the present study. Also for ethinyl E 2, the reported steady state AUe values are in close agreement with literature data: a range of 565 to 1,387 pg/mL per hour (1,904 to 4,674 nmoljL per hour) (7,9,10,12-14) was reported for monophasic desogestreljethinyl E2 compared with 1,091 ± 335 pg/mL per hour (3,681 ± 1,130 pmol/L per hour) in the present study. Tl/2elim reported in this study for 3-keto-desogestrel after the last tablet was 30.1 ± 13.2 hours, which may be longer than was found in the literature for monophasic desogestreljethinyl E 2, which has reported a steady state T 1/2elim range of 20.3 to 24.1 hours (6, 8). The steady state Tl/2elim of 32.8 ± 10.1 hours for ethinyl E2 reported here is compatible with the range of 20.8 to 29.1 hours reported in studies on monophasic desogestreljethinyl E2 (6,8). The results showed that for all three dose phases (50/35, 100/30, and 150/30 ,ug/d desogestreljethinyl E 2) steady state kinetics were attained for both 3-keto-desogestrel and ethinyl E2 because predose serum concentrations 24 hours after the last tablet of each phase did not differ significantly from predose serum concentrations at the last day of each phase. In addition, the absence of a significant increase of serum ethinyl E2 concentrations between days 7 and 21 indicates that there is no significant inhibition of ethinyl E2 metabolism by the progestogenic compound, a phenomenon that has been reported previously for various progestogens by some studies (5, 15) but that could not be confirmed by another (14). At steady state conditions, the kinetics of3-ketodesogestrel for all three doses (50, 100, and 150 ,ug) were linearly related to the dose administered, and the kinetics of ethinyl E2 were comparable for both doses (35 and 30 ,ug). In addition, these findings indicate that neither 3-keto-desogestrel nor ethinyl E2 are accumulating in the body. In this study, use of triphasic desogestreljethinyl E2 results in a statistically significant increase of SRBG serum concentrations between days 1 and 21 650

Archer et a1.

Pharmacokinetics of desogestrel

of the cycle. During a similar time interval, such an increase in serum SRBG also was observed with monophasic desogestreljethinyl E2 (12). As with several other binding proteins, this increase can be attributed to the estrogenic component. Synthetic progestogens suppress the estrogen-induced increase in SRBG to varying degrees depending on the relative androgenicity of the particular progestogen and the dose used (16). Studies have demonstrated that 3-keto-desogestrel is extensively (95% to 99%) bound to serum proteins, predominantly to albumin and SRBG. Protein binding of ethinyl E2 also is extensive (±98.5%) but almost exclusively to albumin (17). After single-dose administration, about 65% of 3-keto-desogestrel is bound to albumin and about 35% is bound to SRBG. The ethinyl E 2-induced increase in SRBG after multiple dosing of desogestreljethinyl E2 combinations has appeared to result in a redistribution of 3-keto-desogestrel over the binding proteins and therefore protein-binding shifts to about 35% bound to albumin and about 65% to SRBG (17). The change in binding characteristics of 3-keto-desogestrel caused by ethinyl E 2induced increase of serum SRBG after multiple dosing may partly explain the differences between single-dose and steady state pharmacokinetics with desogestreljethinyl E2 combinations. Acknowledgment. We thank Mr. Paul Geurts (medical writer; Organon Inc., West Orange, NJ) for data collection and substantial editorial contributions to this manuscript. Addendum. David F. Archer, M.D., served as a consultant to Organon Inc. in gynecology.

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