Pharmacokinetics of medroxyprogesterone acetate after single and multiple injection of cyclofem® in Chinese women

ORIGINAL RESEARCH ARTICLE

Pharmacokinetics of Medroxyprogesterone Acetate After Single and Multiple Injection of Cyclofemt in Chinese Women Xiao-fei Zhou,* Qing-xiang Shao,* Xue-jun Han,† Li-ju Weng,† and Guo-wei Sang*

To provide pharmacokinetic data for safety evaluation on prolonged treatment with Cyclofem®, which contains 25 mg medroxyprogesterone acetate (MPA) and 5 mg estradiol cypionate in 0.5 mL microcrystalline aqueous suspension, the pharmacokinetic profiles of MPA after single and multiple administration of this monthly injectable contraceptive were investigated in Chinese women. Nine healthy fertile women received Cyclofem based on a once-a-month regimen for up to 1 year. Blood samples were collected immediately prior to drug administration and on days 1, 3, 5, 7, 14, 21, and 28 after injection. After the 1st, 6th, and 12th injection, the maximum serum concentrations (Cmax) of MPA were observed on days 3.4 6 0.9, 4.3 6 2.2, and 3.7 6 2.6, respectively. Cmax of serum MPA during the 1st, 6th, and 12th treatment cycles were 3.75 6 1.27, 5.54 6 1.79, and 5.55 6 1.80 nmol/L, whereas the areas under the curve (AUC0 –28 days) were 55.84 6 28.15, 95.45 6 26.56, and 98.81 6 21.84 nmol/Lzday, respectively. There was significant interindividual variation in the pharmacokinetics of MPA after intramuscular injection of Cyclofem. No significant change was demonstrated in mean residence time (MRT) of MPA after single and multiple injection. There was a tendency of increase in Cmax and AUC0 –28 days of MPA during the first 6 months of treatment, whereas no further enhancement was found between the 6th and 12th injection (p . 0.05). Peak levels of estradiol (E2) observed in Cyclofem users were within the normal range of the preovulatory phase. Results of this long-term study suggest that no drug accumulation occurred after repeated administration of Cyclofem in the Chinese women. CONTRACEPTION 1998;57:405– 411 © 1998 Elsevier Science Inc. All rights reserved.

*Department of Clinical Pharmacology, Zhejiang Academy of Medical Sciences, Hangzhou, and †Beijing Chaoyang Hospital, Beijing, People’s Republic of China Name and address for correspondence: Zhou Xiao-fei, 60 Tian Mu Shan Road, Zhejang Academy of Medical Sciences, Hangzhou, ZJ 31003, People’s Republic of China. Fax: 186-571-8075447 Submitted for publication December 16, 1997 Revised April 13, 1998 Accepted for publication April 21, 1998

© 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

KEY WORDS:

medroxyprogesterone acetate, pharmacokinetics, Cyclofemt, monthly injectable contraceptive, estradiol

Introduction The frontiers of reproductive medicine are constantly pushed back as new breakthroughs occur. Medroxyprogesterone acetate (MPA), first synthesized in 1958,1 was soon proved to be one of a new class of potent progestogens, and a formulation as a microcrystalline suspension permitted a prolonged duration of action. Depo-Proverat (Upjohn SA, Puurs, Belgium), an injectable contraceptive containing 150 mg MPA, is one of the most rigorously studied antifertility agents in the history of contraceptive research and found throughout the world to be a safe, effective, nonpermanent method of birth control. Nevertheless, progestin-only formulas induce considerable disturbance of the normal menstrual cycle, giving rise to both irregular bleeding and amenorrhea. DepoProvera users also may experience the cessation of menstrual periods, especially after the first year of administration, and resumption of ovulation may sometimes be delayed,2 which is not suitable for some women who want return of fertility soon after the drug has cleared from the body. The monthly injectable with a combination of synthetic progestins and short- or medium-acting estrogen esters appears to influence the endometrium in a way similar to that observed in the normal menstrual cycle and generates satisfactory bleeding patterns. Extensive pharmacokinetic/pharmacodynamic studies and clinical trials have been carried out for optimization of the dosage regimen to minimize side effects for a new hormonal contraceptive preparation.3 Cyclofemt (MPA, 25 mg, plus estradiol cypionate, 5 mg, Pharmacia-Upjohn, Me´xico City, Me´xico) and Mesigynat (northisterone enanthate, 50 mg, plus estradiol valerate, 5 mg, Schering AG, Berlin, Germany) are viewed as prominent agents in expanding women’s access to a full range of ISSN 0010-7824/98/$19.00 PII S0010-7824(98)00048-1

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contraceptive options.4 –7 Although a large body of literature demonstrated the pharmacokinetic profile of MPA after a single dose of depot MPA (DMPA), few data are available on multiple treatment with the progestin-estrogen combined monthly injectable contraceptive. It seems necessary to fill this gap and provide pharmacokinetic data for safety evaluation on long-term use of Cyclofem. In the present study, with intraindividual comparison of pharmacokinetic parameters of medroxyprogesterone acetate after single and multiple injections of Cyclofem in Chinese women, data are provided for assessment on possible accumulation of MPA during longitudinal treatment with this long-acting preparation for fertility regulation. Serum levels of estradiol (E2) were also monitored at regular intervals for concerns regarding continued exposure to the estrogenic component of this combined injectable contraceptive.

Materials and Methods Preparation Cyclofem (medroxyprogesterone acetate or 6a-methyl17-acetoxy-4-pregnene-3,20-dione, 25 mg, combined with estradiol cypionate, 5 mg) was manufactured and formulated as a 0.5-mL microcrystalline aqueous suspension by Pharmacia-Upjohn. Study Design Nine healthy, fertile women received Cyclofem by intramuscular injection on a monthly basis for up to 1 year. Blood samples were drawn immediately prior to drug administration and on days 1, 3, 5, 7, 14, 21, and 28 during the 1st, 6th, and 12th treatment cycle. All blood samples were kept at 4°C until coagulation. The serum was separated by centrifugation and stored at 220°C until laboratory analysis. Study Population The demographic data of the volunteers are presented in Table 1. All subjects were healthy, fertile women, ranging in age from 27 to 34 years old. They were not pregnant or lactating, and experienced regular menstrual cycles for 3 months prior to entrance to the study. All women had not been given any contraceptives for at least 4 months before taking part in the research. Excluded from recruitment were women who had any contraindication to contraceptive steroids or were taking a concomitant medication, such as barbiturates, rifampine, cimetidine, systemic steroids, or any preparation used prophylactically on a long-term basis, which might interfere with the pharmacokinetics of MPA and estradiol cypionate. Also

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Table 1. Demographic data of subjects Subject 1 2 3 4 5 6 7 8 9 Mean SD

Age (years)

Weight (kg)

Height (cm)

Quetelet Index

29 32 33 33 28 27 34 28 32 30.7 2.6

57 62 62 56 50 54 60 52 65 57.6 5.1

159 169 166 170 162 159 160 162 159 162.9 4.4

22.5 21.7 22.5 19.4 19.1 21.4 23.4 19.8 25.7 21.7 2.1

ineligible were women who smoked heavily. A signed informed consent was submitted by each subject, and the study was reviewed and approved by the local ethical committee. Analytical Methods Quantification of MPA was performed by radioimmunoassay (RIA) using reagents provided by World Health Organization Human Reproduction Program (WHO/HRP).8 The antiserum was raised in goats against MPA-3-carboxy methoxime-bovine serum albumin (MPA-3-CMO-BSA), and 3H-MPA was used as tracer. Transferred 50-mL aliquots of serum were extracted by adding 2 mL diethyl ether. Each aliquot was extracted two times. After the ether was evaporated, the extracts were diluted with steroid assay buffer to a total of 200 mL, which was taken for analysis. The efficiency of extraction was monitored by recovery measurements. Aliquots (100 mL of working tracer solution were added to pooled serum as “recovery” tubes, which were then equilibrated for about 30 min at room temperature and extracted in the same way as samples. The efficiency of extraction was judged by calculating the percentage of recovery. If the percentage of recovery was lower than 85%, the results of the assay batch were rejected because of poor extraction efficiency. All serum samples were measured at the end of the study, and samples of each subject were analyzed in one assay batch. Quality control of the MPA RIA was performed by measuring the spiked serum pools, with nominal concentrations of 0.65, 3.25, and 6.5 nmol/L, which were included in each assay. Intra-assay precision was between 8% and 10%, and interassay precision ranged from 9% to 13%. The deviation of measured concentrations of MPA from the nominal values ranged from 0% to 31%. (The highest deviation of 31% was seen in the low quality control sample. The deviation of the medium and the high

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Table 2. Pharmacokinetic parameters of MPA after single injection of Cyclofem Subject 1 2 3 4 5 6 7 8 9 Mean SD

Tmax (day)

Cmax (nmol/L)

AUC0–28 days (nmol/L z day)

MRT (day)

Cday 28 (nmol/L)

3 3 3 5 5 3 3 3 3 3.44 0.88

3.36 3.58 3.48 6.71 3.77 2.81 2.14 4.32 3.62 3.75 1.27

33.07 78.75 49.68 121.14 33.66 49.01 35.71 50.39 51.11 55.84 28.15

11.56 14.32 11.14 12.65 12.59 11.37 11.27 10.86 12.07 11.98 1.08

0.76 3.42 0.55 3.16 1.80 1.25 0.33 0.89 1.56 1.52 1.11

control samples from the nominal values was less than 10%.) The lower limit of quantification was 0.1 nmol/L. Serum E2 levels were measured using RIA kits also provided by HRP/WHO.9 The antiserum was raised in rabbits against estradiol-6-CMO-BSA, and [2,4,6,73 H]-estradiol was used as tracer. Transferred 150-mL aliquots of serum were extracted by adding 2 mL of diethyl ether; each aliquot was extracted two times. After the ether was evaporated, the extracts were diluted with steroid assay buffer to a total of 500 mL, which was taken for analysis. The efficiency of extraction and solution of the residue in buffer were monitored by recovery measurements which are briefly described in the MPA assay. Three sets of quality control samples, with the concentration range of 344 to 2240 pmol/L, were included in each assay. Intra-assay precision was between 4% and 11%, and interassay precision ranged from 6% to 10%. The lower limit of quantification was 50 pmol/L.

Evaluation of Pharmacokinetic Parameters and Statistical Analysis All listed parameters were estimated on a modelindependent basis. Maximum serum concentration (Cmax), Tmax, and day 28 serum concentration (Cday 28) were directly read from the laboratory analysis results. The 28-day area under the curve (AUC0 –28 days) values were calculated according to the linear trapezoidal rule. The mean residence time (MRT), which indicates the duration necessary for 63.5% of a given dosage to leave the body from the time that the drug is administered, was calculated as follows: MRT 5 AUMC/AUC (AUMC 5 area under the moment curve). The comparison of pharmacokinetic parameters during the 1st, 6th, and 12th treatment cycles was performed by ANOVA (analysis of variance) and repeated measures ANOVA (significance level a 5 0.05).

Results Pharmacokinetic Profile of MPA After Single Dose of Cyclofem Pharmacokinetic parameters of MPA after single injection of Cyclofem are presented in Table 2. After the first injection, the maximum concentration of MPA was observed on day 3.44 6 0.88 and amounted to 3.75 6 1.27 nmol/L with a wide range of interindividual variation. Thereafter, there was a gradual decline and mean levels of MPA remained in the circulation above 1.0 nmol/L on day 28 (Cday 28), just prior to the next injection. The mean value of AUC0 –28 days in the first treatment cycle was 55.84 6 28.15 nmol/ L z day and also exhibited significant deviation among subjects. The MRT after a single dose of Cyclofem was 11.98 6 1.08 days.

Pharmacokinetic Profile of MPA After Multiple Dosing With Cyclofem Serum levels of MPA on day 1, 3, 5, 7, 14, 21, and 28 after the 1st, 6th, and 12th administration are listed in Table 3. During the 6th and 12th treatment cycles, peak levels of MPA were detected on day 4.3 6 2.2 and 3.7 6 2.6 post-injection, respectively. Cmax after the 6th and 12th injections reached 5.54 6 1.79 and 5.55 6 1.80 nmol/L, respectively, and were much higher than that in the first cycle (p ,0.05). AUC0 –28 days amounted to 95.45 6 26.56 and 98.81 6 21.84 nmol/L z days after the 6th and 12th doses of Cyclofem, respectively. The MRT indicated no statistically significant difference among the three treatment cycles. Table 4 shows a summary of pharmacokinetic parameters of MPA after single and multiple use of Cyclofem. The MPA serum concentration-time profiles during the 1st, 6th, and 12th cycles are illustrated as Figure 1.

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Table 3. Serum levels of MPA (mean 6 SD) during the 1st, 6th, and 12th treatment cycle (n 5 9) Days after Injection (Prior to injection) 1 3 5 7 14 21 28

Treatment Cycle 1

6

12

(0) 2.45 6 0.92 3.50 6 0.84 2.92 6 1.63 2.54 6 1.44 1.95 6 0.94 1.73 6 1.11 1.52 6 1.11

(2.59 6 1.25) 4.33 6 1.45 4.46 6 2.22 3.76 6 1.23 4.07 6 1.48 3.69 6 1.27 2.83 6 0.92 2.43 6 0.70

(2.64 6 1.16) 4.35 6 1.99 4.40 6 1.53 4.27 6 1.19 4.45 6 1.47 3.43 6 0.93 2.85 6 0.66 2.85 6 1.14

Serum E2 Levels During the 1st, 6th, and 12th Treatment Cycle Serum E2 levels in the nine subjects during the study period were measured and a summary of E2 levels are listed in Table 5. The ranges of serum E2 levels in the 1st, 6th, and 12th cycle were 269 –1066, 360 –1344, and 243–1145 pmol/L with mean values of 652 6 310, 795 6 384, and 677 6 348 pmol/L, respectively. Figure 2 shows the fluctuation of serum E2 levels after the 1st, 6th, and 12th dose of Cyclofem. MPA Levels on Day 28 (Cday 28) in the 1st, 6th, and 12th Treatment Cycle MPA trough levels (Cday 28) in the three treatment cycles are illustrated in Figure 3. The mean values of Cday 28 in the 1st, 6th, and 12th cycle were 1.52 6 1.11, 2.43 6 0.7, and 2.49 6 1.14 nmol/L, respectively.

Discussion The major advantages of the monthly combined injectable appear to be the maintenance of regular bleeding pattern and lower incidence of menstrual disturbance. In some societies, these may be sufficient to outweigh the disadvantages of the relatively more frequent injections and the addition of estrogen.10 Cyclofem is a microcrystalline aqueous suspension with poor solubility in body fluid, and this results in prolonged release from the injection site to

the systemic circulation. In the present study, the pharmacokinetic profiles of MPA after single and multiple administration of Cyclofem at 1-month intervals up to 1 year have been evaluated among nine Chinese women. Although the serum concentration of MPA initially varied widely between individuals, it was swiftly elevated to contraceptively effective levels (.0.5 ng/ml)2 within 24 h, with a mean value of 2.45 nmol/L (;0.8 ng/ml) after a single injection. This seems likely to be due to an initial rapid release of MPA to the surrounding tissues and the bloodstream because some free MPA is present on the crystal surface.11 Maximum concentrations (Cmax) of MPA after a single dose of Cyclofem demonstrated wide variation among volunteers ranging from 2 to 7 nmol/L with a mean value of 3.75 6 1.27 nmol/L, which was similar to that observed in Mexican women and lower than that found in Thai women.12 Differences in the formulation particle size may have contributed to these results with diet, body mass, fat distribution, or genetic factors also involved in variability in different populations. The elimination of drug showed remarkable intersubject variation, which was consistent with the clinical observation of Cyclofem users who experienced more variability in bleeding patterns in the multicentered phase III comparative clinical trial conducted in China.7 Intraindividual comparisons of pharmacokinetic

Table 4. Pharmacokinetic parameters (mean 6 SD) of MPA after the 1st, 6th, and 12th injection of Cyclofem (n 5 9) Pharmacokinetic Parameters Tmax (day) Cmax (nmol/L) AUC0–28 days (nmol/L z day) MRT (day) Cday 28 (nmol/L)

Treatment Cycle 1

6

12

3.44 6 0.88 3.75 6 1.27 55.84 6 28.15 11.98 6 1.08 1.524 6 1.106

4.3 6 2.2 5.54 6 1.79* 95.45 6 26.56* 12.77 6 0.47 2.429 6 0.698**

3.7 6 2.6 5.55 6 1.80** 98.81 6 21.84*** 12.43 6 0.64 2.485 6 1.143**

*P ,0.05, **p ,0.01, ***p ,0.001 (compared to the 1st administration).

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Pharmacokinetics of Medroxyprogesterone Acetate

Figure 1. Serum concentration-time curves of medroxyprogesterone acetate (MPA) after the 1st, 6th, and 12th injection of Cyclofem.

parameters of MPA during the 1st, 6th, and 12th cycle showed that no significant changes were observed in Tmax of MPA during the three treatment cycles, suggesting that absorption of the drug was not influenced after multiple injections. Compared to the first injection, significant increases in Cmax and AUC0 –28 days were detected after the 6th and 12th injections, whereas no statistically significant difference was observed between the latter two cycles (p .0.05). MPA belongs to the 17a-acetoxy-6a-methyl progestin group of steroids, which appear to have a high capacity and low affinity for albumin.13 The increase of Cmax in the 6th and 12th cycles may be attributed to an increase in albumin binding of MPA after repeated dosing with Cyclofem. It is important to note that the MRT of MPA during the three cycles was fairly similar (p .0.05), suggesting no marked effect on drug elimination kinetics after multiple injections of Cyclofem. The duration of action of the estrogenic component of a monthly injectable is critical to achieve a regular bleeding pattern and establish a proper estrogenprogestogen ratio to avoid any endometrial over-

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Figure 2. Serum levels of estradiol (E2) during the 1st, 6th, and 12th treatment cycle.

stimulation. A preliminary study of the estrogen component of monthly injectable formulations indicated that E2 valerate (E2-Val) and E2 cypionate (E2Cyp) are more suitable than E2 benzoate, and E2-Cyp gave significantly lower peak levels of E2 and estrone than that of E2-Val.14 In the present research, the serum profile of E2 was documented after the 1st, 6th, and 12th drug administration because of great concerns about continued exposure to estrogen. The results revealed that maximum E2 levels observed in Cyclofem users were similar to the normal range of the preovulatory phase.15 An exogenous E2 peak occurred 1–2 day(s) after injection, followed by a rapid decline, inducing an estrogen withdrawal bleeding 2–3 weeks after injection of Cyclofem, which was reported previously.7 Indeed, the duration of elevated estrogen levels was approximately 11 days after the administration of E2-Cyp.14 Because serum concentration of MPA still remained fairly high 30 days after the injection of Cyclofem, it is obvious that the latter half of each menstrual cycle was dominated by progestogenic effects, which is desirable from the safety perspective for prolonged treatment with progestinestrogen combined preparations.3

Table 5. A summary of E2 levels (pmol/L) during the 1st, 6th, and 12th treatment cycle (n 5 9) Cycle 1

Cycle 6

Cycle 12

Days after Injection

Mean

(95% CI)

Mean

(95% CI)

Mean

(95% CI)

0 1 3 5 7 14 21 28

268.7 1065.5 914.2 934.6 777.8 545.4 376.2 332.7

(199.1–338.3) (775.9–1355.1) (640.2–1188.2) (616.9–1252.3) (611.9–943.6) (384.2–706.6) (286.7–465.7) (213.5–451.9)

359.6 1344.1 1120.1 1125.9 933.6 676.6 451.5 376.2

(258.1–461.1) (948.9–1739.00) (830.2–1409.9) (822.1–1429.6) (694.9–1172.3} (464.1–889.1) (329.1–573.9) (274.0–478.3)

242.5 1145.2 953.3 999.0 840.6 518.9 397.9 315.1

(160.6–324.4) (730.6–1559.8) (562.1–1344.5) (717.1–1280.9) (666.3–1014.9) (314.5–723.3) (161.6–634.1) (220.0–410.2)

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to be a highly effective, safe formula for fertility regulation, which means more contraceptive choice for all women of the world.

Acknowledgment This study received financial support from the Special Programme of Research, Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland.

References

Figure 3. Serum MPA levels of nine subjects on day 28 after the 1st, 6th, and 12th injection of Cyclofem.

MPA trough concentrations (Cday 28) in the 1st, 6th, and 12th cycle were monitored to ensure that they remained above the contraceptively effective level. No subject showed Cday 28 in the three treatment cycles below 0.3 nmol/l, which was consistent with a fairly low failure rate (0.11%) reported in the phase III clinical trial in China,6 making this one of the most effective methods of contraception available. There was a marked increase of Cday 28 during the first 6 months of treatment, however, there was no statistically significant difference between the 6th and 12th injections, which confirms that no further drug accumulation occurred during the next 6 months of administration. In conclusion, a noticeable interindividual variability in the pharmacokinetic profile of MPA was demonstrated after intramuscular injection of Cyclofem. There was a tendency of the Cmax, Cday 28, and AUC0 –28 days of MPA to increase during the first 6 months of treatment, whereas no statistically significant difference was seen between the 6th and 12th injections. Mean residence times of MPA during the three treatment cycles were fairly close to each other, giving additional evidence that no constant drug accumulation developed after long-term use of Cyclofem in Chinese women. Therefore, Cyclofem, a monthly combined injectable contraceptive, appears

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