Plasma Medroxyprogesterone Acetate Research Articles

Long-acting injectable multipurpose prevention technology for prevention of HIV and unplanned pregnancy

Only condoms are proven to protect against both HIV and unplanned pregnancy, however, poor user acceptability and lack of partner cooperation impede effectiveness. We developed an injectable ultra-long-acting, biodegradable, and removable in-situ forming implant (ISFI) as multipurpose prevention technology (MPT). MPT ISFIs co-formulated an antiretroviral (dolutegravir (DTG)) or cabotegravir (CAB)), and a hormonal contraceptive (etonogestrel (ENG) or medroxyprogesterone acetate (MPA)). All formulations were well-tolerated in mice with no signs of chronic local or systemic inflammation. Plasma CAB and DTG concentrations were above 4× PA-IC90 for 90 days with zero-order and diffusion-controlled absorption, respectively, and no differences when co-formulated with either hormone. Plasma ENG and MPA concentrations were quantifiable for 90 days. Complete removal of CAB/MPA ISFIs resulted in MPA concentrations falling below the limit of quantification after 24 h post-removal, but incomplete CAB elimination from plasma. Collectively, we demonstrated the ability to co-formulate antiretrovirals with contraceptives in an ISFI that is well-tolerated with sustained plasma concentrations up to 90 days.

A Semimechanistic Pharmacokinetic Model for Depot Medroxyprogesterone Acetate and Drug-Drug Interactions With Antiretroviral and Antituberculosis Treatment.

Depot medroxyprogesterone acetate is an injectable hormonal contraceptive, widely used by women of childbearing potential living with HIV and/or tuberculosis. As medroxyprogesterone acetate is a cytochrome P450 (CYP3A4) substrate, drug–drug interactions (DDIs) with antiretroviral or antituberculosis treatment may lead to subtherapeutic medroxyprogesterone acetate concentrations (< 0.1 ng/mL), resulting in contraception failure, when depot medroxyprogesterone is dosed at 12‐week intervals. A pooled population pharmacokinetic analysis with 744 plasma medroxyprogesterone acetate concentrations from 138 women treated with depot medroxyprogesterone and antiretroviral/antituberculosis treatment across three clinical trials was performed. Monte Carlo simulations were performed to predict the percentage of participants with subtherapeutic medroxyprogesterone acetate concentrations and to derive alternative dosing strategies. Medroxyprogesterone acetate clearance increased by 24.7% with efavirenz coadministration. Efavirenz plus antituberculosis treatment (rifampicin + isoniazid) increased clearance by 52.4%. Conversely, lopinavir/ritonavir and nelfinavir decreased clearance (28.7% and 15.8%, respectively), but lopinavir/ritonavir also accelerated medroxyprogesterone acetate’s appearance into the systemic circulation, thus shortening the terminal half‐life. A higher risk of subtherapeutic medroxyprogesterone acetate concentrations at Week 12 was predicted on a typical 60‐kg woman on efavirenz (4.99%) and efavirenz with antituberculosis treatment (6.08%) when compared with medroxyprogesterone acetate alone (2.91%). This risk increased in women with higher body weight. Simulations show that re‐dosing every 8 to 10 weeks circumvents the risk of subtherapeutic medroxyprogesterone acetate exposure associated with these DDIs. Dosing depot medroxyprogesterone every 8 to 10 weeks should eliminate the risk of subtherapeutic medroxyprogesterone acetate exposure caused by coadministered efavirenz and/or antituberculosis treatment, thus reducing the risk of contraceptive failure.

Pharmacokinetics and Pharmacodynamics of Depot Medroxyprogesterone Acetate in African Women Receiving Treatment for Human Immunodeficiency Virus and Tuberculosis: Potential Concern for Standard Dosing Frequency.

Effective contraception is critical to young women with HIV-associated tuberculosis (TB), as unintended pregnancy is associated with increased perinatal morbidity and mortality. The effects of co-administration of efavirenz and rifampicin on the pharmacokinetics of depot medroxyprogesterone acetate (DMPA) are unknown. We hypothesized that clearance of medroxyprogesterone acetate (MPA) would increase when given with rifampicin and efavirenz, thus increasing risk of ovulation. This pharmacokinetics (PK) study assessed DMPA among HIV/TB coinfected women on an efavirenz-based antiretroviral treatment and rifampicin-based TB treatment. Plasma MPA concentrations and progesterone were measured predose (MPA only) and 2, 4, 6, 8, 10, and 12 weeks after a single DMPA 150 mg intramuscular injection. The primary outcome measure, MPA concentration (<0.1 ng/mL) at week 12, was assessed using exact 95% Clopper-Pearson confidence intervals. MPA PK parameters were calculated using noncompartmental analysis. Among 42 PK-evaluable women from 5 African countries, median age was 32 years and median CD4 was 414 cells/mm3. Five women (11.9%; 95% CI, 4.0-25.6%) had MPA <0.1 ng/mL at week 12; of these, one had MPA <0.1 ng/mL at week 10. The median clearance of MPA was 19 681 L/week compared with 12 118 L/week for historical controls. There were no adverse events related to DMPA, and progesterone concentrations were <1 ng/mL for all women for the study duration. DMPA, when given with rifampicin and efavirenz, was safe. MPA clearance was higher than in women with HIV not on ART, leading to subtherapeutic concentrations of MPA in 12% of women, suggesting that more frequent dosing might be needed. NCT02412436.

Rapid Quantification of Medroxyprogesterone Acetate (MPA) in Human Plasma by LC-MS/MS.

Medroxyprogesterone acetate (MPA) is a common contraceptive agent taken both orally and as a subcutaneous or intramuscular injection. Current LC-MS/MS methods for MPA quantification require large sample volumes and low-throughput analytical run times. Therefore, there are opportunities to improve upon existing methods for MPA quantification. MPA was extracted from 600 μL plasma, evaporated to dryness, and the reconstituted solution was injected onto a Waters Acquity liquid chromatography (LC) system via an Agilent Zorbax Eclipse-Plus C18 2.1 × 50 mm (5.0 μm) column. MPA and its internal standard were monitored on a QTRAP® 5500 mass analyzer operated in positive ionization mode. The method was validated according to the Food and Drug Administration Bioanalytical Method Validation guidelines. The analytical measuring range of the assay was 200-10 000 pg/mL. QC samples prepared at the lower limit of quantification (LLOQ; 200 pg/mL) and low (600 pg/mL), mid (1750 pg/mL), and high (8500 pg/mL) levels showed interassay precision and accuracy ≤15.2% and ≤±9.6%, respectively. Stability-challenged samples yielded ≤15% from freshly prepared samples. Dilutional and matrix effects studies were also acceptable. The assay was also assessed in participants prescribed depot medroxyprogesterone acetate; observed concentrations were within the dynamic range of the assay. An LC-MS/MS method for the quantification of MPA in plasma has been developed and validated. The described method is sufficiently sensitive and robust to quantify MPA in plasma and meets the criteria to support clinical trials.

Physiologic doses of depot-medroxyprogesterone acetate do not increase acute plasma simian HIV viremia or mucosal virus shedding in pigtail macaques.

Epidemiologic studies remain inconclusive on whether the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) increases mucosal HIV shedding and transmissibility. Nonhuman primate models may help to determine the effects of DMPA on acute HIV replication. We defined a physiologic dose of DMPA in macaques and assessed the impact of DMPA on acute simian HIV (SHIV) replication. Pigtail macaques received 1-30 mg of DMPA intramuscularly followed by measurements of progesterone and medroxyprogesterone acetate (MPA). Vaginal epithelial thickness, number of cell layers and density of intraepithelial CD3 cells were measured. The effect of DMPA on SHIV viremia and genital virus shedding was investigated in six pigtail macaques infected during monthly treatment cycles with 3 mg DMPA. Six DMPA-untreated macaques were controls. Plasma MPA concentrations directly correlated with changes in epithelial thickness (correlation = 0.84; P < 0.001) and density of intraepithelial CD3 cells (correlation = 0.41; P = 0.02). A 3 mg DMPA dose recapitulated plasma MPA concentrations and changes in vaginal epithelial thickness seen in women. DMPA-treated and untreated macaques showed similar peak plasma viremia and RNA area under the curve values over 12 weeks (P = 0.94), although treated macaques had higher odds of having virus being detected in plasma (odds ratio 6.6, P = 0.02). Rectal and vaginal virus shedding was similar between treated and untreated macaques (P = 0.72 and P = 0.53, respectively). In this pigtail macaque model of DMPA and vaginal SHIV infection, we found little or no effect of DMPA on plasma viremia and mucosal virus shedding during acute infection. These results do not support a role of DMPA in increasing mucosal HIV shedding.

Quantitative determination of medroxyprogesterone acetate in plasma by liquid chromatography/electrospray ion trap mass spectrometry

A sensitive and rapid liquid chromatography/electrospray ion trap mass spectrometry (LC/MS/MS) method has been developed for the quantitative determination of medroxyprogesterone acetate (MPA) in human plasma. Plasma samples (1.0 mL) were simply extracted with pentane and the extracts were analyzed by HPLC with the detection of the analyte in the selective reaction monitoring (SRM) mode. The determination of MPA was accurate and reproducible, with a limit of quantitation of 0.05 ng/mL in plasma. The standard calibration curve for MPA was linear (r = 0.998) over the concentration range 0.05–6.0 ng/mL in human plasma. Analysis precision over the concentration range of MPA was lower than 18.8% (relative standard deviation, RSD) and accuracy was between 96.2 and 108.7%. Copyright © 2001 John Wiley & Sons, Ltd.

Quantitative determination of medroxyprogesterone acetate in plasma by liquid chromatography/electrospray ion trap mass spectrometry.

A sensitive and rapid liquid chromatography/electrospray ion trap mass spectrometry (LC/MS/MS) method has been developed for the quantitative determination of medroxyprogesterone acetate (MPA) in human plasma. Plasma samples (1.0 mL) were simply extracted with pentane and the extracts were analyzed by HPLC with the detection of the analyte in the selective reaction monitoring (SRM) mode. The determination of MPA was accurate and reproducible, with a limit of quantitation of 0.05 ng/mL in plasma. The standard calibration curve for MPA was linear (r = 0.998) over the concentration range 0.05-6.0 ng/mL in human plasma. Analysis precision over the concentration range of MPA was lower than 18.8% (relative standard deviation, RSD) and accuracy was between 96.2 and 108.7%.

Medroxyprogesterone acetate treatment reduces serum interleukin-6 levels in patients with metastatic breast carcinoma

The serum interleukin (IL)-6 concentration was very low in patients with metastatic breast carcinoma who had received oral medroxyprogesterone acetate (MPA) treatment as compared with those who had not. Accordingly, the authors conducted a prospective study to determine whether MPA treatment reduces the serum level of IL-6 in patients with this disease. In 21 consecutive Japanese patients who were scheduled to receive oral MPA treatment at doses of 600, 800 or 1200 mg/day, serum concentrations of IL-6 were determined with a sensitive enzyme-immunoassay prior to the administration of MPA and again at 4 weeks after the treatment was started. In addition, plasma levels of MPA were determined by high-performance liquid chromatography (HPLC). Four weeks after the oral MPA therapy was started, serum IL-6 levels decreased in all 21 patients regardless of whether or not they responded to the treatment. Although the extent of decrease in the serum IL-6 (delta IL-6) did not correlate with the daily dose of MPA, it correlated closely with the plasma MPA level in these patients. Subjective improvement in appetite and weight gain were more frequent in the delta IL-6 > 3 pg/mL group compared with the delta IL-6 < or = 3 pg/mL group (80% vs. 45% and 70% vs. 45%, respectively). Similar results were obtained for improvement in patients' sense of well-being (100% vs. 55%). Oral MPA treatment reduces serum IL-6 concentration in patients with metastatic breast carcinoma, but the decrease is not associated with response to MPA. This observation may indicate a potential of this agent for producing subjective improvement.

Pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate in advanced breast cancer patients.

Medroxyprogesterone acetate (MPA) is one of the major drugs used in endocrine therapy for advanced breast cancer. However, its optimal dose still has not been clearly established. Response to treatment and drug-related side effects were analyzed as a function of plasma MPA concentrations during prolonged MPA treatment. MPA plasma concentrations were measured (high-performance liquid chromatography [HPLC] assay) at steady state (Css min) in 129 patients (mean age, 63 years; range, 34 to 87) treated by MPA (86% were treated orally exclusively with daily doses ranging from 400 to 2,000 mg). A wide interpatient variability was noted in MPA Css min for the 70 patients who received 1,000 mg/d orally (median, 51 ng/mL; range, 10 to 269 ng/mL). Intrapatient analysis of the evolution of MPA Css min during prolonged treatment showed relative stability of MPA concentrations (mean CV, 20.6%). A weak but significant correlation was demonstrated between oral doses and MPA Css min (P = .016). Thirty-five percent of patients (45 of 129) developed MPA-related side effects that were associated with the highest plasma MPA concentrations; medians were 81 and 32 ng/mL for toxic and nontoxic treatments, respectively (P less than .001). Objective response was assessable in 55 patients who were treated by MPA exclusively. Plasma MPA concentrations were significantly different (P = .025) between patients with progressive disease (PD) (median, 46 ng/mL) and those with complete response (CR), partial response (PR), or stable disease (SD) (median 65 ng/mL). Comparison of CR plus PR versus SD versus PD showed only a tendency toward significant differences in MPA Css min (P = .07). Analysis of toxicity and response as a function of the oral dose did not show any significant relationship. These data suggested an optimal therapeutic window for MPA Css min located within 50 to 70 ng/mL. This study demonstrates that plasma MPA concentration, as opposed to the administered dose, is a determining factor for toxicity and response therapy [corrected].

An enzyme linked immunosorbent assay (ELISA) for plasma medroxyprogesterone acetate (MPA)

A single extraction fixed antigen enzyme-linked immunosorbent assay (ELISA) that can be completed in <24 h is described for the measurement of medroxyprogesterone acetate (MPA) in plasma. MPA is covalently coupled to bovine thyroglobulin and passively adsorbed in guanidine hydrochloride to a standard 96-well microtitre plate where it competes with MPA in the extracted plasma sample for goat anti-MPA. Antibody binding to the solid phase is determined via binding of a horse-radish peroxidase second antibody which reacts colorimetrically with its substrate. The reaction is stopped by addition of 1.25 M H 2SO 4 and absorbance read at 492 nm. All steps except for sample addition and extraction can be performed on an automatic ELISA processing machine. The assay is sensitive, specific and precise, with intra- and inter-assay coefficients of variation of <10 and 15%, respectively. Assay sensitivity is 0.08 ng/ml. The assay follows established methodology for other assays in this laboratory which assists standardization, cost structure and sample throughput and thus is a useful alternative to radioimmunoassays for the determination of MPA in plasma.

Improved Bioavailability of a New Oral Preparation of Medroxyprogesterone Acetate

Medroxyprogesterone acetate (MPA) is widely used in the hormonal therapy of breast cancer. So far, oral formulations of MPA commercially available present a very low bioavailability, with a <10% extent of oral absorption. A new oral preparation of MPA has been recently developed. Based on a pilot study, an open, randomized, crossover trial has been performed on 22 breast and endometrial cancer patients to evaluate the relative bioavailability of this new oral formulation (200-mg sachet, twice daily) as compared with a standard formulation (Farlutal, 500-mg tablet, twice daily). The bioavailability evaluation was mainly based on the area under the curve measured between two administrations at steady state, after 15 days of continuous therapy. Wide interpatient variability of MPA plasma levels after oral MPA administration was confirmed. The MPA plasma levels were higher in patients treated with the new formulation than in patients treated with Farlutal. The relative bioavailability of the new preparation was 3.5 times higher than that of the standard. This new formulation represents a great improvement in the extent of oral absorption of MPA and could lead to better management of hormone-responsive tumors by hormonal therapy.

Lipoprotein changes during treatment of pelvic endometriosis with medroxyprogesterone acetate

Ten women with endometriosis were treated with medroxyprogesterone acetate (MPA), 150 mg intramuscularly every second week. After 2 weeks, there was a significant (8%) decrease in the high-density lipoprotein (HDL) concentration. This reduction became more pronounced after 8 and 24 weeks’ medication. The HDL reduction was confined to the HDL 2 subfraction, which was decreased by 15%, 33%, and 58% after 2, 8, and 24 weeks, respectively; there was no significant change in the HDL 3 concentration. During treatment, there was a continuous increase in the mean MPA plasma level and a strong inverse correlation between this level and the mean HDL and HDL 2 cholesterol concentrations. It was concluded that MPA affects HDL metabolism in a dose-dependent way and in the same direction as other progestins.

Lack of correlations between plasma concentration of medroxyprogesterone acetate, hypothalamic-pituitary function, and tumour response in patients with advanced breast cancer.

Plasma medroxyprogesterone acetate (MPA) concentrations were measured in 61 patients with advanced breast cancer, after 3 weeks' treatment using 200 mg PO 8-hourly, to determine whether the previously reported wide interpatient variations correlated with tumour response or toxicity. Seventeen patients (28%) responded to the drug, and their mean plasma MPA concentration was 97 ng/ml +/- 68 SD, compared with 115 ng/ml +/- 87 SD for the patients whose disease progressed. Side-effects attributed to MPA were seen in 18 patients, who had a mean drug concentration of 113 ng/ml +/- 104 SD. This was not significantly higher than that of the patients who did not experience drug toxicity. Because of a suggestion that some of the antitumour activity of the drug could be mediated via an effect on the hypothalamic-pituitary axis, we also measured plasma FSH, LH, and prolactin concentrations after the 3-week treatment with MPA, but found no correlations with either drug concentration or tumour response. These results indicate that with the present treatment schedule the monitoring of plasma MPA concentrations has no role in routine practice and suggest that the inherent sensitivity of the tumour to progesterone is probably the major determinant of response.

Pharmacokinetic and pharmacodynamic basis for the treatment of metastatic breast cancer with high-dose medroxyprogesterone acetate.

Postmenopausal patients with metastatic breast cancer were treated with medroxyprogesterone acetate (MPA) (Clinovir) in dosages between 500 and 1500 mg orally per day. The relation of MPA plasma concentrations and endocrine effects were studied in a longitudinal fashion. MPA exerted suppressive effects on the basal and gonadotropin-releasing hormone (GnRH) stimulated gonadotropin secretion, cortisol, dehydroepiandrosterone (DHEA), and estradiol (E2) in a dose-dependent manner leading to a complete suppression with 1500 mg orally per day. The depression of thyroid hormones (T3 and T4) coincided with a depression of the thyroxine-binding index (TBI). MPA did not affect human growth hormone (hGH), basal and thyrotropin-releasing hormone (TRH) stimulated thyroid-stimulating hormone (TSH) and aldosterone. Basal and TRH-stimulated prolactin (PRL) secretion showed a slight but distinct elevation. From these data it is concluded that in postmenopausal patients MPA exerts its antitumor activity by an interference with the hypothalamo-pituitary adrenal axis in the sense of a selective pharmacologic hypophysectomy leading to complete suppression of adrenal steroid secretion. Additionally, MPA inhibits tumor cell growth through the progesterone receptor. A dual mechanism for the antitumor activity of high dose is postulated MPA: ablative through suppression of the hypothalamo-pituitary-adrenal axis and subsequent estrogen deprivation, and additive via the progesterone receptor directly on the tumor cell. The significance of gonadotropin suppression in the postmenopause for breast cancer growth is unclear. The depression of T3 and T4 is due to a depression of thyroid hormone-binding proteins. The elevation of PRL secretion may be explained by a slight estrogenic activity of MPA metabolites.

The plasma concentration of medroxyprogesterone acetate and ovarian function during treatment with medroxyprogesterone acetate in 5 and 10 mg doses.

Peripheral plasma levels of medroxyprogesterone acetate (MPA) were determined by radioimmunoassay in 5 women after oral administration of 5 and 10 mg medroxyprogesterone acetate daily. Peak levels of MPA in plasma were recorded within 1 - 3 hours of taking the tablet, which indicates a rapid absorption from the gastro-intestinal tract. The levels of medroxyprogesterone acetate 12 hours after taking of the 5 mg tablet remained constant throughout the 8 weeks of study. Peripheral plasma levels of estradiol and progesterone were determined throughout treatment. The estradiol levels indicated development of follicles in 7 out of 10 treatment months in the 5 mg group, and in 3 of the subjects treated with 10 mg MPA. The progesterone levels in those women treated with 5 mg MPA showed normal luteal concentration values in 2 out of 10 treatment months. No woman treated with 10 mg MPA had an increase in progesterone during the 21-day period of treatment. The results obtained in this study suggest that 10 mg MPA daily will inhibit ovulation but 5 mg is not sufficient to inhibit ovulation in all women.

Return of ovulation following a single injection of depo-medroxyprogesterone acetate: A pharmacokinetic and pharmacodynamic study

The effect of a single dose of 150 mg of depo-medroxyprogesterone acetate (DMPA) on pituitary, ovarian and endometrial function was assessed in relation to the peripheral levels of the compound in 8 women. The levels of medroxyprogesterone acetate (MPA), follitropin (FSH), lutropin (LH), prolactin, estradiol (E 2) and progesterone (Prog.) were measured 3 times a week during a pretreatment (control) cycle and then daily during postinjection weeks 14–17, 22–25 and 30–33. An endometrial biopsy specimen was obtained during postinjection weeks 17, 25 and 33. In three out of 8 subjects the daily hormone assays carried out during postinjection weeks 30–33 indicated anovulatory periods; in these subjects peripheral blood was drawn daily during postinjection weeks 46–49 and a fourth endometrial biopsy was taken during week 49. Plasma MPA levels during the 14th postinjection week varied between 0.90 and 2.24 nmol/l, they declined gradually and became undetectable between weeks 17–24 (4 cases) or sometime after week 33 (the other 4 cases). No correlation was found between the time when MPA levels became undetectable and the obesity index. Ovulation as evidenced by the reappearance of adequate Prog. levels occurred between weeks 20 and 21 in one subject and between weeks 25 to 49 in the other 7 subjects. In 7 of the 8 subjects ovulation occurred when MPA levels were no longer detectable. In 6 out of the 8 subjects follicular activity as evidenced by an adequate rise in E 2 levels was re-established earlier than luteal activity. In all anovulatory segments the mean levels of FSH and LH remained in the range of the upper limit of the late follicular phase of the normal cycle and the mean E 2 level in the segments without cyclic follicular activity remained in the range of the early follicular phase. The prolactin levels during the various postinjection weeks were not different from those found in the control samples. The biopsies taken from all subjects during the 17th postinjection week showed either an atrophic endometrium or suppressed proliferation. All biopsies taken during weeks 33 and/or 49 had a normal appearance. The results of this study confirm the previous observation (1) that in our local population a single injection of 150 mg of DMPA might be effective as a contraceptive by suppressing ovulation for at least 4–5 months.

Medroxyprogesterone acetate (MAP) plasma levels after multiple high-dose administration in advanced cancer patients.

Medroxyprogesterone acetate plasma levels were measured in advanced cancer patients after multiple PO or IM administration (500, 1000, 2000, 3000, 4000, and 5000 mg/day PO and 500, 1000, 2000 mg/day IM for 30 days). After PO administration, the plasma concentration rises quickly and plateau level is reached in 4-10 days. Discontinuation of the treatment produces a fast decay (t1/2 = 62.4 h) of the drug levels. When medroxyprogesterone acetate is given IM plasma levels, steadily increase and after drug discontinuation no noticeable decay is observed for at least 6 months; plateau plasma levels are about three times higher than after the corresponding PO treatment. Extremely high interpatient variation in bioavailability is present with both administration routes. These data may well rationalize the results of previous clinical trials and will help in planning treatment schedules.

Determination of medroxyprogesterone acetate in plasma by high-performance liquid chromatography

Determination of medroxyprogesterone acetate in plasma by high-performance liquid chromatography

Medroxyprogesterone acetate (MPA) plasma levels after oral and intramuscular administration in a long-term study.

In a long-term study (1 year) the plasma concentration of medroxyprogesterone acetate (MPA, Depo-Provera, Provera, Upjohn) was measured in 30 patients with endometrial carcinoma treated with MPA in the following dosages: 1) MPA 1 000 mg i.m. weekly; 2) MPA 1 000 mg i.m. once every second week, and; 3) MPA 100 mg orally twice daily. In the orally treated group the blood samples were taken just before the next tablet. The plasma concentration in the orally treated group rapidly reached steady state, while the i.m. treated group showed gradually increasing levels that had a tendency to level off after 6 months. The mean concentration at the end of the year was about three times higher for MPA 1000 mg i.m. weekly than for MPA 100 mg orally twice daily. This does not take into consideration the peak MPA level that occurs 2-4 hours after each tablet. MPA i.m. has a very good depot effect, with release of MPA from the injection site for up to 9 months. The steady initial increase in MPA plasma concentration seen in the i.m. treated groups is probably due to the additions of new depots rather than accumulation in the body generally.

A Preliminary Pharmacokinetic and Pharmacodynamic Evaluation of Depot-Medroxyprogesterone Acetate and Norethisterone Oenanthate

A comparative pilot study was carried out in two World Health Organization Collaborating Centers on Research and Training in Human Reproduction (New Delhi and Stockholm) to assess the pharmacokinetic and pharmacodynamic properties of two injectable steroidal contraceptives, depot-medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-OEN). The assessment also included a variety of biochemical and hematologic indices. The period during which NET was detectable in the blood following injection of NET-OEN was significantly shorter in Indian women than in Swedish women. No difference was apparent with DMPA. None of the four Swedish women ovulated until more than 156 days after injection of DMPA and until plasma medroxyprogesterone acetate (MPA) levels were undetectable. The four Indian women ovulated within 73 days of injection of DMPA, and MPA levels at this time were above 0.6 ng/ml. There was no difference between the two centers in the time of return of ovulation for subjects receiving NET-OEN. For women receiving DMPA, the number of days on which bleeding and spotting occurred and the number of episodes of bleeding were significantly higher than those of women receiving NET-OEN. There were no significant changes in any of the biochemical or hematologic analyses as a result of injection of the gestagens. This preliminary study suggests that responses to the two injectable contraceptives may vary in different populations and emphasizes the need for more detailed comparative investigations in those countries where the formulations are expected to be in widespread use.