A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007.

Preclinical data suggest that medroxyprogesterone acetate (MPA) has both anti-metastatic and anti-angiogenic activity in the absence of hormone receptors (HR). This phase II trial assessed the activity of MPA alone or in combination with low-dose chemotherapy in patients with metastatic HR-negative breast cancer. Postmenopausal women with HR-negative disease were eligible if they had not received more than 3 chemotherapy regimens for metastatic disease. All patients were treated with MPA 1,000-1,500 mg/day orally; patients in cohort two also received low-dose oral cyclophosphamide and methotrexate (ldCM, 50 mg/day and 2.5 mg twice daily on Days 1 and 2 each week). Tissue and circulating biomarkers were assessed serially. The primary endpoint was clinical benefit response defined as objective response or stable disease >6 months. Thirty patients were enrolled (14 MPA monotherapy; 16 MPA + ldCM); median age was 55 (35-80); nearly all had visceral involvement. Despite dose escalation in 90 % of patients, only 17 (57 %) patients ever achieved MPA trough concentrations >50 ng/ml. One patient developed grade 4 renal failure in the setting of rapid disease progression and dehydration. There were no objective responses. One patient in each cohort (~7 %) had stable disease for > 6 months. Skin Nm23 expression increased after 4 weeks of MPA + ldCM, but there were no significant changes in TSP-1, PAI-1 antigen, or PAI-1 activity. MPA had limited activity and does not warrant further development in patients with HR-negative advanced breast cancer. Poor bioavailability limited exposure despite dose escalation.

Depot medroxyprogesterone acetate concentrations in patients with and without the use of antiseizure medications.

OBJECTIVES: To measure plasma concentrations of medroxyprogesterone acetate (MPA) in users with epilepsy treated with antiseizure medications and compare these to MPA concentrations in those without epilepsy. STUDY DESIGN: For this multisite cross-sectional study, we obtained a single blood sample from those with epilepsy treated with various antiseizure medications (n = 18) within the week before their next depot medroxyprogesterone injection. Among the participants without epilepsy (n = 20), 10 similarly were scheduled within the week prior to the next injection, and 10 were scheduled at earlier intervals to attempt to balance the time intervals between groups. MPA concentrations were determined by a validated assay. RESULTS: MPA concentrations were similar among those with epilepsy and controls and between groups with and without the use of enzyme-inducing medications. The lowest MPA concentrations, under 0.07 ng/mL, were observed among two of eight using enzyme-inducing antiseizure medications, one of 10 using noninducing medications, and one of 19 controls had concentrations below 0.2 ng/mL. CONCLUSIONS: In this exploratory study, lower MPA concentrations in some participants using enzyme-inducing antiseizure medications suggest a potential interaction that could reduce depot medroxyprogesterone efficacy.

Clinical trial to evaluate pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after subcutaneous administration of Depo-Provera.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after a single subcutaneous injection in the abdomen of 150 or 300 mg Depo-Provera and compare results to two injections of Depo-SubQ Provera 104 given 3 months apart. DESIGN: Partially randomized, multicenter, parallel-group study. SETTING: Research unit. PATIENT(S): Forty-two women of reproductive age with confirmed ovulatory cycle and body mass index of 18-35 kg/m2. INTERVENTION(S): Women received a single subcutaneous injection of 150 mg (n = 24) or 300 mg (n = 9) of Depo-Provera or two injections of Depo-SubQ Provera 104 (n = 9). MAIN OUTCOME MEASURE(S): Suppression of ovulation as measured by progesterone, serum medroxyprogesterone acetate concentrations, and estimated pharmacokinetics parameters. RESULT(S): No ovulations were observed during 7 months after a single injection of 150 or 300 mg Depo-Provera. The 150 mg group had a similar Cmax as observed over two injection cycles of Depo-SubQ Provera 104 and a similar 6-month trough concentration as the 3-month trough of Depo-SubQ Provera 104. CONCLUSION(S): Our pharmacodynamics and pharmacokinetics data provide proof of concept that Depo-Provera (150 mg) may be an effective contraceptive method when injected subcutaneously every 6 months, with up to a 4-week grace period for reinjections. CLINICAL TRIAL REGISTRATION NUMBER: NCT02456584.

Impact of Formulation Parameters on In Vitro Release from Long-Acting Injectable Suspensions.

The development of long-acting injectable (LAI) suspension products has increased in recent years. A better understanding of the relationship between the physicochemical properties of these products and their in vitro as well as in vivo performance is expected to further facilitate their development and regulatory review. Using Depo-SubQ Provera 104® as the reference listed drug (RLD), four qualitatively and quantitatively (Q1/Q2) equivalent LAI suspensions with different formulation properties were prepared. Two recrystallization methods (solvent evaporation and antisolvent) were utilized to obtain active pharmaceutical ingredient (API) with different properties and solid-state characterization was performed. In addition, two different sources of the major excipient were used to prepare the Q1/Q2 equivalent suspensions. Physiochemical characterization and in vitro release testing of the prepared Q1/Q2 equivalent suspension formulations and the RLD were conducted. In vitro drug release was dependent not only on the particle size, the morphology, and the crystallinity of the API but also on the residual solvent in the API. The excipient source also affected the drug release rates.

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.

A sensitive in vitro performance assay reveals the in vivo drug release mechanisms of long-acting medroxyprogesterone acetate microparticles.

Today, a growing number of subcutaneously administered depot formulations enable continuous delivery of poorly soluble compounds over a longer time period. The modified liberation is considered to be a rate-limiting step in drug absorption and thus impacts therapeutic efficacy and product safety. In the present approach, a mechanism-based pharmacokinetic model of the commercial microparticle formulation depo-subQ provera 104™ (Sauter mean diameter of 5.08 ± 1.63 µm) was established. The model was verified using human pharmacokinetic data from three different clinical trials. Further, the effects of drug release, injection site and patient population on the pharmacokinetic profile were investigated. For this purpose, the drug release was assessed using the novel dispersion releaser technology, whereby a biorelevant medium reflecting major characteristics of the subcutaneous tissue (including ion background, buffer capacity and protein concentration) was used. The established model provided an effective prediction of the key pharmacokinetic parameters, including Cmax, Tmax and AUCall. Only in presence of 55% of fetal bovine serum (using a novel simulated subcutaneous interstitial fluid), the release assay was capable to discriminate between microparticles before and after storage.

Preparation of sterile long-acting injectable medroxyprogesterone acetate microcrystals based on anti-solvent precipitation and crystal habit control.

Background: To overcome the rigorous aseptic process widely adopted by commercial long-acting injections, this work aimed to prepare a sterile MPA injection by manipulating the crystal habit through a bottom-up method. Methods: The habit of the precipitated crystals was modified by changing the process conditions. Wherein, the cubic crystal (MPA-C) was obtained by mixing acetonitrile and water at a ratio of 1:4 (v/v) under an ultrasonic condition. Spherical crystal (MPA-S) was prepared with acetonitrile-water mixture (1:20, v/v). The addition of external additives could stop a certain crystal surface growth to obtain rod-like crystal (MPA-R) and branched crystal (MPA-B). Results: All these crystals were proved to be of the same crystal form with different preferential growth orientation by PXRD, DSC, and SEM. The in vitro release of MPA-R microcrystal suspensions is faster than MPA-DP, while that of MPA-C is slightly slower. The relative bioavailability of MPA-C and MPA-R was 103.3% and 68.5%, respectively. The PK profile of MPA-C was most close to the commercial Depo-Provera® (MPA-DP) after intramuscular administration to male SD rats. Conclusions: A cubic crystal of MPA was successfully prepared by anti-solvent precipitation method with the aid of sonication, providing an alternative strategy for the preparation of long-acting injections.

Pharmacokinetic, biologic and epidemiologic differences in MPA- and NET-based progestin-only injectable contraceptives relative to the potential impact on HIV acquisition in women.

Access to safe and effective contraceptive choices is a reproductive right and contributes tremendously to improvements in maternal and child health. Progestin-only injectables, particularly intramuscularly injected depot medroxyprogesterone acetate (DMPA-IM), have received increased attention given findings suggesting a potential association with increased HIV risk. For women at high risk of HIV, the World Health Organization's Medical eligibility criteria for contraceptive use currently aggregate recommendations for all progestin-only injectables, including DMPA-IM, subcutaneously injected DMPA (DMPA-SC) and intramuscularly injected norethindrone/ norethisterone enanthate (NET-EN), except in the case of some drug interactions. We considered whether published data indicate differences or similarities between these injectables relevant to risk of acquiring HIV. In vitro data confirm different biological activities of these distinct progestins, including that MPA, and not NET, binds and activates the glucocorticoid receptor resulting in different biological effects relevant to immune function. Limited clinical data suggest changes in immunologic activity following DMPA-IM and NET-EN initiation, but interstudy variation and study design differences diminish ability to determine clinical relevance and the degree to which DMPA-IM and NET-EN could act differentially. The highest-quality epidemiologic studies suggest a potential 40% increase in HIV incidence in users of DMPA-IM relative to women not using hormonal contraception but no significant increase in risk in users of NET-EN. In our opinion, most of the available biologic activity and epidemiologic data indicate that DMPA and NET-EN are likely to act differently, and data remain too limited to evaluate differences between DMPA-IM and DMPA-SC.

Medroxyprogesterone acetate concentrations among HIV-infected depot-medroxyprogesterone acetate users receiving antiretroviral therapy in Lilongwe, Malawi.

OBJECTIVE: To compare medroxyprogesterone acetate (MPA) concentrations between HIV-positive women on antiretroviral therapy (ART) and HIV-negative women initiating depot medroxyprogesterone (DMPA) injectable. STUDY DESIGN: Secondary analysis of 28 HIV-positive women on non-nucleoside reverse transcriptase inhibitor-containing ART regimens and 10 HIV-negative women randomized to initiate DMPA in a clinical trial of progestin contraception in Malawi. RESULTS: MPA concentrations were significantly lower among HIV-positive women on ART, compared with HIV-negative women, at week 4 and week 13 (p=.03 for both), but not at day 3 or week 26 post-DMPA initiation. CONCLUSIONS: Antiretroviral medications may affect MPA metabolism in HIV-positive African women.

Quantification of estradiol cypionate in plasma by liquid chromatography coupled with tandem mass spectrometry: Application in a pharmacokinetic study in healthy female volunteers.

The combination of medroxyprogesterone acetate 25 mg + estradiol cypionate 5 mg is a highly effective, monthly injectable contraceptive. For the first time, this study presents the development and validation of a sensitive method for estradiol cypionate analysis in human plasma by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Aliquots (500 µL) of plasma were extracted with ethyl ether (100%) and derivatized with dansyl chloride. Its separation was performed on a Jones Chromatography Genesis C8 column and the quantification was performed with a mass spectrometer equipped with an electrospray interface operating in negative ion mode. The run time was 6 min and the calibration curve was linear over the range of 0.005-0.15 ng/mL. The method was applied to evaluate the pharmacokinetics of estradiol cypionate in plasma collected up to 1008 h (42 days) after a single intramuscular administration of 25 mg/mL medroxyprogesterone acetate +5 mg/mL estradiol cypionate to healthy female volunteers (n = 12). The estradiol cypionate maximum plasma concentration (Cmax) was 0.14 ± 0.08 ng/mL reached at 16.83 ± 21.07 h and the area under the plasma concentration versus time curve (AUC0-last) was 14.07 ± 6.32 ng.h/mL. Elimination half-life (t½), apparent volume of distribution (Vd/F), apparent clearance (CL/F) and mean residence time (MRT) were 89.65 ± 76.04 h, 28038 ± 9636 L, 49.02 ± 10.62 L/h and 576.05 ± 238.32 h, respectively, showing that the estradiol cypionate release from the administration site was prolonged and there was no drug accumulation.

Effect of Hormonal Contraception on Pharmacokinetics of Vaginal Tenofovir in Healthy Women: Increased Tenofovir Diphosphate in Injectable Depot Medroxyprogesterone Acetate Users.

OBJECTIVE: Endogenous and exogenous contraceptive hormones may affect mucosal pharmacokinetics (PKs) of topical antiretrovirals such as tenofovir. We present PK data from healthy women using tenofovir vaginal gel, at baseline (follicular and luteal phases) and after oral contraceptive pill (OCP) or depot medroxyprogesterone acetate (DMPA) use. METHODS: CONRAD A10-114 was a prospective, interventional, open-label, parallel study. We enrolled 74 women and 60 completed the study (32 and 28 who selected OCPs or DMPA, respectively). Participants used 2 doses of tenofovir gel separated by 2 hours, without intercourse, and were examined 3 or 11 hours after the last dose. We assessed pharmacokinetics in plasma, cervicovaginal (CV) aspirate, and vaginal tissue. RESULTS: In general, there were no significant differences in mucosal tenofovir and tenofovir diphosphate concentrations (P > 0.23) in the follicular and luteal phases, except for lower mean tenofovir tissue concentrations (P < 0.01) in the follicular phase. Tenofovir concentrations significantly decreased in CV aspirate (P < 0.01) after contraceptive use, but overall remained very high (>10 ng/mL). Mean tissue tenofovir diphosphate increased to 6229 fmol/mg after DMPA use compared with 3693 and 1460 fmol/mg in the follicular and luteal phases, respectively (P < 0.01). The molecular conversion of tenofovir into tenofovir diphosphate was more effective in DMPA users (molecular ratio of 2.02 versus 0.65 luteal phase, P < 0.01). CONCLUSIONS: Both menstrual cycle phase and exogenous hormones affect topical tenofovir mucosal and systemic PKs. However, high levels of tenofovir and tenofovir diphosphate were observed in the CV mucosa in the presence or absence of OCPs and DMPA, with tissue levels exceeding benchmarks of predicted mucosal anti-HIV efficacy (tenofovir >1.00 ng/mL in CV aspirate and tenofovir diphosphate >1000 fmol/mg).

Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions.

We conducted an open-label, steady-state pharmacokinetic (PK) study of drug interactions among HIV-infected women treated with depo-medroxyprogesterone acetate (DMPA) while on nucleoside analogues plus nelfinavir (N=21), efavirenz (N=17), or nevirapine (N=16); or nucleosides only or no antiretroviral therapy as a control group (N=16). PK parameters were estimated using non-compartmental analysis, with between-group comparisons of medroxyprogesterone acetate (MPA) PKs and within-subject comparisons of ARV PKs before and 4 weeks after DMPA dosing. Plasma progesterone levels were measured at baseline and at 2, 4, 6, 8, 10, and 12 weeks after DMPA dosing. There were no significant changes in MPA area under the concentration curve, peak or trough concentrations, or apparent clearance in the nelfinavir, efavirenz, or nevirapine groups compared to the control group. Minor changes in nelfinavir and nevirapine drug exposure were seen after DMPA, but were not considered clinically significant. Suppression of ovulation was maintained.

Low-dose oral medroxyprogesterone acetate in the management of the paraphilias.

BACKGROUND: There are no reports on the use of low-dose oral medroxyprogesterone acetate (MPA) in the treatment of the paraphilias. High-dose depot MPA treatment (500-800 mg i.m. weekly) has proven to control the behavioral manifestations of the paraphilias when testosterone levels decrease from pretreatment to prepubescent levels, but at the price of significant morbidity. METHOD: Oral MPA (60 mg/day for an average of 15.33 months) was given in an open nonblind trial to seven patients who met criteria for DSM-III-R paraphilias. Four of the subjects had shown inadequate improvement after 1 year of psychotherapy. RESULTS: Six subjects responded at 60 mg/day. Testosterone levels decreased by 50% to 75% (range, 100-400 ng/dL). No patient displayed significant side effects. All patients described significantly fewer paraphilic fantasies, and no patient reported engaging in paraphilic behaviors during oral MPA treatment. CONCLUSION: Double-blind placebo and phallometrically controlled tumescence studies need to be carried out to test the results of this study.

Pharmacokinetic study of low- versus high-dose medroxyprogesterone acetate (MPA) in women.

The present study was conducted to compare the pharmacokinetics (PK) of low-dose versus high-dose medroxyprogesterone (MPA) as a once-daily oral administration. Of 32 patients, all women, enrolled in this PK study, 18 received 600 mg MPA daily and 14 received 1200 mg daily. Detailed PK data were obtained on day 1 and after more than 4 weeks of MPA treatment. In addition, multiple data for the minimum steady-state concentration (Css min) were analyzed. The MPA serum concentrations were measured by high-performance liquid chromatography. Wide interpatient variability was found in the PK parameters obtained both on day 1 and after more than 4 weeks. There were no clear relationships between the oral dose and the MPA peak concentration (Cmax), area under the time versus concentration curve (AUC), or mean Css min. Weight gains of 10% or more were demonstrated more frequently in the high-dose group (P < 0.01). Liver dysfunction (n = 5) did not influence the PK of MPA. Five patients demonstrated extremely low AUC and Cmax (< 10 ng/ml) values on day 1. Phenobarbital, dexamethasone and betamethasone were being taken concomitantly with the MPA each by one patient. The serum MPA concentrations were markedly increased after the discontinuation of phenobarbital in that patient, suggesting a drug interaction. At present we cannot recommend the high dose of MPA, except in clinical studies, from a PK or a pharmacodynamic points of view.

Suppression of ovulation by a new subcutaneous depot medroxyprogesterone acetate (104 mg/0.65 mL) contraceptive formulation in Asian women.

BACKGROUND: A new progestin-only, nondaily depot medroxyprogesterone acetate (DMPA) SC injectable contraceptive suspension (104 mg/0.65 mL) has been developed. Clinical trials (including dose-ranging, pharmacokinetic/pharmacodynamic, and contraceptive efficacy studies) indicating the effectiveness of this new formulation were conducted primarily in white women. However, results of an early study by the World Health Organization suggested that in Thai women, medroxyprogesterone acetate (MPA) may be metabolized in <91 +/- 7 days (the range for effective suppression of ovulation established in clinical trials), resulting in a faster return to ovulation in this population. OBJECTIVES: This study was designed to determine the duration of ovulation suppression and investigate the pharmacokinetic profile of MPA after a single SC injection of DMPA 104 mg/0.65 mL in Asian women. It also assessed the effect of ethnicity and injection site on the duration of ovulation suppression. METHODS: : This was a single-center, single-dose, open-label outpatient trial conducted in Singapore in Asian women aged 18 to 40 years. After 1 control cycle, women with confirmed ovulation were randomized in a 1:1 ratio to receive an SC injection of DMPA 104 mg/0.65 mL in either the anterior thigh or the abdomen. Serum concentrations of MPA, progesterone, estradiol, luteinizing hormone, and follicle-stimulating hormone were measured during the 91-day dosing interval and for an additional 15 days thereafter. RESULTS: Twenty-four Asian women (mean [SD] age, 33.8 [43] years; range, 22.7-40.1 years; mean [SD] body mass index, 22.4 [3.0] kg/m(2)) belonging to 5 ethnic groups (Chinese, Filipino, Indian, Malaysian, and Thai) were included in the study Ovulation suppression was maintained throughout the 91-day dosing interval, regardless of ethnicity or injection site. Ovulation was suppressed for at least 112 days after injection in 23 (95.8%) women, as evidenced by maintenance of serum progesterone concentrations <4.7 ng/mL. The pharmacokinetic parameters for MPA in these Asian women were similar to those previously reported in white women. The most frequently reported adverse events were flulike symptoms and headache, all of mild to moderate intensity. No serious adverse events were reported. CONCLUSIONS: In this study, SC DMPA 104 mg/0.65 mL provided effective suppression of ovulation for at least 91 days in Asian women. Ethnicity and injection site had no effect on MPA profiles.

Drug release from an ensemble of swellable crosslinked polymer particles.

This paper presents a new model suitable to describe the drug release from drug delivery systems constituted by an ensemble of drug loaded crosslinked polymer particles. The model accounts for the main factors affecting the drug release such as the particle size distribution, the physical state and the concentration profile of the drug inside the polymeric particles, the viscoelastic properties of the polymer-penetrant system and the dissolution-diffusion properties of the loaded drug. In order to check the validity of the model, release experiments were performed by using crosslinked polyvinyl-pyrrolidone (PVP) particles and two different model drugs, MAP (medroxyprogesterone acetate) and TEM (Temazepam). MAP and TEM were chosen because of their completely different dissolution behaviours in water. In particular, TEM undergoes a phase transition to the crystalline state upon dissolution when it is loaded in the polymeric network in the amorphous state. The comparison with the experimental results confirms that the most important factors determining the drug release kinetics can be properly accounted for.

Receptor density dictates the behavior of a subset of steroid ligands in glucocorticoid receptor-mediated transrepression.

By co-expressing glucocorticoid receptor (GR) and transcriptional reporter systems in GR-deficient Cos-7 cells, we profiled potency and efficacy of a panel of GR ligands as a function of GR expression levels (density). Our results show that potency and efficacy for GR full agonists, such as dexamethasone, in these transrepression assays are affected by receptor density. Intriguingly, receptor density dramatically influenced the behavior of the GR antagonist RU486 or the GR agonist medroxyprogesterone acetate (MPA). At high receptor density, both MPA and RU486 behaved as full agonists in transrepression: reducing GR density, however, resulted in conversion of these ligands from full agonist to full antagonists. In contrast, varying GR density could not convert cortisol and budesonide from GR agonists to antagonists. These results have clearly demonstrated, for the first time, an effect of receptor density on the agonist and antagonist properties of RU486 and MPA in GR-mediated transrepression.

Pharmacokinetics of estradiol valerate and medroxyprogesterone acetate in different age groups of postmenopausal women.

OBJECTIVES: To study whether ageing affects the pharmacokinetics of estradiol valerate (E2V) or medroxyprogesterone acetate (MPA) in postmenopausal women. METHODS: Forty-six postmenopausal women from two essentially similar pharmacokinetic studies were divided into three age categories: under 60 years (n = 15), between 60 and 65 years (n = 18) and over 65 years (n = 13). They all were treated for 12 days or 14 days with four galenically identical tablets containing combinations of 1 mg or 2 mg E2V and 2.5 mg or 5 mg MPA. The studies followed an open, randomised cross-over design with no washout between the periods. Serum estradiol and MPA concentrations were measured at steady state on study day 12 or 14 of each period. RESULTS: No statistically significant differences were observed in the peak concentration (Cmax), time to peak (t(max)), AUC or elimination half-life for estradiol or MPA between the different age groups. In spite of the lack of statistical significance the AUC was on an average 1.6-fold and Cmax 1.40-fold higher in the oldest group of women than in the youngest group and age was found significant as a continuous variable for AUC and Cmax for MPA but not for estradiol. CONCLUSIONS: The results suggest that there would be no significant changes in the pharmacokinetics of estradiol between women under 60 and over 65 years of age. However, a significant trend towards higher MPA concentrations and bioavailability was observed with increasing age. The results suggest that from the pharmacokinetic point of view the relationship between estradiol and MPA dose to be used in elderly could be different from that in younger postmenopausal women, while no pharmacokinetic reasons to use lower estradiol doses in the elderly were observed.

Plasma concentrations of medroxyprogesterone acetate, estradiol and estrone following oral administration of Klimaxil, Trisequence/Provera and Divina. A randomized, single-blind, triple cross-over bioavailability study in menopausal women.

The absorption of estradiol and medroxyprogesterone acetate was investigated in a randomized single-blind, triple cross-over study, in 12 menopausal women, for four different HRT drugs (Klimaxil, a combination tablet containing 17 beta-estradiol 2 mg and medroxy-progesterone acetate 5 mg; Divina, a combination tablet containing 17 beta-estradiol valerate 2 mg and medroxyprogesterone acetate 10 mg; Trisequence, a triphasic preparation containing 17 beta-estradiol 2 mg in the first phase; Provera, a tablet containing medroxyprogesterone acetate 5 mg). Trisequence and Provera were ingested simultaneously. In conclusion, there was no statistically significant difference between the drugs with respect to the estradiol levels. The estrone concentration, however, differed between the different drugs. The serum concentration was higher after intake of tablets containing estradiol than after intake of tablets containing the valerate ester. There was a significant increase in the MPA levels between periods 1 and 3. Finally, Divina produced higher MPA concentrations than Klimaxil and the combination of Trisequence and Provera, although the mean AUC was not twice as high, as might have been expected.

Toxicology of depot medroxyprogesterone acetate.

Depo-Provera (depot-medroxyprogesterone acetate or DMPA), administered either subcutaneously or intramuscularly, has undergone a thorough toxicological evaluation in a number of animal species. DMPA has been tested in short- and long-term toxicity studies in rodents, rabbits, and monkeys. It has been examined for its effects on reproduction in mice, rats, and rabbits, and for carcinogenic potential in rats, mice, beagle dogs, and rhesus monkeys. Genotoxicity tests have been performed in vitro and in vivo. This paper describes the toxicology data submitted to the US FDA in support of the New Drug Application (NDA) for Depo-Provera as well as data published in the literature. When interpreted in the light of the available pharmacokinetic information, these data demonstrate that DMPA is not significantly different from other contraceptive progestogens in its toxic and tumorigenic potential.

PIP: This paper reviews Depo-Provera (depot-medroxyprogesterone acetate or DMPA) toxicologic and carcinogenic studies and addresses possible reasons why animal-derived data failed to raise concerns for use in women. DMPA was found to be nontoxic following single-dose treatments in rats (8 g/kg body weight) and mice (4 g/kg body weight). Chronic toxicity studies in female rabbits and Rhesus monkeys indicated that DMPA has a low toxicity at the doses given. For rabbits, intramuscular injections of DMPA were given every 3 months for 1 year at dosages of 3, 10, and 30 mg/kg body weight. For Rhesus monkeys, the treatment regime was the same as stated above for the rabbits, except that the treatment period lasted for 28 months. Reproductive effects have been studied in a number of pregnant animals. The effects of DMPA on reproductive tissue have been inconsistent, but there appear to be some effects on both the male and female reproductive organs. Studies on DMPA mutagenic and carcinogenic potentials indicate that chromosomal aberrations occur in hamsters and dogs. DMPA was found to produce tumors in dogs. It was concluded that a dose-related effect for the tumor production response in dogs was evident. Different test animal species responded differently to the levels of DMPA dosages. All available toxicological and pharmacokinetic data collected throughout the extensive testing of DMPA suggests that DMPA meets the overall safety standards as established by the US Food and Drug Administration.