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.

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.

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.

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.

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.

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).

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.

Anticoncepción con métodos reversibles de larga duración / No disponible

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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.

A pilot study of depot medroxyprogesterone acetate pharmacokinetics and weight gain in adolescent females.

OBJECTIVE: To explore the relationship between medroxyprogesterone acetate (MPA) pharmacokinetic (PK) parameter estimates and weight gain. STUDY DESIGN: Prospective study of adolescents (N=40; age 12-21 years) initiating DMPA. PK parameters were calculated: maximum MPA concentration (Cmax, ng/mL), time to Cmax (Tmax, days) and elimination rate constant (ng/mL/day). Optimal PK cut points were determined for predicting body mass index (BMI) increase ≥10%. RESULTS: Cmax <2.88 ng/mL and elimination rate constant <0.021 ng/mL/day were associated (p<.05) with BMI increase ≥10%. Elimination rate constant was most predictive of weight gain. CONCLUSIONS: PK evaluation may help identify adolescents at risk of excessive DMPA-associated weight gain.

Use of medroxyprogesterone acetate for hormone therapy in postmenopausal women: is it safe?

Medroxyprogesterone acetate (MPA) has been in clinical use for over 30 years, and was generally considered to be safe until the results of long-term studies of postmenopausal hormone therapy (HT) using treatment with conjugated equine estrogens (CEE) combined with MPA and CEE alone suggested that MPA, and perhaps other progestogens, may play a role in the increased risk of breast cancer and cardiovascular diseases. This review examines critically the safety of MPA in terms of breast cancer and cardiovascular disease risk, and its effects on brain function. Research into mechanisms by which MPA might cause adverse effects in these areas, combined with the available clinical evidence, suggests a small increase in relative risk for breast cancer and stroke, and a decline in cognitive function, in older women using MPA with an estrogen for postmenopausal HT. However, short-term (less than 5 years) use of MPA with an estrogen in the years immediately after the onset of menopause for the management of vasomotor symptoms does not appear to be associated with any increased risk of these disorders.

Pharmacokinetics of subcutaneous depot medroxyprogesterone acetate injected in the upper arm.

BACKGROUND: The abdomen and thigh are recommended injection sites in the label for Depo-SubQ Provera 104™. We evaluated the pharmacokinetic profile of medroxyprogesterone acetate (MPA) following injection of Depo-SubQ Provera 104 in the upper arm, a preferred injection site in developing countries. STUDY DESIGN: Twenty-six women in Norfolk, VA, received a single injection of Depo-SubQ Provera 104 in the upper arm in this prospective noncomparative study. We measured MPA serum concentrations prior to injection (day 1) and 11 times postinjection (days 2, 4, 8, 14, 30, 44, 60, 74, 91, 104 and 120). RESULTS: Serum MPA levels peaked at 0.953 ng/mL 2-14 days (interquartile range; median=8) after dosing. Mean AUC0-91 was 45.1 ng·day/mL. Mean MPA levels at days 91, 104 and 120 were 0.427, 0.367 and 0.327 ng/mL, respectively. A total of 15 individual measurements of MPA were below 0.2 ng/mL. All women but one had MPA levels above 0.1 ng/mL on day 91. CONCLUSIONS: Injection of Depo-SubQ Provera 104™ in the upper arm provided sufficient MPA levels for contraceptive protection for 3 months (13 weeks). The uptake and metabolism of MPA when injected in the upper arm may be different from the abdomen and thigh.

Tissue-specific bioconcentration of the synthetic steroid hormone medroxyprogesterone acetate in the common carp (Cyprinus carpio).

The steroid hormone medroxyprogesterone acetate (MPA), commonly used in oral and injectable contraceptives, has been detected in surface and wastewaters near urban and agricultural areas in several rivers of the world. The objectives of this study were to examine the accumulative potential and tissue distribution of MPA in fish. A freshwater species, the common carp (Cyprinus carpio), was exposed to 100 µg/L of MPA for a 7-day period followed by a depuration phase in which fish were maintained in dechlorinated tap water for an additional 7 days. Tissues (muscle, brain, plasma, and liver) were sampled during the uptake (days 1, 3, and 7) and depuration (day 14) phases of the experiment. Tissue-specific bioconcentration factors (BCF) ranged from 4.3 to 37.8 and uptake was greatest in the liver>brain>plasma and lowest in the muscle. From a regulatory standpoint, MPA shows little tendency to bioaccumulate in fish.

Drug interactions between antiretrovirals and hormonal contraceptives.

INTRODUCTION: Significant advances in antiretroviral therapy have transformed HIV into a chronic manageable disease, and millions of women living with HIV now have the opportunity to reconsider their reproductive choices, be it contraception or pregnancy planning. Hormonal contraceptives are metabolized by cytochrome P450 isoenzymes and sulfate and glucuronide conjugation in the liver. Many antiretrovirals have inducing or inhibiting effects on the cytochrome P450 system. As such, the pharmacokinetics of hormonal contraceptives can be affected by antiretroviral therapy with potential for significant clinical impact. AREAS COVERED: This article presents the pharmacology and metabolism of selected antiretrovirals and hormonal contraceptives, and highlights the potential interactions between these two classes of drugs. Furthermore, the authors present the pharmacokinetic evidence of interactions from available clinical trials, product monographs, and international conference abstracts. EXPERT OPINION: Drugs most likely to interact with combined oral contraceptives, transdermal and implant contraceptives include protease inhibitors, the NNRTIs efavirenz and nevirapine, and cobicistat-boosted elvitegravir. There do not appear to be significant pharmacokinetic interactions with depo-medroxyprogesterone or intrauterine systems and antiretrovirals, although further study is needed. Clinicians working with HIV-positive women need to know the significance of these interactions in order to properly counsel patients and prevent unplanned pregnancies.

Medroxyprogesterone acetate and estradiol cypionate injectable suspension (Cyclofem) monthly contraceptive injection: steady-state pharmacokinetics.

BACKGROUND: Cyclofem is a combined injectable contraceptive, containing medroxyprogesterone acetate (MPA) and estradiol cypionate. The objective was to characterize the steady-state pharmacokinetics (PK) using tandem liquid chromatography/mass spectrometry and compare these data to a previous PK study of this formulation in US women. STUDY DESIGN: Fifteen ovulatory, surgically sterile women received three Cyclofem injections, once every 28 days, with serum PK measurements on 23 separate days. Trough levels of estradiol and MPA were obtained on Days 1, 29 and 57, prior to each of the three injections. Steady-state concentrations of MPA and estradiol were assessed during the third treatment month on Days 58, 60, 62, 64, 67, 69, 71, 75, 78 and 85. MPA and serum progesterone levels were measured during the follow-up phase to assess MPA clearance (Days 92, 99, 106, 113, 120, 127, 134 and 141) and return of ovulation (Days 103, 106, 131 and 134). RESULTS: In the steady state, mean serum MPA concentrations peaked at 1.31 ng/mL at 4.1 days. Mean estradiol levels peaked at 254 pg/mL by 3.3 days. Ovulation was suppressed for at least 77 days post third injection in all but one woman. CONCLUSIONS: Once monthly injections of Cyclofem resulted in contraceptive levels of MPA without accumulation of hormones, consistent with a previous US study.