Levonorgestrel Concentrations Research Articles

Lack of Clinically Meaningful Effect of Cariprazine on the Pharmacokinetics of a Combined Oral Contraceptive.

Cariprazine (CAR) is a potent dopamine receptor partial agonist antipsychotic approved by the EMA and the FDA. To address the uncertainty regarding the effectiveness of hormonal contraceptives during CAR co-administration and whether a second barrier method is necessary, a drug-drug interaction study with an oral contraceptive was conducted post-approval. The phaseI, fixed-sequence multicenter study involved two periods with 24 patients with schizophrenia, aiming to evaluate the effect of CAR on the pharmacokinetics (PK) of a combined oral contraceptive (COC) containing 30μg ethinylestradiol (EE) and 150μg levonorgestrel (LNG). In periodA, a single dose of COC alone was administered on day1. In periodB, the highest therapeutic dose of 6mg CAR was administered once daily from day4, and a second dose of COC was given concomitantly on day31. Overall, CAR had no clinically meaningful effect on the PK of the COC. The terminal half-life and the time of maximum plasma concentration of EE and LNG were not altered by CAR co-administration. The highest difference observed was a decrease of 14% in the maximum plasma concentration of EE, with only slight deviation of the 90% confidence interval (CI) of the test/reference ratio (77.09-96.81) from the generally accepted bioequivalence range of 80-125%, which is not considered clinically relevant. Confidence intervals of all other exposure measures were within the 80-125% range for both EE and LNG. According to these results, hormonal contraceptives can be considered effective during CAR treatment. Trial registration number (EudraCT) 2018-003722-80.

The contraceptive active ingredient levonorgestrel disrupts the physiology of Macrocyclops albidus.

Active pharmaceutical ingredients, such as levonorgestrel (LNG), continue to increase in aquatic ecosystems and are detected in environmental matrices; however, their ability to bioaccumulate and cause reproductive, developmental, and biochemical defects in benthic organisms, such as Macrocyclops albidus, is unknown. This study investigated the effects of LNG on the oxidative stress response, reproduction, and development of M. albidus. Levonorgestrel induced a significant (p<0.05) increase in total protein with increasing concentrations from 10ngL-1. Intracellular hydrogen peroxide levels were elevated after exposure to LNG (p<0.05). Malondialdehyde level declined as LNG concentration increased at day 7 and increased at higher LNG at day 14. Peroxidase activity was significantly (p<0.05) elevated by lower (1-100ngL-1) than higher (1000-10000ngL-1) concentrations of LNG. Glutathione S-transferase activity declined with increasing concentrations of LNG. Increased metamorphosis from the nauplii to the copepodite stage was significantly induced by 1000 and 10000ngL-1 LNG within four days of exposure. In addition, higher concentrations of LNG induced early production of egg sacs in female M. albidus within four days. Levonorgestrel bioaccumulated in M. albidus, with higher tissue concentrations occurring at high exposures. This study revealed that LNG is readily absorbed and causes stress by interfering with reproduction and metamorphosis in M. albidus, thereby highlighting the role of this zooplankton as a sensitive bioindicator of endocrine disruptors in aquatic ecosystems.

Levonorgestrel at emergency contraception dose has no effect on ciliary beat frequency and muscular contraction of the human fallopian tube: an in vitro experimental study.

Levonorgestrel (LNG) acts as an emergency contraceptive mainly by inhibiting or postponing ovulation. We carried out this study to investigate whether LNG at concentration relevant for emergency contraception (EC) affect ciliary beat frequency and muscular contraction of the human Fallopian tube, which might contribute additional actions for EC. This was an in vitro experimental study on human Fallopian tube tissue collected from ten women undergoing hysterectomy. The tubal explants were cultured in vitro, primed with oestradiol and progesterone at concentrations resembling the physiological early luteal phase, and treated with LNG at 0, 1, 10 and 100 ng/ml concentrations. Ciliary beat frequency was measured from the tubal epithelial strips, and the basal tone, amplitude and frequency of contractions were recorded from longitudinal smooth muscle strips. These parameters at different LNG concentrations were compared against the control (LNG 0 ng/ml). Treatment of tubal tissue strips with LNG at all concentrations studied did not significantly alter the ciliary beat frequency nor basal muscle tone (p > 0.05 for both) compared with control. Significant reduction in the amplitude and frequency of tubal muscular contractions was shown after treatment with LNG only at 100 ng/ml (p < 0.05 for both) but not lower concentrations (p > 0.05) compared with control. LNG did not significantly inhibit ciliary beat frequency and muscular contraction of the human Fallopian tube at the doses used for EC, suggesting that the Fallopian tube is unlikely a target for the EC action of LNG.

Transgenerational effects of the levonorgestrel-based birth control pill in zebrafish offspring

The consumption of hormone-derived medicines, such as levonorgestrel (LNG), is increasing worldwide, and its discharge into the environment reaches non-target organisms. In our previous study, we exposed the parental generation of zebrafish to environmentally relevant concentrations of LNG during the developmental phase. Subsequently, they had grown in a tank with clean water until adulthood. Now, we allowed this parental generation to reproduce to obtain F1 progeny unexposed to LGN, in order to analyze the transgenerational effects of parental LNG exposure on the survival and hatching of unexposed F1 embryos and the stress and behavior of F1 larvae. Here, we found decreased survival rates with higher LNG concentrations, providing a transgenerational effect. This highlights the environmental impact of exposure to LNG, causing damage at the individual and population level and affecting the next generation at the beginning of development, impacting qualities in the survival of the species.

Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings.

Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy. Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported. There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12). The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.

Extended Use of Levonorgestrel-Releasing Intrauterine System (LNG-IUS) 52 mg: A Population Pharmacokinetic Approach to Estimate In Vivo Levonorgestrel Release Rates and Systemic Exposure Including Comparison With Two Other LNG-IUSs

ABSTRACT With over 30 years of use, levonorgestrel-releasing intrauterine systems (LNG-IUSs) have proven to be highly effective methods of contraceptives. The active ingredient in LNG-IUS, levonorgestrel (LNG), is released directly into the uterine cavity, which causes suppression of endometrial maturation and thickened cervical mucus. A variety of LNG-IUS options exhibit well-established safety profiles and efficacy, providing anywhere between 2 and 18 times lower systemic exposure when compared with LNG-containing pills or implants. Patient-centered decision-making regarding product choice may be encouraged through standardized comparisons of LNG release and exposure during the time of their respective usage periods. Evaluation of the efficacy, safety, and PK of extended Mirena use from beyond 5 years to the conclusion of 8 years was designed in the Mirena Extension Trial (MET), thereby facilitating comparisons with LNG-IUS 19.5 mg and LNG-IUS 13.5 mg. Using validated liquid chromatography-tandem mass spectrometry methods and SHBG concentrations, the authors determined concentrations of plasma LNG levels. Dichloromethane was used for extracting residual LNG from the elastomer material from removed IUS devices, which was then quantified via liquid chromatography and external calibration on a reversed-phase column. Although previous models used measured LNG and SHBG (serum) concentrations, the population pharmacokinetics (popPK) allows for a uniform method of comparison among different pharmacologic studies. The popPK approach allows for a reliable estimates of in vivo LNG exposure and release during the entirety of the 8-year use period. The MET enrolled premenopausal women aged 18–35 years for a multicenter, single-arm study regarding patients who had used LNG-IUS 52 mg for the last 4.5–5 years for up to 8 years. The study took place from December 22, 2016 to May 28, 2021 throughout 54 US centers, with the primary outcome of contraceptive efficacy and failure rate. Participants each provided written, informed consent. Study strengths of the popPK approach included its robust methodology, its ability to provide in vivo release rate estimates, a stepwise demo of model suitability from use years 6 to 8, model-based estimation of unbound LNG, and the ability to provide estimates for both population and individual PK profiles from sparse available sampling. Limitations include the possibility of findings being group effects possibly inapplicable to all LNG-IUS users. In addition, the data fail to provide local endometrial and cervical LNG concentrations due to the systemic nature of the LNG exposure. Finally, the popPK Mondale should not be used for theoretical question addressing (such as creating rate release estimates outside of available data sets). In conclusion, a broad data set indicates that reliable LNG exposure is delivered by 8-year popPK and release models for up to 7 years of LNG-IUs 52 mg use. Efficacy is data-supported for 6–8 years of use, with constant LNG release throughout this time frame. Systemic LNG exposure from LNG-IUD 52 mg proved both comparable to other LNG-IUS devices and significantly lower than oral and implanted LNG-containing contraceptives.

The Effectiveness, Changes in Body Weight, and Menstrual Cycle Between 2 Rods and 1 Rod Contraceptive Implants after 12 Months of Insertion

Background: Implant as long-acting reversible contraception (LARC) is ideal for Indonesian women. Two-rod implant (2x75mg levonorgestrel) is the most common implant used in Indonesia. Another alternative method is a one-rod implant (1x150mg levonorgestrel). Objective: This study evaluated the effectiveness, changes in body weight (BW), and menstrual cycle between the one-rod and two-rod implant acceptors. Methods: This study was an RCT design with phase II clinical trials; 179 subjects were recruited. Subjects were met with inclusion and exclusion criteria and divided into one-rod and two-rod groups. The variables were evaluated within 12 months. Results: This study involved 70 subjects in the one-rod implant group and 66 subjects in the two-rod implant group. At 12 months, there were no differences between the effectiveness of the two types of contraception, and pregnancy was reported in 1.26% vs 1.31%. The concentration of levonorgestrel in the one-rod group was 0.31 ng/dL as the median (IQR: 0.33 ng/dL) and 0.34 ng/dL as the median (IQR: 0.33 ng/dL) in the two-rod group (p = 0.438). The BW in the two-rod group increased significantly in month six (p = 0.035) and twelve (p = 0.017) but not in the one-rod group. Menstrual cycle changes occurred in 51.4% of subjects and 57.6% of subjects in the one- and two-rod groups (p = 0.584), respectively. Conclusion: At 12 months, one-rod and two-rod implants had similar effectiveness and concentration of levonorgestrel. Significant weight gain happened in the two-rod group, and the weight gain increased in months six and twelve. Menstrual cycle changes have occurred in both.

Effect of double-dose levonorgestrel subdermal implant in women taking efavirenz-based antiretroviral therapy: The DoubLNG pharmacokinetic study

ObjectiveWe evaluated the pharmacokinetics of double-dose levonorgestrel (LNG) implants to overcome the drug–drug interaction with efavirenz-based antiretroviral therapy (ART). Study designWe conducted a nonrandomized, open-label, parallel-group, longitudinal pharmacokinetic study among Ugandan women ages 18–45 years. Participants with HIV on ART containing efavirenz 600 mg received 300 mg of LNG implants (Jadelle®, Bayer, New Zealand): 300LNG+ART group. We compared our outcomes with women without HIV using standard dose, 150 mg of LNG implants: 150LNG group. The implant was placed on day zero in both groups, and we quantified plasma LNG concentrations over 48 weeks post implant insertion. LNG pharmacokinetic parameters were estimated using noncompartmental techniques. Our primary outcome was the geometric mean ratio with 90% confidence intervals of LNG area under the concentration–time curve over 24 weeks (AUC0–24w) between groups. Demographic data were described as median (interquartile range). A secondary outcome compared between-group percent of LNG concentrations ≥300 pg/mL, a minimum threshold selected a priori based on observed pregnancies in Ugandan women on standard-dose LNG implants plus efavirenz. ResultsWe enrolled 27 women in the 300LNG+ART group (34 [28.0 to 40.5] years and 61.0 [49.8–66.0] kg) and 19 women in the 150LNG group (33 [30.0 to 34.5] years and 64.9 [59.0 to 74.5] kg). LNG AUC0–24w was 34% lower for 300LNG+ART versus 150LNG (geometric mean 9998 vs. 15,231 pg*week/mL, respectively [geometric mean ratio 0.66 (90% confidence intervals, 0.54 to 0.80)]). The percentage of participants with LNG concentrations ≥300 pg/mL was not statistically different between groups at week 24 (300LNG+ART: 74.1%; 150LNG: 89.5%; p = 0.27). ConclusionDouble-dose LNG implant did not completely overcome the drug–drug interaction with efavirenz. ImplicationIn women using ART containing efavirenz, placing two implant systems (300 mg) did not normalize LNG pharmacokinetics compared with the standard-dose implant (150 mg), and some women had evidence of ovulatory activity. Alternative ART without drug–drug interactions, such as dolutegravir, is recommended with contraceptive implants.

Extended use of levonorgestrel-releasing intrauterine system (LNG-IUS) 52 mg: A population pharmacokinetic approach to estimate in vivo levonorgestrel release rates and systemic exposure including comparison with two other LNG-IUSs

ObjectiveTo characterize performance of levonorgestrel-releasing intrauterine system (LNG-IUS) 52mg (Mirena) over 8 years of use and facilitate comparisons with LNG-IUS 19.5mg and LNG-IUS 13.5mg. Study designWe estimated in vivo levonorgestrel (LNG) release rates and LNG plasma/serum concentrations for LNG-IUS 52mg up to 8 years of use with a population pharmacokinetic (popPK) approach using data from the Mirena Extension Trial (MET) and earlier clinical trials. We compared these with previously published release rates and exposure data for LNG-IUS 19.5mg and 13.5mg. Our 8-year popPK and release models were developed based on measured plasma/serum LNG and sex hormone-binding globulin concentrations and residual LNG content from removed LNG-IUS 52mg devices. ResultsModel-based estimated LNG release rates for LNG-IUS 52mg decreased from ∼21 µg/d after insertion to ∼7.0 µg/d after 8 years, similar to LNG-IUS 19.5mg after 5 years (7.6 µg/d) and higher than LNG-IUS 13.5mg after 3 years (5.5 µg/d). Model-based estimated and measured plasma/serum LNG concentrations showed satisfactory agreement. Average model-based estimated LNG concentrations after 8 years of LNG-IUS 52mg use (100 ng/L [coefficient of variance 39.9%]) were similar to LNG-IUS 19.5mg after 5 years (84.8 ng/L [39.9%]) and higher than LNG-IUS 13.5mg after 3 years (58.1 ng/L [40.8%]). ConclusionsThe 8-year release and popPK models provide reliable in vivo LNG release rates and concentration estimates, respectively, facilitating direct comparisons between the 3 studied LNG-IUSs. LNG release rates from LNG-IUS 52mg at 8 years are similar to LNG-IUS 19.5mg at 5 years and higher than LNG-IUS 13.5mg at 3 years. ImplicationsLevonorgestrel release from intrauterine system reservoirs declines with duration of use in a predictable way, and in relation to the initial load. As release rates and plasma concentrations of levonorgestrel may influence endometrial and systemic side effects, these data may assist clinical decision-making.

Pharmacokinetics of levonorgestrel and etonogestrel contraceptive implants over 48 weeks with rilpivirine- or darunavir-based antiretroviral therapy.

Pharmacokinetic data are lacking for progestin-releasing subdermal contraceptive implants when used with either rilpivirine- or darunavir/ritonavir-based ART. To characterize the pharmacokinetics of etonogestrel or levonorgestrel implants when administered with these ART regimens over 48 weeks. Two separate, parallel, three-group, non-randomized, pharmacokinetic studies evaluated either etonogestrel or levonorgestrel in women receiving rilpivirine- or darunavir-based ART compared with women without HIV (control group). Participants on ART were switched to rilpivirine-based ART with a run-in period of 6 weeks or darunavir-based ART with a run-in of 2 weeks prior to implant insertion. Plasma was collected on Day 0, and 1, 4, 12, 24, 36 and 48 weeks post-insertion. Plasma progestin concentrations were compared between ART and control groups by geometric mean ratio (GMR) and 90% CI. At the primary endpoint of Week 24, progestin concentrations were similar between the rilpivirine and control groups [etonogestrel: 1.18 (0.99-1.37); levonorgestrel: 1.16 (0.97-1.33)]. At Week 24, progestin exposure was higher in the darunavir groups compared with the control group [etonogestrel: 2.56 (1.69-3.28); levonorgestrel: 1.89 (1.38-2.29)]. Results remained consistent through to Week 48. No differences in etonogestrel-related adverse events were observed, but both ART groups experienced more menstrual abnormalities versus the control group with levonorgestrel. Etonogestrel and levonorgestrel concentrations were not altered by rilpivirine-based ART. Although progestin concentrations were higher in the ART groups containing ritonavir-boosted darunavir, no implant-related serious adverse events were observed. Both progestin-releasing implants are an appropriate contraceptive option with either rilpivirine- or darunavir/ritonavir-based ART.

A biodegradable long-term contraceptive implant with steady levonorgestrel release based on PLGA microspheres embedded in PCL-coated implant

The biodegradable subcutaneous implants of levonorgestrel (LNG) have emerged as the most promising agents in long-term contraception, but there are still problems with burst release of drugs and unsteady LNG concentrations in blood. In this study, the aim was the development of biodegradable LNG implants for steady LNG release. Specifically, LNG was firstly loaded in biodegradable poly (lactic-co-glycolic acid) (PLGA) microspheres by emulsion-solvent evaporation method. The size, encapsulation efficiency (EE) and drug loading (DL) of microspheres were ∼3 μm, 83.71 ± 3.59% and 11.12 ± 0.47%, respectively. Then, the LNG-PLGA microspheres were directly compressed into tablets and subsequently coated with polycaprolactone (PCL) to prolong drug release duration, achieving LNG-PLGA-PCL tablets used as contraceptive implants. In vitro release studies demonstrated LNG-PLGA-PCL implant can continuously and steady release LNG for 90 days. After subcutaneous implantation, such tablets showed more steady drug plasma concentration and longer retention in vivo than those of subcutaneous injection microspheres. Moreover, these in vivo properties of LNG-PLGA-PCL implant are comparable to the commercial subcutaneous implanted LNG-silicone rods. Summarily the LNG-PLGA-PCL implant displayed long-term controlled release and outstanding biodegradation properties, which could be promising for avoiding secondary injury to users and reasonably considered as a candidate to replace commercial LNG-silicone rods in future.

Comparison of levonorgestrel level and creamatocrit in milk following immediate versus delayed postpartum placement of the levonorgestrel IUD

BackgroundBreastfeeding and postpartum contraception critically influence infant and maternal health outcomes. In this pilot study, we explore the effects of timing and duration of postpartum levonorgestrel exposure on milk lipid and levonorgestrel content to establish baseline data for future research.MethodsThis sub-study recruited a balanced convenience sample from 259 participants enrolled in a parent randomized controlled trial comparing immediate to delayed (4–8 weeks) postpartum levonorgestrel IUD placement. All planned to breastfeed, self-selected for sub-study participation, and provided the first sample at 4–8 weeks postpartum (before IUD placement for the delayed group) and the second four weeks later. We used the Wilcoxon rank sum (inter-group) and signed rank (intra-group) tests to compare milk lipid content (creamatocrit) and levonorgestrel levels between groups and time points.ResultsWe recruited 15 participants from the immediate group and 17 from the delayed group with 10 and 12, respectively, providing both early and late samples. Initially, median levonorgestrel concentration of the immediate group (n = 10) (32.5 pg/mL, IQR: 24.8, 59.4) exceeded that of the delayed group (n = 12) (17.5 pg/mL, IQR: 0.0, 25.8) (p = 0.01). Four weeks later, the values aligned: 26.2 pg/mL (IQR: 20.3, 37.3) vs. 28.0 pg/mL (IQR: 25.2, 40.8). Creamatocrits were similar between both groups and timepoints.ConclusionsImmediate postpartum levonorgestrel IUD placement results in steady, low levels of levonorgestrel in milk without apparent effects on lipid content. These findings provide initial support for the safety of immediate postpartum levonorgestrel IUD initiation, though the study was not powered to detect noninferiority between groups.Trial Registration: This randomized controlled trial was registered with ClinicalTrials.gov (Registry No. NCT01990703) on November 21, 2013.

Comparative pharmacokinetic analysis of levonorgestrel-releasing intrauterine systems and levonorgestrel-containing contraceptives with oral or subdermal administration route

Objective To compare systemic exposure to levonorgestrel (LNG) released from commercially available intrauterine systems (IUSs), a subdermal implant, and oral contraceptives. Methods An integrated population pharmacokinetic (popPK) analysis of data from over 3400 individuals in ten clinical studies with six different LNG-releasing contraceptives (four long-acting reversible contraceptives [LARCs: LNG-IUS 8, 12, and 20, initially releasing LNG 14, 17.5, and 20 μg/day, a subdermal implant initially releasing LNG 100 μg/day according to label]; progestin-only pill [POP: LNG 30 μg/day]; and combined oral contraceptive [COC] pill [LNG 100 μg/day and ethinylestradiol 20 μg/day]), was conducted to generate a popPK model. LNG release rates, and total and unbound serum/plasma LNG concentrations with LARCs were estimated over the indicated period of use; maximum (Cmax) and average (Cav) serum LNG concentrations were estimated at steady state for oral contraceptives. Influence of body weight on LNG PK was also investigated. Results Serum LNG concentration with LARCs increased with increasing daily LNG release rate, being lowest with LNG-IUS 8, higher with LNG-IUS 12 and LNG-IUS 20, and highest with the subdermal implant (1.7–2.1-times that with LNG-IUS 20). Compared with early serum LNG concentrations with LNG-IUS 20, Cav and Cmax were 1.7- and 4.5-fold higher with POP, and 8.6- and 18-fold higher with COC. Total LNG bioavailability was >97% for the LNG-IUSs and 66–80% with other contraceptives. Serum/plasma LNG concentrations decreased with increasing body weight. Conclusions Among the contraceptives examined, COC had the highest and LNG-IUSs the lowest systemic exposure to LNG. Systemic LNG concentration was inversely correlated to body weight.

Levonorgestrel Salınımlı Rahimiçi Sistemin Kontraseptif Kullanımı: Olgu Serisi

Aim: Levonorgestrel intrauterine system (LNG-RIS) is a highly effective, safe and reversible contraceptive method. It suppresses endometrial cell proliferation, thickens cervical mucus, disrupts tubal motility by creating a high levonorgestrel concentration in the endometrium and tubal mucosa. In our country, LNG-RIS is mostly used in Gynecology and Obstetrics clinics in the treatment of pathologies such as adenomyosis, endometriosis, hyperplasia and their symptoms such as menorrhagia, dysmenorrhea, pelvic pain, and is prescribed at the hospitals due to a medication report. It has a high level of protection (99.9%), and its contraceptive effect is considered to last five years, and fertility returns rapidly after removal. In this study it was aimed to evaluate retrospectively the continuation rate, the presence of unwanted effects and the patient satisfaction after insertion of LNG-RIS. Method: This is a retrospective, descriptive study of women who had been inserted LNG-IUS with contraceptive purpose in the family planning unit of the Marmara University Pendik Training and Research Hospital, between 2013-2019; the data of a total 38 patients were retrospectively analyzed. Results: The average age of the participants was 36±5 years. No pregnancy is detected during the use of the method. Five-year usage rate was 21% among users. A total of nine patients discontinued the method; one because being diagnosed with a glial tumor, two because of excessive bleeding, one other patient because having hysterectomy due to myoma uteri, two patients because the threads were not visible, two others because they have been told that their LNG-IUS had slipped down and one patient because of her pregnancy plan. The satisfaction rate was 52.6%. There was a decrease in both the duration and the amount of bleeding of menstruation but this decrease was not statistically significant. Conclusion: LNG-RIS is an effective, reliable contraception method with low side effect. It is still limited in primary care and it will be more appropriate to spread its use.

Pearl Index study with levonorgestrel-releasing intravaginal rings: using pharmacokinetic results to investigate treatment compliance as a potential contributor for contraceptive failure.

What is the reason for insufficient contraceptive efficacy of levonorgestrel (LNG) delivered by intravaginal ring (IVR) releasing comparable amounts of LNG as approved progestogen-only pills (POPs)? The pharmacokinetic (PK) evaluation in a subpopulation indicated that the steady-state concentration of plasma LNG was markedly lower in the participants in the USA compared to those in Japan suggesting non-compliance in the US participants which may explain a clearly higher Pearl Index (PI) in USA (8.2, unadjusted PI) compared to Japan (1.4, unadjusted PI). Contraceptive efficacy of LNG in POPs has been demonstrated following different routes of administration (e.g. orally, implants, intrauterine systems), and the PK is well-characterized including a target exposure needed for contraception. Exposure above this target concentration was reached in Phase 1 studies using IVR delivering 40 µg LNG per day. The primary objective of this multicenter, open-label, single-arm study conducted in the USA and in Japan was to assess the contraceptive efficacy of an LNG-containing IVR during a planned treatment period of 1 year in healthy women 18-35 years of age. The study was planned to be conducted in 1600 participants (1300 in the USA, 300 in Japan). The study was prematurely terminated after approximately one-third of the planned exposure was reached due to a high number of pregnancies (28) in the US study population. In total, 1471 participants were treated (1166 participants in the USA and 305 participants in Japan). The PI as a measure of contraceptive efficacy was calculated from the frequency of unintended pregnancies during treatment. LNG exposure in the systemic circulation was assessed during treatment in 136 participants (PK subgroups: 106 in the USA and 30 in Japan). The PK evaluation in the PK subgroups indicated that the steady-state concentration of plasma LNG after 6 months was markedly lower in the participants in the USA (geometric mean 91.2 ng/l) compared to those in Japan (263.8 ng/l). This PK finding cannot be explained by the regional differences in body weight observed between the PK subgroups, thus suggesting non-compliance in the US participants. In 15.7% of the samples collected in the USA and 3.5% samples in Japan, the LNG concentration at steady state was below the lower limit of quantification (10 ng/l), which is not expected with the required continuous use of the IVR documented in most of the eDiaries. The planned duration of treatment was 12 months, but due to the premature termination of the study none of the participants completed the 12-month treatment. All data collected until the study termination were considered, but it is to be noted that the amount of missing data limits the conclusions that can be drawn from the data. The results of this study triggered the termination of the project, because the objective to show sufficient contraceptive efficacy of the LNG IVR was not met. The choice of a user-dependent contraceptive method with an LNG dose that is not inhibiting ovulation is not advisable for women who may have compliance issues. The study was funded by Bayer AG and all authors are employees of Bayer AG. NCT02403401.

Pharmacokinetics of Oral Levonorgestrel in Women After Roux-en-Y Gastric Bypass Surgery and in BMI-Matched Controls

BackgroundWomen are advised to primarily use non-oral contraceptive alternatives after Roux-en-Y gastric bypass since it is not known if the surgery affects the pharmacokinetics of oral contraceptives.MethodsThis is a multi-center, open label, phase 2 pharmacokinetic study performed at the University Hospital of Linköping and the Clinical Trials Center, Department of Obstetrics and Gynecology, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden. Fifteen women aged 18–40 years who had previously undergone Roux-en-Y gastric bypass surgery and reached a BMI < 30 were included. Fifteen BMI-matched women with no previous history of Roux-en-Y gastric bypass surgery served as a control group. After administration of a single dose of a combined oral contraceptive containing 0.03 mg ethinylestradiol/0.15 mg levonorgestrel, serum levonorgestrel concentrations were determined during a 24-h period using ultra performance liquid chromatography/tandem mass spectrometry. The area under the plasma concentration time curve of levonorgestrel (AUC0–24h) was the main outcome measure.ResultsThere were no significant differences in the studied pharmacokinetic parameters, AUC0–24h, total AUC, peak serum concentration (Cmax), time to peak serum concentrations (Tmax), apparent oral clearances of levonorgestrel (CLoral), or terminal half-lives (t½) between the groups.ConclusionThis is to our knowledge the first study to evaluate the pharmacokinetics of oral levonorgestrel in women with a BMI < 30 at least 1 year after RYGB compared with a BMI-matched group of women. We could not find any significant pharmacokinetic differences between the groups, suggesting that oral levonorgestrel may be used in non-obese women after Roux-en-Y gastric bypass once a stable body weight has been reached.Clinical Trial NumberEudraCT 2014–004677-17.

Effect of efavirenz on levonorgestrel concentrations among Malawian levonorgestrel implant users for up to 30 months of concomitant use: a subanalysis of a randomized clinical trial

ObjectivesOur primary objective was to compare geometric mean levonorgestrel concentrations between levonorgestrel implant users who were or were not taking the antiretroviral efavirenz, for up to 30 months after implant initiation. Our secondary objective was to evaluate the pregnancy rate among levonorgestrel implant users on efavirenz. Study designWe performed a subanalysis of 42 Malawian women randomized to initiate the levonorgestrel implant as part of a parent randomized clinical trial. Our subset included 30 HIV-infected women taking efavirenz and 12 HIV-uninfected women not taking efavirenz. They underwent urine pregnancy testing every 3 months and serum levonorgestrel testing at day 3 and months 1, 3, 6, 12, 18, 24, 27 and 30 after implant initiation. Geometric mean levonorgestrel concentrations were calculated for efavirenz users and non-efavirenz users at each time point. ResultsThe geometric mean levonorgestrel concentrations were lower for efavirenz users than non-efavirenz users at every time point; the geometric mean ratio for efavirenz users:non-efavirenz users ranged from 0.60 [90% confidence interval (CI) 0.46–0.79] at 1 month to 0.27 (90% CI 0.12–0.61) at 30 months after implant insertion. No pregnancies occurred over 60 woman-years of concomitant levonorgestrel implant and efavirenz use, although 11 women had levonorgestrel concentrations <180 pg/mL (the previously suggested minimum threshold concentration for efficacy). ConclusionsEfavirenz users had lower levonorgestrel concentrations than non-efavirenz users, and one third of our concomitant efavirenz and levonorgestrel implant users had concentrations <180 pg/mL. Continued evaluation of the contraceptive efficacy of the levonorgestrel implant may be needed for efavirenz users. ImplicationsAmong 42 Malawian women using the levonorgestrel implant for contraception, women who were taking the antiretroviral efavirenz had lower serum levonorgestrel concentrations than women who were not taking efavirenz. However, none of the women who were taking efavirenz became pregnant over 60 women-years of follow-up.

Combined effects of increased temperature and levonorgestrel exposure on zebrafish female liver, using stereology and immunohistochemistry against catalase, CYP1A, HSP90 and vitellogenin

Climate change and pharmaceuticals contamination constitute two of the most relevant stressors on the aquatic ecosystems, however, there is a huge lack of information regarding the interactive effects of both stressors. For that, a mesocosm experiment was implemented where adult zebrafish were exposed to combined temperature and the progestin levonorgestrel (LNG) for 21 days. Considering that the liver is one of the organs where there is a greater metabolization and accumulation of toxicants, the main objective of this work was to assess the effects of both stressors on the female zebrafish hepatocytes morphology and functioning, through stereological and immunohistochemical techniques.Our results revealed an increase of coefficient of variation of the number distribution of hepatocytes volume (CVN(υ)) for individuals exposed to LNG, which denotes an increase of the hepatocytes size variability and is suggestive of functional impacts. This was corroborated by the signs of increased glycogen content with the exposure to increased LNG concentrations and temperature, indicating modified hepatocyte glycogen metabolism. Such disturbances can be considered indicators that the fish had to deal with impacts caused by the stress factors.Regarding the immunoreactivity, from the four proteins selected (catalase, CYP1A, HSP90 and Vtg), just in two of them (catalase and Vtg) were observed some responses to both stressors. For catalase there was a hormetic response, in which exposure to lower LNG concentrations caused a significant higher positive immunostaining than under higher LNG concentrations. While, for Vtg, significant effects of temperature and LNG existed, in which a decline in Vtg immunostaining was observed with exposure to higher temperature and lower LNG concentrations. These results should be seen as a warning sign about fine impacts of multiple stressors, such as temperature and progestogens, on the structure and functioning of zebrafish liver and potentially in other aquatic organisms, and on their health implications.

Pharmaceutical jewelry: Earring patch for transdermal delivery of contraceptive hormone

Lack of adherence to medication dosing schedules is a significant cause of morbidity and mortality with large associated financial costs. This is especially true for contraceptive hormones, which provide almost perfect prevention of pregnancy when used correctly, but have significant failure rates in typical use, due largely to poor adherence. To increase medication acceptability and adherence, we introduce pharmaceutical jewelry, in which a transdermal patch is incorporated into jewelry worn on skin. To demonstrate the approach, we incorporated transdermal patches containing the contraceptive hormone levonorgestrel (LNG) into an earring, a ring, a necklace, and a wrist watch. Transdermal delivery of LNG from earring patches across porcine skin ex vivo achieved a steady state flux of 1.7 μg/cm2·h. Pharmacokinetic analysis in hairless rats yielded LNG delivery rates that maintained serum LNG levels near 1500 pg/ml throughout the 1-week patch application period, which is well above the human contraceptive threshold concentration of 200 pg/ml. When patches were applied cyclically for 16 h on and 8 h off to simulate earring removal at night, serum LNG concentrations dipped during off periods, but remained well above the human contraceptive threshold. Earring patches were well tolerated by the rats. We conclude that pharmaceutical jewelry can provide a novel method of drug delivery, especially for contraceptive hormones, that has the potential to improve acceptability and increase medication adherence.

Altered pharmacokinetics of combined oral contraceptives in obesity — multistudy assessment

ObjectiveThe objective was to evaluate the pharmacokinetics (PKs) of levonorgestrel (LNG)-containing combined oral contraceptives (COCs) in obese women. Study designWe pooled and reanalyzed data from 89 women with different body mass index (BMI) categories from four clinical studies. The LNG and ethinyl estradiol (EE) PKs were analyzed utilizing a zero-order absorption (K0), two-compartment PK model to evaluate key PK parameters in relation to a range of weights, BMI and body surface area (BSA). ResultsIncreasing of body habitus metrics is correlated with decreasing Cmax (p<.0001) and AUCτ (p<.05) for both LNG and EE, but no correlation was found for Cmin (p≥.17). Increasing weight and BMI were associated with a modest increase (p≤.056) of clearance (CL) and appreciable increases of central volume (V1, p<.05), distribution clearance (CLd, p≤.001) and peripheral volume (V2, p<.0001) for LNG. For EE, increases in CL (p≤.009) were found with greater weight, BMI and BSA. Values of V1, CLd and V2 also increased (p<.0001) in obese subjects. The half-life and steady-state volume were greater among obese women (p<.0001) for both LNG and EE. LNG and EE PK parameters correlated well (p≤.006 for all), indicating that individual subject physiology affected both drugs similarly. ConclusionsThe primary effects of obesity on LNG and EE were a modest increase in CL and a marked increase in distribution parameters. We observed no obesity-related differences in trough LNG and EE concentrations. ImplicationsThis population PK analysis demonstrated reduced systemic exposure to LNG/EE oral contraceptives in obese subjects (Cmax and AUCτ); these particular differences are unlikely to lower contraceptive effectiveness among obese women who are correctly using LNG-containing contraceptives.