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Background and Objective: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated., Methods: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives)., Results: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUC inf ) and the maximum concentration (C max ) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUC inf of caffeine by 40% with lack of effect on C max ., Conclusions: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives., Clinical Trials Registration: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516., (© 2024. The Author(s).)

Filgotinib (FIL) is a potent and selective JAK1 inhibitor in clinical development for treatment of severe inflammatory diseases. A drug-drug interaction study to evaluate the potential effect of FIL on the pharmacokinetics (PK) of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted. This was a phase 1, open-label, randomized, crossover study in healthy female subjects (N = 24). Subjects received a single dose of LEVO (150 μg)/EE (30 μg) alone (reference), or in combination with multiple-dose FIL (200 mg once daily for 15 days; test). Intensive PK sampling was conducted, and safety was assessed throughout the study. PK interactions were evaluated using 90% confidence intervals of the geometric least squares mean ratios of the test versus reference treatments. All 24 subjects enrolled completed study treatments. Coadministration of FIL with the oral contraceptive did not alter the PK of LEVO and EE; the 90% confidence intervals of the geometric least squares mean ratios were contained within bioequivalence bounds (80%-125%). Exposures of FIL were consistent with observed clinical exposure data. Study treatments were generally well tolerated. All adverse events were mild. Coadministration with FIL did not alter the PK of LEVO/EE, and hormonal contraceptives can serve as an effective contraception method for subjects on FIL treatment., (© 2020, The American College of Clinical Pharmacology.)

It is known that co-administration of CYP3A inducers may decrease the effectiveness of oral contraceptives containing progestins as mono-preparations or combined with ethinylestradiol. In a randomized clinical drug-drug interaction study, we investigated the effects of CYP3A induction on the pharmacokinetics of commonly used progestins and ethinylestradiol. Rifampicin was used to induce CYP3A. The progestins chosen as victim drugs were levonorgestrel, norethindrone, desogestrel, and dienogest as mono-products, and drospirenone combined with ethinylestradiol. Postmenopausal women (n = 12-14 per treatment group) received, in fixed sequence, a single dose of the victim drug plus midazolam without rifampicin, with rifampicin 10 mg/day (weak induction), and with rifampicin 600 mg/day (strong induction). The effects on progestin exposure were compared with the effects on midazolam exposure (as a benchmark). Unbound concentrations were evaluated for drugs binding to sex hormone binding globulin. Weak CYP3A induction, as confirmed by a mean decrease in midazolam exposure by 46%, resulted in minor changes in progestin exposure (mean decreases: 15-37%). Strong CYP3A induction, in contrast, resulted in mean decreases by 57-90% (mean decrease in midazolam exposure: 86%). Namely, the magnitude of the observed induction effects varied from weak to strong. Our data might provide an impetus to revisit the currently applied clinical recommendations for oral contraceptives, especially for levonorgestrel and norethindrone-containing products, and they might give an indication as to which progestin could be used, if requested, by women taking weak CYP3A inducers-although it is acknowledged that the exact exposure-response relationship for contraceptive efficacy is currently unclear for most progestins., (© 2020 Bayer AG. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The 2019 Conference on Retroviruses and Opportunistic Infections included many exciting advances in antiretroviral therapy (ART). Investigators presented a case report of a second patient possibly cured of HIV through an allogeneic hematopoietic stem cell transplant from a CC chemokine receptor 5-delta 32 donor. Two clinical trials of long-acting injectable cabotegravir and rilpivirine showed promising safety, efficacy, and tolerability as maintenance ART. Test-and-treat and rapid-ART-start strategies show promise in advancing progress toward the HIV care cascade 90-90-90 Joint United Nations Programme on HIV/AIDS/World Health Organization targets. However, late diagnosis and mortality after ART initiation remain high, even in the context of HIV service scale-up, and mortality from unintentional opioid overdose in people living with HIV in the United States is on the rise. In vitro studies were presented that identified and evaluated the effect of resistance-associated mutations on ART susceptibility and elucidated mechanisms of resistance. Epidemiologic data were reported on the prevalence, impact, regional variation, and changes over time of resistance-associated mutations. Decreasing regional and national rates of resistance may be a benefit of increasing use of integrase strand transfer inhibitors (InSTIs). New findings were presented on maternal and fetal health outcomes in women of reproductive potential, drug-drug interactions between hormonal contraception and ART, and further exploration of the association between InSTIs and birth defects.

Objectives: The aim of the study was to evaluate hormonal contraception use in women with epilepsy and to assess the risk of potential interactions between contraceptives and antiepileptic drugs (AEDs)., Material and Methods: Data on hormonal contraception were obtained prospectively in women of childbearing age treated in the university epilepsy clinic., Results: We evaluated 334 women with epilepsy (mean age 30.2 years). The majority of patients took one AED (193, 58%); the most commonly prescribed AEDs were: valproate, levetiracetam or lamotrigine. Hormonal contraception was used by 19 (5.7%) of all women of childbearing age. Only 7 patients (37%) of all those using hormonal contraception used prepa- rations that did not interact with AEDs; what is more 145 (46%) patients who did not use hormonal contraception were prescribed AEDs with high teratogenic potential (valproate or/and topiramate)., Conclusions: A very small percentage of women with epilepsy of childbearing potential used hormonal contraception. More than a half of that group simultaneously took AEDs that may interact with oral contraceptives. A large proportion of women taking AEDs with high teratogenic potential were not using hormonal contraception. As interaction between OC and AEDs are common, nonhormonal, highly effective methods, such as IUDs, may be ideal for women with epilepsy. The results of the study indicate the need for closer cooperation between neurologist and gynecologist caring for women with epilepsy.

Current formulations of combined oral contraceptives (COC) containing ethinylestradiol (EE) have ≤35 μg due to increased risks of cardiovascular diseases (CVD) with higher doses of EE. Low-dose formulations however, have resulted in increased incidences of breakthrough bleeding and contraceptive failure, particularly when coadministered with inducers of cytochrome P450 enzymes (CYP). The developed physiologically based pharmacokinetic model quantitatively predicted the effect of CYP3A4 inhibition and induction on the pharmacokinetics of EE. The predicted C max and AUC ratios when coadministered with voriconazole, fluconazole, rifampicin, and carbamazepine were within 1.25 of the observed data. Based on published clinical data, an AUC ss value of 1,000 pg/ml.h was selected as the threshold for breakthrough bleeding. Prospective application of the model in simulations of different doses of EE (20 μg, 35 μg, and 50 μg) identified percentages of the population at risk of breakthrough bleeding alone and with varying degrees of CYP modulation., (© 2018 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Hormonal contraceptive agents (HCAs) are widely used throughout the world, and women taking HCAs are likely to take other medications. However, little is known about the clinical effect of most drug-drug interactions (DDIs) associated with HCAs. A team of interdisciplinary outcomes and pharmacometric researchers from academia and industry jointly engage in a research project to (i) quantitatively elucidate DDI impacts on unintended pregnancies and breakthrough bleeding, and (ii) establish a DDI-prediction framework to inform optimal use of HCAs., (© 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Objective: The purpose of this study was to determine whether interactions between non-rifamycin antibiotics and hormonal contraceptives result in decreased effectiveness or increased toxicity of either therapy., Study Design: We searched MEDLINE, Embase, clinicaltrials.gov, and Cochrane libraries from database inception through June 2016. We included trials, cohort, case-control, and pharmacokinetic studies in any language that addressed pregnancy rates, pharmacodynamics, or pharmacokinetic outcomes when any hormonal contraceptive and non-rifamycin antibiotic were administered together vs apart. Of 7291 original records that were identified, 29 met criteria for inclusion., Study Appraisal and Synthesis Methods: Two authors independently assessed study quality and risk of bias using the United States Preventive Services Task Force evidence grading system. Findings were tabulated by drug class., Results: Study quality ranged from good to poor and addressed only oral contraceptive pills, emergency contraception pills, and the combined vaginal ring. Two studies demonstrated no difference in pregnancy rates in women who used oral contraceptives with and without non-rifamycin antibiotics. No differences in ovulation suppression or breakthrough bleeding were observed in any study that combined hormonal contraceptives with any antibiotic. No significant decreases in any progestin pharmacokinetic parameter occurred during co-administration with any antibiotic. Ethinyl estradiol area under the curve decreased when administered with dirithromycin, but no other drug., Conclusion: Evidence from clinical and pharmacokinetic outcomes studies does not support the existence of drug interactions between hormonal contraception and non-rifamycin antibiotics. Data are limited by low quantity and quality for some drug classes. Most women can expect no reduction in hormonal contraceptive effect with the concurrent use of non-rifamycin antibiotics., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality., Outcomes: Overall efficacy of cited contraceptive methods, assessing reduction in pregnancy rate, safety, and side effects; the effect of cited contraceptive methods on sexual health and general well-being; and the availability of cited contraceptive methods in Canada., Evidence: Medline and the Cochrane Database were searched for articles in English on subjects related to contraception, sexuality, and sexual health from January 1994 to December 2015 in order to update the Canadian Contraception Consensus published February-April 2004. Relevant Canadian government publications and position papers from appropriate health and family planning organizations were also reviewed., Values: The quality of the evidence is rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice are ranked according to the method described in this report., Summary Statements: RECOMMENDATIONS., (Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Evidence on the effects of hormonal contraceptives on female sexuality is conflicting. We enrolled 556 women, divided into six groups: two composed of subjects using a combined hormonal contraceptive (COC) containing 0.020 ("COC20") and 0.030 ("COC30") mg of ethynyl estradiol (EE), "natural", using COC containing 1.5 mg of estradiol (E 2 ), "ring", using a vaginal ring releasing each day 0.015 mg of EE + 0.120 of etonogestrel, "subcutaneous", using a progestin only subcutaneous contraceptive implant releasing etonogestrel and "controls", using no hormonal contraceptive methods. The subjects were required to answer to the McCoy female sexuality questionnaire and were subjected to a blood test for hormonal evaluation. An ultrasound evaluation of the dorsal clitoral artery was also performed. The higher McCoy sexological value were recorded in the subdermal group; significant differences were recorded among the groups in terms of hormone distribution, with the higher levels of androstenedione in subdermal and control groups. The ultrasound evaluation of dorsal clitoral artery shows a significative correlation between pulsatility and resistance indices and orgasm parameters of McCoy questionnaire. The recorded difference in the sexual and hormonal parameters among the studied hormonal contraceptives may guide toward the personalization of contraceptive choice.

Background: With dramatic improvements in life expectancy for cystic fibrosis (CF) patients, contraception for women with CF has become an important issue. There are theoretical concerns that hormonal contraceptive use among women with CF may impact disease severity or risk for other adverse health outcomes, including thrombosis and poor bone health, as well as concerns that malabsorption or altered drug metabolism might impact contraceptive effectiveness., Objective: To evaluate evidence on the safety and effectiveness of contraceptive methods among women with CF., Search Strategy: We searched the PubMed database for all articles published from database inception through October 2015., Selection Criteria: We included studies that examined measures of disease severity, other health outcomes or indicators of contraceptive effectiveness among women with CF initiating or continuing a contraceptive method., Results: Seven studies met our inclusion criteria. Three observational studies of fair to poor quality suggest that use of oral contraceptives (OCs) does not negatively impact CF disease severity, defined as changes in pulmonary function, number of exacerbations or need for intravenous antibiotics. Three small studies of poor quality reported on contraceptive failure among women with CF using combined hormonal contraceptives (combined OCs, patch or ring). One pregnancy was reported in a patch user out of 43 hormonal contraceptive users across all studies. One pharmacokinetic study reported that women with CF achieve steroid hormone plasma concentrations similar to healthy women after ingestion of combined OCs., Conclusions: Limited evidence suggests that hormonal contraceptive use does not negatively impact disease severity among women with CF and that hormonal contraceptive effectiveness is not impaired by CF. Studies were limited by small sample sizes and short duration of follow-up. No studies examined the effect of hormonal contraception on thrombosis or bone health among women with CF., (Published by Elsevier Inc.)

Objective: To examine whether the co-administration of hormonal contraceptives (HC) and psychotropic drugs commonly used to treat anxiety and/or depression results in safety or efficacy concerns for either drug., Methods: We searched PubMed and Cochrane libraries for clinical or pharmacokinetic (PK) studies that examined co-administration of any HC with psychotropic drugs [selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), oral benzodiazepines, bupropion, mirtazapine, trazadone, buspirone, hydroxyzine, monoamine oxidase inhibitors (MAOIs), or atypical antipsychotics] in reproductive aged women., Results: Of 555 articles identified, 22 articles (18 studies) met inclusion criteria. We identified 5 studies on SSRIs, four on TCAs, one on bupropion, three on atypical antipsychotics and five on oral benzodiazepines. No articles met inclusion criteria for SNRIs, mirtazapine, trazadone, buspirone, hydroxyzine or MAOIs. Overall, clinical studies did not demonstrate differences in unintended pregnancy rates when HCs were administered with and without psychotropic drugs or in psychotropic drug treatment outcomes when psychotropic drugs were administered with and without HCs. PK studies did not demonstrate changes in drug exposure related to contraceptive safety, contraceptive effectiveness or psychotropic drug effectiveness for most classes of psychotropic drugs. However, limited PK data raise concern for HCs increasing systemic exposure of amitriptyline and imipramine (both TCAs), theoretically posing safety concerns., Conclusion: Limited quality and quantity evidence on use of psychotropic drugs and HCs suggests low concern for clinically significant interactions, though no data exist specifically for non-oral formulations of HC. Given the high frequency of use for both HCs and psychotropic drugs among reproductive-age women in the US, this review highlights a need for further research in this area., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The rising rate of overweight and obesity is a public health crisis in the United States and increasingly around the globe. Rates of contraceptive use are similar among women of all weights, but because contraceptive development studies historically excluded women over 130% of ideal body weight, patients and providers have a gap in understanding of contraceptive efficacy for obese and overweight women. Because of a range of drug metabolism alterations in obesity, there is biologic plausibility for changes in hormonal contraception effectiveness in obese women. However, these pharmacokinetic changes are not linearly related to body mass index or weight, and it is unknown what degree of obesity begins to affect pharmacokinetic or pharmacodynamics processes. Overall, most studies of higher quality do not demonstrate a difference in oral contraceptive pill effectiveness in obese compared with non-obese women. However, data are scant for women in the highest categories of obesity, and differences by progestin type are incompletely understood. Effectiveness of most non-oral contraceptives does not seem to be compromised in obesity. Exceptions to this include the combined hormonal patch and oral levonorgestrel emergency contraception, which may have lower rates of effectiveness in obese women. The purpose of this review is to summarize evidence on contraceptive use in women with obesity, including differences in steroid hormone metabolism, contraceptive effectiveness, and safety, compared with women of normal weight or body mass index using the same methods., (Copyright © 2016 American Society for Reproductive Medicine. All rights reserved.)

Family planning options, including hormonal contraceptives, are essential for improving reproductive health among the more than 17 million women living with HIV worldwide. For these women, prevention of unintended pregnancy decreases maternal and child mortality, as well as reduces the risk of perinatal HIV transmission. Similarly, treatment of HIV with antiretroviral therapy (ART) is essential for reducing morbidity and mortality among HIV-positive individuals, as well as preventing HIV transmission between sexual partners or from mother to child. Importantly, despite the benefits of hormonal contraceptives, barriers to effective family planning methods exist for HIV-positive women. Specifically, drug-drug interactions can occur between some antiretroviral medications and some hormonal contraceptives, which may influence both contraceptive efficacy and tolerability. In addition, safety concerns have been raised about the impact of hormonal contraceptives on HIV disease progression, tolerability, and the risk of female-to-male HIV transmission. This review article summarizes the potential for drug-drug interactions, tolerability, and contraceptive effectiveness when hormonal contraceptives are combined with ART. In addition, the evidence surrounding the influence of hormonal contraceptives on HIV transmission and HIV disease progression in women living with HIV are summarized., Competing Interests: Kimberly Scarsi, Kristin Darin, Catherine Chappell, Stephanie Nitz, and Mohammed Lamorde have no conflicts of interest that are directly relevant to this content.

Background and Objective: A new combination contraceptive tablet containing 0.02 mg ethinyl estradiol (EE) and 0.10 mg levonorgestrel (LNG) with potential advantages has been developed in China. This study was aimed to describe the pharmacokinetic characteristics of this new combination contraceptive tablet in female Chinese volunteers., Methods: This study was designed as phase I, open-label, and one-sequence clinical trial. 12 healthy nonpregnant female Chinese volunteers received a single dose (1 tablet) and multiple dose (1 tablet per day) administration for 21 consecutive days under fasting condition. Blood samples were analyzed with 2 validated LC-MS/MS methods for EE and LNG, respectively., Results and Conclusion: After the single dose administration, the C max of EE and LNG were 44.76±18.64 pg/mL and 2.256±1.008 ng/mL, respectively. The steady-state condition of EE was achieved on the 6(th) day after the beginning of the multiple dose administration, while the steady-state condition of LNG was achieved on the 21(st) day. For EE, the mean MRT 0-72 and t 1/2 increased by 40.2 and 30.6%, meanwhile the mean Cl/F and Vd/F decreased by 18.5 and 29.1%, respectively from Day 1 to Day 24. For LNG, the mean MRT 0-72 increased by 27.1%, while the mean Cl/F and Vd/F decreased by 62.4 and 86.3%, respectively from Day 1 to Day 24. The t 1/2 remained unchanged for LNG. The exposure of LNG significantly increased with repeated dosing, but that of EE just slightly increased., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: To compare the pharmacokinetics (PKs) of a combination oral contraceptive (OC) when given alone or concomitantly with the selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056)., Methods: This open-label, fixed-sequence, two-period study included 30 healthy female subjects aged 18-40 years. In period 1, a single oral dose of an OC containing 30 μg ethinyl estradiol (EE)/150 μg levonorgestrel (LNG) was administered alone. In period 2, the OC was administered with a clinically relevant multiple dose of mavoglurant 100 mg b.i.d. under steady-state conditions. Plasma concentrations of EE and LNG were measured up to 72 hours post administration, and the PK parameters Cmax and AUClast were estimated using noncompartmental methods., Results: The geometric mean ratios of EE Cmax and AUClast obtained with and without mavoglurant were 0.97 (90% confidence interval (CI): 0.90-1.06) and 0.94 (90% CI: 0.86-1.03), respectively. The corresponding Cmax and AUClast for LNG were 0.81 (90% CI: 0.75-0.87) and 0.68 (90% CI: 0.63-0.73), respectively., Conclusions: In conclusion, EE PK was unchanged, whereas Cmax and AUClast of LNG were 19% and 32% lower, respectively, when given with mavoglurant Further investigation regarding the impact on contraceptive efficacy is warranted.

Quartette (levonorgestrel [LNG]/ethinyl estradiol [EE] and EE) is an ascending-dose, extended-regimen combined oral contraceptive (COC) that consists of a constant dose of LNG 150 µg on days 1 to 84 with EE 20 µg on days 1 to 42, 25 µg on days 43 to 63, 30 µg on days 64 to 84, and 10 µg of EE monotherapy on days 85 to 91. A population pharmacokinetic (PK) model for EE was developed using nonlinear mixed-effects modeling to characterize the PK profile of EE administered in Quartette and other extended-regimen LNG/EE COCs. Model-predicted plasma concentration-time profiles demonstrated a stepwise increase in systemic exposure to EE during the first 84 days of the cycle following each EE dose change. Lower concentrations of EE were noted during the final 7-day period of EE 10 µg. Gradual increases in EE seen with Quartette may decrease the incidence of unscheduled bleeding frequently observed during early cycles of extended-regimen COCs., (© The Author(s) 2014.)

Among women, human immunodeficiency virus type 1 (HIV-1) infection is most prevalent in those of reproductive age. These women are also at risk of unintended or mistimed pregnancies. Hormonal contraceptives (HCs) are one of the most commonly used methods of family planning worldwide. Therefore, concurrent use of HC among women on antiretroviral medications (ARVs) is increasingly common. ARVs are being investigated and have been approved for pre-exposure prophylaxis (PrEP), and therefore, drug-drug interactions must also be considered in HIV-1-negative women who want to prevent both unintended pregnancy and HIV-1 infection. This article will review four main interactions: (i) the effect of HCs on ARV pharmacokinetics (PK) and pharmacodynamics (PD) during therapy, (ii) the effect of ARVs on HC PK and PD, (iii) the role of drug transporters on drug-drug interactions, and (iv) ongoing research into the effect of HCs on pre-exposure prophylaxis PK and PD., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Unlabelled: Rilpivirine is a human immunodeficiency virus Type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor., Objective: Rilpivirine metabolism involves cytochrome P450 3A4 (CYP3A4). This trial (ClinicalTrials. gov number: NCT00739622) evaluated the interaction between rilpivirine and ethinylestradiol/norethindrone (combination oral contraceptives), which are metabolized by multiple pathways, including CYP3A4., Methods: During three consecutive 28-day cycles, 18 HIV-negative females received once-daily ethinylestradiol (35 μg)/norethindrone (1 mg) (Days 1 - 21); Days 22 - 28 were pill-free. Only in Cycle 3 was once-daily rilpivirine (25 mg) co-administered (Days 1 - 15). Minimum and maximum plasma concentrations (Cmin; Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24h) of ethinylestradiol/norethindrone (Day 15, Cycles 2 and 3) and rilpivirine (Day 15, Cycle 3) were evaluated., Results: Rilpivirine coadministration had no effect on (least square mean ratio, 90% confidence interval) ethinylestradiol Cmin (1.09, 1.03 - 1.16) or AUC24h (1.14, 1.10 - 1.19), but increased Cmax by 17% (1.17, 1.06 - 1.30), which is unlikely to affect ethinylestradiol pharmacodynamics. Norethindrone pharmacokinetics were unaffected by rilpivirine (AUC24h: 0.89, 0.84 - 0.94; Cmin: 0.99, 0.90 - 1.08; Cmax: 0.94, 0.83 - 1.06). Steady-state rilpivirine pharmacokinetics with ethinylestradiol/norethindrone was comparable with historical data for rilpivirine alone. Rilpivirine with ethinylestradiol/norethindrone was generally well tolerated. No new safety events were identified., Conclusions: Co-administration of rilpivirine, at the therapeutic dosing regimen, with ethinylestradiol/norethindrone does not affect hormone pharmacokinetics, and is, therefore, unlikely to affect the efficacy or safety of this oral hormonal contraceptive. Rilpivirine pharmacokinetics was not affected by ethinylestradiol/norethindrone. Rilpivirine (25 mg once daily) can be co-administered with ethinylestradiol/norethindrone-based contraceptives without dose modification.

Background: Despite several drawbacks, the Pearl Index continues to be the most widely used statistical measure of contraceptive failure. However, Pearl indices reported in studies of newer hormonal contraceptives appear to be increasing., Study Design: We searched PubMed and Medical Intelligence Solutions databases for prospective trials evaluating oral contraceptive (OC) efficacy to examine potential factors that could contribute to increasing Pearl indices., Results: Numerous potential factors were identified, including an increased rate of failures of newer OCs, deficiencies in methods of calculating contraceptive failure rates, differences in study design and changes in patient populations resulting in increased rates of contraceptive failures due to the inappropriate or inconsistent use of the method., Conclusions: The two most likely important contributors to the increase in Pearl indices are more frequent pregnancy testing with more sensitive tests and less adherent study populations. Because study populations appear to be increasingly representative of the likely actual users once the product is marketed, we can expect to see even higher failure rates in ongoing and future studies. This result poses challenges for companies and regulatory agencies., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background and Objective: The identification and quantification of potential drug-drug interactions is important for avoiding or minimizing the interaction-induced adverse events associated with specific drug combinations. Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine (Lu AA21004) and co-administered agents, including fluconazole (cytochrome P450 [CYP] 2C9, CYP2C19 and CYP3A inhibitor), ketoconazole (CYP3A and P-glycoprotein inhibitor), rifampicin (CYP inducer), bupropion (CYP2D6 inhibitor and CYP2B6 substrate), ethinyl estradiol/levonorgestrel (CYP3A substrates) and omeprazole (CYP2C19 substrate and inhibitor)., Methods: The ratio of central values of the test treatment to the reference treatment for relevant parameters (e.g., area under the plasma concentration-time curve [AUC] and maximum plasma concentration [C max]) was used to assess pharmacokinetic interactions., Results: Co-administration of vortioxetine had no effect on the AUC or C max of ethinyl estradiol/levonorgestrel or 5'-hydroxyomeprazole, or the AUC of bupropion; the 90 % confidence intervals for these ratios of central values were within 80-125 %. Steady-state AUC and C max of vortioxetine increased when co-administered with bupropion (128 and 114 %, respectively), fluconazole (46 and 15 %, respectively) and ketoconazole (30 and 26 %, respectively), and decreased by 72 and 51 %, respectively, when vortioxetine was co-administered with rifampicin. Concomitant therapy was generally well tolerated; most adverse events were mild or moderate in intensity., Conclusion: Dosage adjustment may be required when vortioxetine is co-administered with bupropion or rifampicin.

Obesity is a major public health concern affecting an increasing proportion of reproductive-aged women. Avoiding unintended pregnancy is of major importance, given the increased risks associated with pregnancy, but obesity may affect the efficacy of hormonal contraceptives by altering how these drugs are absorbed, distributed, metabolized or eliminated. Limited data suggest that long-acting, reversible contraceptives maintain excellent efficacy in obese women. Some studies demonstrating altered pharmacokinetic parameters and increased failure rates with combined oral contraceptives, the contraceptive patch and emergency contraceptive pills suggest decreased efficacy of these methods. It is unclear whether bariatric surgery affects hormonal contraceptive efficacy. Obese women should be offered the full range of contraceptive options, with counseling that balances the risks and benefits of each method, including the risk of unintended pregnancy.

Background: This study analyzes levels of progesterone, estradiol, norethindrone (NET) and ethinyl estradiol (EE) in serum and levels of NET in cervical mucus on the last day of the hormone-free interval (HFI) in users of 24/4 [norethindrone acetate (NETA)/EE-24] vs. 21/7 (NETA/EE-21) regimens., Study Design: This was a randomized controlled, crossover, equivalency trial. Subjects were randomized to receive NETA/EE-24 or NETA/EE-21 for 2 months and then switched between study drugs. Blood and cervical mucus samples were obtained on Days 12-16 and on the last day of the HFI., Results: From April 2010 to November 2011, 32 subjects were enrolled with 18 subjects completing all study visits. There were no statistically significant differences in either day 12-16 (p=.54) or last hormone-free day (p=.33) cervical mucus NET concentrations between the regimens. On the last day of the HFI, median serum progesterone levels did not differ significantly; however, users of NETA/EE-24 had higher levels of serum NET (p<.001) and users of NETA/EE-21 had higher levels of serum estradiol (p=.01)., Conclusion: This data supports the fact that inhibition of the pituitary-ovarian axis occurs during oral contraceptive use and during the HFI. We demonstrated that a reduced HFI of 4 days resulted in better suppression of the ovarian hormone production, thereby reducing the risk of ovulation and potential contraceptive failure., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Empagliflozin is a potent, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of patients with type 2 diabetes mellitus. Oral contraceptives may be co-administered with antidiabetic agents over long periods of time, therefore potential drug-drug interactions between oral contraceptives and antidiabetic drugs should be investigated., Objective: The effect of multiple oral doses of empagliflozin 25 mg once daily (qd) on the steady-state pharmacokinetics of the combined oral contraceptive ethinylestradiol (EE) 30 μg/levonorgestrel (LNG) 150 μg qd was investigated., Study Design: This was a phase I, open-label, two-period, fixed sequence study., Setting: The study was performed at the Human Pharmacology Centre/Department of Translational Medicine, Boehringer Ingelheim, Biberach, Germany., Participants: Eighteen healthy premenopausal women participated in the study., Intervention: There was a mandatory run-in period in which participants received EE 30 μg/LNG 150 μg qd for 21-48 days followed by a treatment-free interval of 7 days. Participants then received EE 30 μg/LNG 150 μg qd for 14 days (reference; period 1), followed by EE 30 μg/LNG 150 μg qd plus empagliflozin 25 mg qd for 7 days (test; period 2)., Main Outcome Measures: The pharmacokinetics of EE and LNG at steady state based on the primary endpoints of area under the steady-state plasma concentration-time curve during a dosage interval τ (AUC(τ,ss)) and maximum steady-state plasma concentration during a dosage interval (C (max,ss)) were the main outcome measures., Results: The pharmacokinetics of EE and LNG were not affected by co-administration with empagliflozin. Geometric mean ratios (90 % CI) of AUC(τ,ss) and C (max,ss) for EE were 102.82 % (97.58, 108.35) and 99.22 % (93.40, 105.39), respectively. For LNG, these values were 101.94 % (98.54, 105.47) and 105.81 % (99.47, 112.55), respectively. The 90 % CIs were within the standard bioequivalence boundaries of 80-125 %. There were no relevant changes in the time to reach peak levels (t (max,ss)) or terminal elimination half-life (t (½,ss)) of EE and LNG between test and reference treatments. Ten women in each treatment had at least one adverse event (AE). Severe AEs were reported by three women in the reference period and one woman in the test period. There were no serious AEs or premature discontinuations., Conclusion: The combination of EE 30 μg/LNG 150 μg and empagliflozin 25 mg was well tolerated. Based on standard bioequivalence criteria, empagliflozin had no effect on the pharmacokinetics of EE and LNG, indicating that no dose adjustment of EE 30 μg/LNG 150 μg is required when empagliflozin is co-administered.

Several commonly prescribed antiepileptic drugs (AEDs)-including phenobarbital, phenytoin, and carbamazepine-stimulate the synthesis of a broad range of monooxygenase and conjugating enzymes. These agents are well known to reduce the duration and action of many lipid- and non-lipid-soluble drugs, including anticoagulants, cytotoxics, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, immunosuppressants, and of course, other AEDs. This process, therefore, may be associated with a number of clinical problems including higher cancer mortality, progressive AIDS, transplant rejection, and unwanted pregnancy. Withdrawal of enzyme-inducing AEDs will increase the concentration of induced drugs, bringing with it substantial risk of toxicity if doses are not concomitantly reduced. Yet the potential widespread adverse health consequences of these interactions, both with AED initiation and withdrawal, remain largely underappreciated. Furthermore, induction also affects enzymes involved in endogenous metabolic pathways, and can alter bone biochemistry, gonadal steroids, and lipid markers. Therefore, enzyme-inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease. This process continues as long as the patient takes the inducer. Modern AEDs that do not possess this property have similar efficacy for the common epilepsies. Accordingly, perhaps consideration should be given to starting treatment with, or even switching patients to, non-enzyme-inducing AEDs., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Background: We evaluated the effects of cytochrome P450 3A4 (CYP3A4) induction and inhibition on steady-state pharmacokinetics of the components of a novel oral contraceptive (OC) containing estradiol valerate (E₂V) and dienogest (DNG)., Study Design: CYP3A4 induction was assessed in an open-label, one-arm study. Sixteen healthy postmenopausal women received E₂V 2 mg/DNG 3 mg (days 1-17) and concomitant rifampicin (600 mg, days 12-16). Ratios of the area under the serum concentration-time curve between 0 and 24 h [AUC(0-24 h)] and maximum serum concentration (C(max)) of E₂ and DNG on days 17 and 11 (after and before rifampicin intervention) are presented. CYP3A4 inhibition was investigated in an open-label, parallel-group study in 24 healthy postmenopausal women receiving E₂V 2 mg/DNG 3 mg (days 1-14) and concomitant ketoconazole (400 mg, n=12) or erythromycin (500 mg three times daily, n=12) on days 8-14. Mean ratios of AUC(0-24 h) and C(max) of E₂ and DNG on days 7 and 14 are presented., Results: Concomitant administration of rifampicin decreased systemic drug exposure and yielded geometric mean ratios for E₂C(max) and AUC(0-24 h) of 75% and 56%, respectively. Corresponding mean ratios for DNG were 48% and 17%, respectively. Ketoconazole coadministration increased systemic drug exposure and yielded ratios of E₂ of 165% and 157%, respectively, and ratios of DNG of 194% and 286%, respectively. Erythromycin coadministration also resulted in increased mean C(max) and AUC(0-24 h) of both E₂ and DNG. Geometric mean ratios of C(max) and AUC(0-24 h) for E₂ were 151% and 133%, respectively. Corresponding ratios for DNG were 133% and 162%, respectively., Conclusions: Significant drug-drug interactions are apparent when CYP3A4 modulators are coadministered with the components of a novel OC containing E₂V/DNG. Coadministration of CYP3A4 modulators should be avoided where possible, and another type of contraception should be used when coadministration of CYP3A4 inducers like rifampicin is unavoidable., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Neural tube defects (NTDs) are congenital malformations that occur during early embryonic development. Suboptimal maternal folate status is a well-known risk factor for the occurrence of NTDs, and periconceptional folic acid supplementation has been shown to reduce the risk of NTDs. Folate-supplemented oral contraceptives (OCs) offer a means of improving folate status in women of childbearing potential by increasing their likelihood of having raised folate levels at the time of conception., Objective: This study aimed to demonstrate bioequivalence of ethinylestradiol (EE), drospirenone and L-5-methyl-tetrahydrofolate (L-5-methyl-THF; active moiety of levomefolate calcium) when taken as a new folate-supplemented OC containing EE/drospirenone/levomefolate calcium, with the respective OC containing EE/drospirenone and a tablet containing levomefolate calcium only., Methods: This was a randomized, open-label, three-period crossover study carried out at a single centre in Germany. The study included 45 healthy women (age range 18-38 years). The women were randomly assigned to single doses of (i) EE 0.03 mg/drospirenone 3 mg/levomefolate calcium 0.451 mg (SAFYRAL®), (ii) EE 0.03 mg/drospirenone 3 mg (Yasmin®), and (iii) levomefolate calcium 0.451 mg, administered using a crossover design, with one or more menstrual cycle washout between doses. The primary variables were maximum concentrations (C(max)) and area under the concentration versus time curve (AUC) values for EE, drospirenone and L-5-methyl-THF., Results: The bioavailability of EE and drospirenone was similar after administration of EE/drospirenone/levomefolate calcium and EE/drospirenone. The geometric mean ratios (GMRs) and its 90% confidence intervals (CIs) for AUC values and C(max) were within the pre-specified range (80.00-125.00%) for bioequivalence for EE and drospirenone in both formulations. The bioavailability of L-5-methyl-THF was similar after administration of EE/drospirenone/levomefolate calcium and levomefolate calcium. The respective GMRs and 90% CIs of baseline-uncorrected and -corrected AUC(last) (AUC from time zero to time of last measurable concentration) and C(max) were also within the 80.00-125.00% range., Conclusion: The novel folate-supplemented OC EE/drospirenone/levomefolate calcium is bioequivalent to the established OC Yasmin® (EE/drospirenone components) and to levomefolate calcium (folate component).

Background: Estradiol valerate/dienogest (E2V/DNG) is a combined oral contraceptive (COC) with 2 new hormonal entities and a unique 4-phasic dosing regimen indicated for women to prevent pregnancy., Objective: The purpose of this article is to review the pharmacology, pharmacokinetics, clinical efficacy, tolerability, and cost of E2V/DNG., Methods: MEDLINE (1966-June 2011) and EMBASE (1966-June 2011) were searched for original research and review articles published in the English language using the terms Natazia or Qlaira or estradiol valerate and dienogest. The reference lists of identified articles were reviewed for additional pertinent publications. Abstracts from the 2005 to 2011 American Society of Reproductive Medicine and American College of Obstetricians and Gynecologists meetings were searched using the same terms., Results: The search provided 56 articles that addressed the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of E2V/DNG in women of reproductive age. Articles reporting efficacy or tolerability in the setting of menopause were excluded. The initial efficacy of E2V/DNG on ovulation inhibition was investigated in 2 prospective, randomized, open-label, Phase II dose-finding studies. The dose that was approved by the Food and Drug Administration resulted in 3.13% of women ovulating in the second cycle of treatment (90% CI, 0.2%-6.05%). Rate of pregnancy prevention with this agent was reported with a Pearl Index ranging from 0.73 to 1.27 (unadjusted) to 0.34 to 0.72 (adjusted for method failure only). The mean duration of withdrawal bleeding was 4.3 days (range, 4.0-4.6 days) among 2266 women receiving 13 treatment cycles. Adverse events reported in >1% of patients included abdominal pain, acne, breast pain, dysmenorrhea, emotional lability, headache, nausea, and weight increase., Conclusions: Estradiol valerate/dienogest is a new contraceptive formulation. It offers efficacy, tolerability, and an acceptable safety profile with a potentially better bleeding pattern than levonorgestrel-containing COCs. This COC may be especially useful for older women of reproductive age who are adherent to therapy and looking for shorter and/or lighter menstrual cycles. Studies will need to be performed to determine whether clinically significant differences in outcomes exist among E2V/DNG and other available COCs., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Purpose: Antiepileptic drugs (AEDs) are widely used in reproductive-age women. The AED carbamazepine (CBZ) induces the hepatic cytochrome P450 system, thereby accelerating hormone metabolism. We sought to assess the pharmacodynamic effects of CBZ on breakthrough bleeding and ovulation during oral contraceptive (OC) use., Methods: A double-blind, randomized, crossover study of healthy women ages 18-35 years. Participants took an OC containing 20 μg ethinyl estradiol (EE) and 100 μg levonorgestrel (LNG) for 4 months. Concurrently, participants took 600 mg CBZ or a matching placebo for 2 months each, administered in random order. During the second month of CBZ or placebo, we measured EE and LNG levels 12 times over 24 h, ovarian follicular diameters with eight biweekly vaginal ultrasounds, weekly progesterone levels, and bleeding (using a diary)., Key Findings: We enrolled 25 women; 10 completed the study. Five women discontinued because of reversible CBZ side effects. Mean area under the curve (AUC) measurements were lower during CBZ use compared to placebo for EE (1,778 vs. 986 pg*h/ml, p < 0.001) and LNG (24.8 vs. 13.8 pg*h/ml, p = 0.04). Ovulation occurred in 5 of 10 CBZ cycles compared to 1 of 10 placebo cycles (p = 0.06). Three or more days of breakthrough bleeding occurred during 8 of the 10 CBZ cycles compared to 2 of the 10 placebo cycles (p = 0.07)., Significance: A commonly used dose of CBZ decreased levels of contraceptive steroids, increased breakthrough bleeding, and permitted ovulation during use of a low-dose OC. Women treated with CBZ are not adequately protected from pregnancy by low-dose OCs., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

The effect of obesity on drug metabolism and pharmacokinetics is poorly understood, and this is particularly true in regard to contraceptive steroids. This article will review the known and theoretical physiologic and pharmacologic interactions between obesity and contraceptive steroids., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The rate of obesity worldwide is currently at epidemic proportions. As part of obesity, the metabolic syndrome describes a clustering of metabolic abnormalities that increase the cardiovascular and diabetes risk. In particular, women from developing countries have diabetes in the reproductive age resulting in more pregnancies where both the mother and the fetus are at high risk. Consequently, use of safe and effective contraceptive methods is of paramount importance. Paradoxically, both obese and diabetic women are less likely to use contraception as compared to women of normal weight. Modern types of hormonal contraceptives are safe and provide important noncontraceptive benefits. The impact of obesity on drug pharmacokinetics may result in lower blood levels of steroid contraceptives that reduce their ability to prevent pregnancy, but the actual change is probably minimal. In women with uncomplicated diabetes, hormonal contraception should therefore be part of the highly needed preconception care and metabolic control., (© 2010 New York Academy of Sciences.)

The purpose of this study was to develop smart polymer based controlled delivery systems to deliver steroidal hormones after single subcutaneous (s.c.) injection at predetermined rates over extended period of time. In vivo absorption and pharmacokinetics of levonorgestrel (LNG) and testosterone (TSN) were investigated from the thermosensitive and phase sensitive polymeric controlled delivery systems. A selective, reliable, and rapid method for determination of serum LNG concentration was developed using high-performance liquid chromatography-tandom mass spectrometry with atmospheric pressure chemical ionization interface (HPLC-MS-MS with APCI), while TSN in serum samples was detected and quantified by a competitive immunoassay. The delivery systems controlled the absorption of LNG in rabbits up to 6 weeks from thermosensitive and approximately 4 weeks from phase sensitive polymeric delivery systems. In vivo study of TSN delivery systems in castrated rabbits controlled the release of TSN for at least 2 months from both thermosensitive and phase sensitive polymers. Thermosensitive and phase sensitive polymer formulations significantly (p < 0.05) increased relative bioavailability of steroidal hormones compared to control. In conclusion, thermosensitive and phase sensitive polymer based delivery systems controlled the release in vivo in rabbits for longer duration after single s.c. injection., ((c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association)

This review summarizes the pharmacology, safety and clinical efficacy of nomegestrol acetate, based on the available published literature, and assesses the pharmacological characteristics that underlie a role in different gynaecological disorders and hormone replacement therapy (HRT), and a potential role in combination estrogen/progestogen oral contraception. Nomegestrol acetate is a potent, orally active progestogen with a favourable tolerability profile and neutral metabolic characteristics. Unlike the majority of older progestogens, which were 19-nortestosterone derivatives synthesized primarily for their antigonadotropic activity as a component of hormonal contraception in combination with an estrogen, nomegestrol acetate is a 19-norprogesterone derivative designed to bind specifically to the progesterone receptor, and is relatively lacking in affinity for other steroid receptors. Nomegestrol acetate exerts strong antiestrogenic effects at the level of the endometrium and has potent antigonadotropic activity, but without any residual androgenic or glucocorticoid properties. At a dosage of 1.25 mg/day, nomegestrol acetate inhibits ovulation while permitting follicle growth, whereas at dosages of 2.5 or 5 mg/day, both ovulation and follicle development are suppressed. The antigonadotropic action of nomegestrol acetate is mediated, like other progestins, at the hypothalamic and pituitary level. Moreover, nomegestrol acetate has partial antiandrogenic activity. Absorption of nomegestrol acetate is rapid after oral administration, reaching a peak serum concentration within 4 hours, with a terminal half-life of approximately 50 hours. Nomegestrol acetate has been used successfully for the treatment of some gynaecological disorders (menstrual disturbances, dysmenorrhoea, premenstrual syndrome) and as a component of HRT in combination with estradiol for the relief of menopausal symptoms; it has been approved in Europe as monotherapy for the treatment of the menopausal syndrome, uterine diseases and menorrhagia, and in combination with an estrogen for the treatment of menopausal symptoms. In vitro data suggest that nomegestrol acetate preserves the beneficial haemostatic effects of estrogen; furthermore, nomegestrol acetate has a neutral or beneficial effect on lipid profiles, and does not adversely affect glucose metabolism or bodyweight. Nomegestrol acetate has shown a lack of profilerative activity in normal and cancerous breast tissue, and does not have a deleterious effect on bone remodelling. These potent antigonadotropic properties, and other beneficial metabolic and pharmacological characteristics, suggest that nomegestrol acetate can be an effective progestogen for use in combination with an estrogen in oral estrogen/progestogen contraceptive treatment and in HRT, while it also provides some non-contraceptive benefits for women's health.

Objectives: To review available information on pharmacokinetic effects of HIV antiretrovirals on hormonal contraceptives., Methods: A PubMed search was conducted from 1964 to 2006 using each antiretroviral generic name and the keywords contraceptive, contraception, ethinyl oestradiol, oestrogen, and progestin. Abstracts from the annual Conference on Retroviruses and Opportunistic Infections and International AIDS Society Conferences from 1998-2006 as well as package product inserts were reviewed for completeness., Results: Antiretroviral regimens containing protease inhibitors and non-nucleoside reverse transcriptase inhibitors may decrease the area under the curve (AUC) levels of steroids released by hormonal contraceptives. Some antiretroviral-hormonal contraceptive pairs do not decrease steroid hormone levels., Conclusion: Pharmacokinetic interactions of antiretrovirals on hormonal contraceptives are specific to the type of antiretroviral and hormonal contraceptive being utilized. HIV-positive women may be counselled to use dual methods of hormonal and barrier contraception to prevent pregnancy with maximal efficacy as well as to reduce possibility of HIV transmission. Oral contraceptives might be administered with non-ritonavir boosted atazanavir or non-ritonavir boosted indinavir without a loss of contraceptive efficacy. Depot medroxyprogesterone acetate may be safe to administer with efavirenz, nevirapine, and nelfinavir. However, further studies are needed to determine the clinical relevance of the interactions between hormonal contraceptives and antiretrovirals and to explore potential dose adjustments to improve contraceptive efficacy.

Nearly 50 years ago, the introduction of Enovid (norethynodrel 10 microg and mestranol 150 microg), which provided convenient and reliable contraception, revolutionized birth control. Reports of interactions between oral contraceptives (OCs) and other drugs began to trickle into the literature. At first, these drug interactions appeared to be random and unrelated. Increased understanding of P450 enzymes and phase II reactions of sulfation and glucuronidation has permitted preliminary categorization and assessment of the clinical relevance of these drug interactions.

The U.S. Food and Drug Administration considers generic and brand name oral contraceptive (OC) products clinically equivalent and interchangeable. The American College of Obstetricians and Gynecologists supports patient or clinician requests for branded OCs or continuation of the same generic or branded OCs if the request is based on clinical experience or concerns regarding packaging or compliance, or if the branded product is considered a better choice for that individual patient.

Two semi-automated, relatively high throughput methods using ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) were developed for the simultaneous determination of ethinyl estradiol (EE) in combination with either 19-norethindrone (NE) or levonorgestrel (LN) in human plasma. Using 300 microL plasma, the methods were validated over the concentration ranges of 0.01-2 ng/mL and 0.1-20 ng/mL for EE and NE (or LN), respectively. The existing methods for the determination of the oral contraceptives in human plasma require large volumes of plasma (> or =500 microL), and sample extraction is labor-intensive. The LC run time is at least 6 min, enabling analysis of only about 100 samples a day. In the present work the throughput was greatly improved by employing a semi-automated sample preparation process involving liquid-liquid extraction and derivatization with dansyl chloride followed by UPLC separation on a small particle size column achieving a run time of 2.7 min. The validation and actual sample analysis results show that both methods are rugged, precise, accurate, and well suitable to support pharmacokinetic studies where approximately 300 samples can be extracted and analyzed in a day.

Background: Avosentan (SPP301) is a potent and highly selective ETA receptor blocker and is clinically investigated in diabetic nephropathy. This study was designed to evaluate whether avosentan influences the pharmacokinetics of steroid oral contraceptives., Methods: During a run-in phase, 16 healthy females received an oral contraceptive containing ethinylestradiol 0.03 mg and levonorgestrel 0.15 mg for the first 21 days of a minimum of one menstrual cycle. In a subsequent double-blind, randomized two menstrual cycle crossover treatment phase, subjects received either avosentan 25 mg or placebo once daily concomitantly with the oral contraceptive. Serum ethinylestradiol and plasma levonorgestrel concentrations were measured on Days 14 and 15 of the two treatment periods for the evaluation of the 24-hour kinetic parameters, and an additional sample was collected on Day 21 to determine their trough concentrations. Serum progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels as well as plasma avosentan and Ro 68-5925 levels were determined on Days 13, 14, 15 and 21 of each cycle of the treatment phase., Results: Avosentan had a statistically significant lowering effect of 9 - 15% on the ethinylestradiol serum concentration levels. The 90% confidence intervals of the pharmacokinetic parameters did not include 1 or exceeded the 0.8 - 1.25 acceptance range for lack of interaction. The plasma concentration-time curves and pharmacokinetic parameters of levonor-gestrel were not statistically different during concomitant treatment with either avosentan or placebo. Compared to placebo, avosentan lowered the serum concentrations of progesterone statistically significantly by about 8% and increased slightly the LH and FSH serum concentrations. Safety and tolerability patterns were comparable during avosentan and placebo administration., Conclusion: Because of the effect of avosentan on the concentration levels of ethinylestradiol and progesterone, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during avosentan treatment.

Purpose: This is the first report comparing intrasubject lamotrigine (LTG) plasma concentrations between hormonal contraceptive (HC) intake and week-off phases in epilepsy patients receiving combined LTG and HC treatment. We describe the variation in LTG plasma concentrations with hormonal contraceptive (HC) monthly intake cycles in a series of eight patients with epilepsy., Methods: Venous blood samples were prospectively drawn from patients before their first morning dose of LTG, once between days 18 and 21 of HC intake and once between days 5 and 7 of the HC-free week., Results: Median LTG plasma concentrations were significantly higher during the HC washout week than during the phase of HC intake (p = 0.02). The median value of intrasubject percentage increase was 27%, with a wide interpatient variability., Conclusions: These findings are in line with a preliminary report on healthy volunteers. Standardization of blood sampling in relation to HC intake cycles is advisable when planning LTG therapeutic monitoring in patients receiving HC.

Antiepileptic drugs that induce hepatic enzyme activity may alter the metabolism of most hormonal methods of contraception, and this affects the contraceptive regime. This effect should be considered in the choice of both the treatment of the epilepsy and the choice of contraceptive method. This review considers these interactions and offers advice about their management.

Purpose: To determine potential changes in total and unbound serum valproic acid (VPA) concentrations at steady-state during a cycle of intake of combined hormonal contraceptive (HC) steroids., Methods: Blood samples were collected from nine women stabilized on VPA monotherapy on two separate randomized occasions: (i) at the end of the 4- to 7-day HC-free interval, and (ii) on the last day of the HC intake period. Trough concentrations of VPA in serum and serum ultrafiltrates were determined by fluorescence polarization immunoassay., Results: In all women, total and unbound VPA concentrations were higher during the HC-free interval than during HC intake (means +/- SD: 425 +/- 184 vs. 350 +/- 145 micromol/L, respectively, for total VPA, p = 0.002, and 55 +/- 37 vs. 39 +/- 25 micromol/L, respectively, for unbound VPA, p = 0.005). Compared with the HC-free interval, HC intake was associated with a mean 21.5% increase in VPA total apparent oral clearance (from 8.0 +/- 5.2 to 9.7 +/- 6.4 ml/h/kg, p = 0.01) and a 45.2 % increase in VPA unbound apparent oral clearance (from 79 +/- 81 to 115 +/- 121 ml/h/kg, p = 0.029)., Conclusions: The apparent oral clearance of total and unbound VPA increases during the HC intake period compared with the HC-free interval, probably due to induction of glucuronosyltransferase by ethinylestradiol. The magnitude of the change varies across individuals, being potentially clinically relevant in some cases. Serum VPA concentrations should be monitored when adding or discontinuing HC steroids, and possibly during the on-off intervals of a HC cycle.

This open-label, randomized study compared the pharmacokinetics of ethinylestradiol (EE) from the contraceptive vaginal ring NuvaRing (15 microg EE/day), the transdermal patch (20 microg EE/day) and a combined oral contraceptive (COC) containing 30 microg EE. After 2-8 weeks of synchronization by COC treatment, subjects were randomized to 21 days of treatment with NuvaRing, patch or COC. Analysis of area under the EE concentration-versus-time curve (AUC) during 21 days of treatment showed that exposure to EE in the NuvaRing group was 3.4 times lower than in the patch group (p < .05) and 2.1 times lower than in the pill group (p < .05). Serum EE levels of subjects showed much lower variation with NuvaRing than with the patch or the COC. Thus, exposure to EE was significantly lower with NuvaRing than with the patch and pill methods, demonstrating that NuvaRing is a low-estrogen-dose contraceptive method that also results in low estrogen exposure.

Purpose: To study the interaction between lamotrigine (LTG) and hormonal contraception., Methods: LTG serum concentrations of female patients using either no hormonal contraception (n=18), an ethinyl estradiol (EE)-containing (n=11), or a progestogen (PG)-only-containing compound (n=16) were analyzed. Patients were recruited prospectively, and blood samples were drawn during drug fasting and at steady-state conditions. Comedication with enzyme inducers, valproate, topiramate, or sertraline was not allowed. Some patients changed groups and thus served as their own controls. Samples were analyzed by a gas chromatography/ mass spectroscopy method. The Mann-Whitney U test was used for statistical comparison of the groups., Results: The LTG serum concentration-to-dose ratio (CDR), expressed as (mg/L)/(mg/d) was significantly lower in women using EE than in the control group (mean+/-SD, 0.010+/-0.004 vs. 0.017+/-0.006; p=0.003). The CDR in women using PG was 0.02+/-0.007, which was not statistically different from controls. No difference was found in CDR between women using either oral, topical, or parenteral PG. Five women switched from the control to the EE group and experienced a considerable reduction in CDR. An increase of the CDR toward control level was seen in the two women who changed from EE to PG., Conclusions: It is the EE component of oral contraceptives that interacts with LTG. The PG-only compounds did not alter LTG serum concentrations in this study. These findings should be considered when counselling women with epilepsy in the childbearing ages.