Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

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 (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. 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.

Lack of Drug-Drug Interaction Between Filgotinib, a Selective JAK1 Inhibitor, and Oral Hormonal Contraceptives Levonorgestrel/Ethinyl Estradiol in Healthy Volunteers.

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.

The Effects of Weak and Strong CYP3A Induction by Rifampicin on the Pharmacokinetics of Five Progestins and Ethinylestradiol Compared to Midazolam.

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.

CROI 2019: advances in antiretroviral therapy.

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.

Hormonal contraception in patients with epilepsy.

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.

Establishing a Multidisciplinary Framework to Study Drug-Drug Interactions of Hormonal Contraceptives: An Invitation to Collaborate.

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.

[Antiretroviral HIV therapy and hormonal contraceptives].

HIV guidelines recommend assessment of conception issues for all people living with HIV. Studies have shown negligible risk of HIV transmission from well-treated patients with HIV, and therefore condoms are no longer recom-mended to reduce HIV transmission. Some antiretroviral agents are metabolised through the same enzyme systems in the liver as hormonal contraceptives, which can affect the plasma concentration of both drug classes and the effect of the drugs, including reduced contraceptive efficacy. This review discusses the interactions between antiretroviral agents and hormonal contraceptives.

Risk-Benefit Assessment of Ethinylestradiol Using a Physiologically Based Pharmacokinetic Modeling Approach.

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 Cmax 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 AUCss 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.

Drug interactions between non-rifamycin antibiotics and hormonal contraception: a systematic review.

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.

No. 329-Canadian Contraception Consensus Part 4 of 4 Chapter 9: Combined Hormonal Contraception.

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.

The sexuological impact of hormonal contraceptives based on their route of administration.

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 (E2), "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.

Hormonal contraception and obesity.

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.

Drug-Drug Interactions, Effectiveness, and Safety of Hormonal Contraceptives in Women Living with HIV.

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.

Drug interactions between hormonal contraceptives and psychotropic drugs: a systematic review.

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.

Contraceptive safety among women with cystic fibrosis: a systematic review.

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.

[Contraception for women taking antiepileptic drugs]. / Prevensjon for kvinner som bruker antiepileptika.

Most women of fertile age want safe contraception. This is especially important for women with epilepsy, as some antiepileptic drugs may have harmful effects on the foetus. When hormonal contraception is combined with antiepileptic drugs, it is essential to be aware that certain antiepileptic drugs may reduce the efficacy of hormonal contraceptives and vice versa, which may result in a reduced effect for both drugs. Non-hormonal contraception, such as the copper coil and barrier methods may, however, be used safely in this patient group.

Pharmacokinetics of Oral Combination Contraceptive Drugs Containing Ethinyl Estradiol and Levonorgestrel in Healthy Female Chinese Volunteers.

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.

Effect of mavoglurant (AFQ056), a selective mGluR5 antagonist, on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women.

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.