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

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

Atogepant Has No Clinically Relevant Effects on the Pharmacokinetics of an Ethinyl Estradiol/Levonorgestrel Oral Contraceptive in Healthy Female Participants.

The incidence of migraine is higher among women than men and peaks during the reproductive years, when contraceptive medication use is common. Atogepant, a potent, selective antagonist of the calcitonin gene-related peptide receptor-in development for migraine prevention-is thus likely to be used by women taking oral contraceptives. This phase 1, open-label, single-center, 2-period, fixed-sequence study examined the effect of multiple-dose atogepant 60 mg once daily on the single-dose pharmacokinetics of a combination oral contraceptive, ethinyl estradiol 0.03 mg and levonorgestrel 0.15 mg (EE/LNG), in healthy postmenopausal or oophorectomized women. For participants in period 1, a single dose of EE/LNG was followed by a 7-day washout. In period 2, atogepant was given once daily on days 1-17; an oral dose of EE/LNG was coadministered with atogepant on day 14. Plasma pharmacokinetic parameters for EE and LNG were assessed following administration with and without atogepant. Twenty-six participants aged 45-64 years enrolled; 22 completed the study in accordance with the protocol. The area under the concentration-time curve extrapolated to infinity (AUC0-∞ ) of LNG was increased by 19% when administered with atogepant. Coadministration of atogepant and a single dose of EE/LNG did not substantially alter the pharmacokinetics of EE; the ∼19% increase in plasma AUC0-∞ of LNG is not anticipated to be clinically significant. Overall, atogepant alone and in combination with EE/LNG was generally well tolerated, with no new safety signals identified.

A Multi-Center, Open-Label, Pharmacokinetic Drug Interaction Study of Erenumab and a Combined Oral Contraceptive in Healthy Females.

BACKGROUND: Erenumab is a human anti-calcitonin gene-related peptide monoclonal antibody developed for migraine prevention. Migraine predominately affects women of childbearing age; thus, it is important to determine potential drug-drug interactions between a common oral contraceptive and drugs used to treat migraine. OBJECTIVES: We sought to evaluate potential drug-drug interactions between erenumab and a common oral contraceptive. METHODS: Healthy women received three cycles of a norgestimate/ethinyl estradiol-containing oral contraceptive with a single 140-mg subcutaneous dose of erenumab during cycle three. Norgestimate metabolites (norgestrel and norelgestromin) and ethinyl estradiol pharmacokinetics were evaluated in the absence and presence of erenumab. Primary endpoint was peak plasma concentration (Cmax) and area under concentration-time curve from time 0 to 24 h (AUCtau). Luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations were evaluated as pharmacodynamic markers. RESULTS: Erenumab did not influence the pharmacokinetics of norelgestromin, norgestrel, or ethinyl estradiol. Least-squares mean estimates (90% confidence interval) for Cmax ratios were 1.05 (0.90-1.23), 1.06 (0.97-1.16), and 1.04 (0.88-1.22) for norelgestromin, norgestrel, and ethinyl estradiol, respectively. Respective AUCtau ratios were 1.02 (0.94-1.12), 1.03 (0.96-1.10), and 1.02 (0.91-1.14). Luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations were similar after exposure to oral contraceptive alone and with erenumab. CONCLUSION: Erenumab did not alter the pharmacokinetics of the active components of an estrogen/progestin combination oral contraceptive. Thus, no change in contraceptive efficacy is expected with erenumab. TRIAL REGISTRATION: ClinicalTrials.gov NCT02792517.

Elevation of Oxidized Lipoprotein of Low Density in Users of Combined Oral Contraceptives / Elevação da Lipoproteína de Baixa Densidade Oxidada em Usuárias de Contraceptivo Oral Combinado

Abstract Background: The use of combined oral contraceptive (COC) has been related to changes in glycemic, lipid metabolism, increased oxidative stress, and systemic blood pressure, which could suggest a higher oxidation of low-density lipoprotein cholesterol (LDL-cholesterol) in women on use of COC. Objective: To test the hypothesis that there is a difference in the plasma values of oxidized LDL among women who use and do not use COC, as well as to evaluate the correlation between it and the lipid profile and high-sensitivity C-reactive protein (hs-CRP). Methods: Forty-two women with ages between 18 and 35 years old, who were eutrophic, irregularly active, with triglycerides < 150 mg/dL, blood glucose < 100 mg/dL, and who used or did not use COC were selected. These women were allocated in the COC group, formed by 21 women on COC use for at least 1 year; and a control group (CG), consisting of 21 women who had not used any type of hormonal contraceptive for at least 1 year. A significance level of 5% was adopted for statistical analyses. Results: It was observed that GCOC showed higher values of oxidized LDL than the CG, respectively 384 mU/mL versus 283 mU/mL (p < 0.01). A positive correlation between oxidized LDL and LDL-cholesterol (r = 0.3, p < 0.05), with total cholesterol (r = 0.47, p < 0.01) and with triglycerides (r = 0.32, p < 0.03) was observed, and there was no correlation with the hs-CRP. In the categorized analysis of oxidized LDL, 71.4% of GCOC women, and 28.6% of the CG remained above the established cutoff point. Conclusion: Women who use COC have higher plasma levels of oxidized LDL, and there is a positive correlation between oxidized LDL and other lipid variables.

Resumo Fundamento: O uso de contraceptivo oral combinado (COC) tem sido relacionado com alterações no metabolismo glicêmico, lipídico, maior estresse oxidativo e pressão arterial sistêmica, o que poderia sugerir maior oxidação da lipoproteína de baixa densidade colesterol (LDL-colesterol) em mulheres que utilizam COC. Objetivo: Testar a hipótese de que existe diferença nos valores plasmáticos da LDL-oxidada entre mulheres que utilizam e não utilizam COC, bem como avaliar a correlação entre ela e o perfil lipídico e proteína C reativa de alta sensibilidade (PCR-as). Métodos: Foram selecionadas 42 mulheres com idade entre 18 e 35 anos, eutróficas, irregularmente ativas, com triglicerídeos < 150 mg/dL, glicemia < 100 mg/dL e que utilizavam ou não COC. Essas foram alocadas no grupo COC, formado por 21 mulheres em uso COC há pelo menos 1 ano; e grupo controle (GC), composto por 21 mulheres que não utilizavam nenhum tipo de contraceptivo hormonal há pelo menos 1 ano. Adotado um nível de significância de 5% para as análises estatísticas. Resultados: Foi observado que o GCOC apresenta valores mais elevados da LDL-oxidada que o GC, respectivamente 384 mU/mL versus 283 mU/mL (p < 0,01). Também foi observado correlação positiva entre a LDL-oxidada e a LDL-colesterol (r = 0,3, p < 0,05), com o colesterol total (r = 0,47, p < 0,01) e com os triglicerídeos (r = 0,32, p < 0,03), não havendo correlação com a PCR-as. Na análise categorizada da LDL-oxidada, 71,4% das mulheres do GCOC e 28,6% do GC mantiveram-se acima do ponto de corte estabelecido. Conclusão: Mulheres que utilizam COC apresentam valores plasmáticos mais elevados da LDL-oxidada, existindo, correlação positiva entre a LDL-oxidada e outras variáveis lipídicas.

Elevation of Oxidized Lipoprotein of Low Density in Users of Combined Oral Contraceptives.

BACKGROUND: The use of combined oral contraceptive (COC) has been related to changes in glycemic, lipid metabolism, increased oxidative stress, and systemic blood pressure, which could suggest a higher oxidation of low-density lipoprotein cholesterol (LDL-cholesterol) in women on use of COC. OBJECTIVE: To test the hypothesis that there is a difference in the plasma values of oxidized LDL among women who use and do not use COC, as well as to evaluate the correlation between it and the lipid profile and high-sensitivity C-reactive protein (hs-CRP). METHODS: Forty-two women with ages between 18 and 35 years old, who were eutrophic, irregularly active, with triglycerides < 150 mg/dL, blood glucose < 100 mg/dL, and who used or did not use COC were selected. These women were allocated in the COC group, formed by 21 women on COC use for at least 1 year; and a control group (CG), consisting of 21 women who had not used any type of hormonal contraceptive for at least 1 year. A significance level of 5% was adopted for statistical analyses. RESULTS: It was observed that GCOC showed higher values of oxidized LDL than the CG, respectively 384 mU/mL versus 283 mU/mL (p < 0.01). A positive correlation between oxidized LDL and LDL-cholesterol (r = 0.3, p < 0.05), with total cholesterol (r = 0.47, p < 0.01) and with triglycerides (r = 0.32, p < 0.03) was observed, and there was no correlation with the hs-CRP. In the categorized analysis of oxidized LDL, 71.4% of GCOC women, and 28.6% of the CG remained above the established cutoff point. CONCLUSION: Women who use COC have higher plasma levels of oxidized LDL, and there is a positive correlation between oxidized LDL and other lipid variables.

Simultaneous quantitation of multiple contraceptive hormones in human serum by LC-MS/MS.

OBJECTIVE: The objective was to develop a method to simultaneously quantify five commonly used hormonal contraceptives (HCs) and two endogenous sex steroids by liquid chromatography-tandem triple quadrupole mass spectrometry (LC-MS/MS) and apply this method to human serum samples. STUDY DESIGN: We developed a method to simultaneously analyze ethinyl estradiol (EE2), etonogestrel (ENG), levonorgestrel (LNG), medroxyprogesterone acetate (MPA) and norethisterone (NET), along with estradiol (E2) and progesterone (P4), in human serum for a Shimadzu Nexera-LCMS-8050 LC-MS/MS platform. We analyzed serum collected from women self-reporting use of oral contraceptives, contraceptive implants or injectable contraceptives (n=14) and normally cycling women using no HC (n=15) as well as pooled samples from women administered various HCs (ENG, n=6; LNG, n=14; MPA, n=7; NET, n=5). RESULTS: Limits of quantitation were 0.010ng/mL for E2, EE2 and P4; 0.020ng/mL for ENG, LNG and MPA; and 0.040ng/mL for NET. Precisions for all assays, as indicated by coefficient of variation, were less than or equal to 12.1%. Accuracies for all assays were in the range of 95%-108%. Endogenous hormone values obtained from analysis of human serum samples are in agreement with levels previously reported in the literature for normally cycling women as well as for women taking the appropriate HC. CONCLUSIONS: We have developed a robust, accurate and sensitive method for simultaneously analyzing commonly used contraceptive steroids and endogenous sex steroids in human serum. IMPLICATIONS: This analytical method can be used for quantitating contraceptive steroid levels in women for monitoring systemic exposure to determine drug interactions, nonadherence, misreporting and proper dosing.

Effects of Flibanserin on the Pharmacokinetics of a Combined Ethinylestradiol/Levonorgestrel Oral Contraceptive in Healthy Premenopausal Women: A Randomized Crossover Study.

PURPOSE: This study aimed to investigate the effect of steady-state exposure to flibanserin, a 5-HT1A agonist/5-HT2A antagonist approved for the treatment of hypoactive sexual desire disorder in premenopausal women, on the single-dose pharmacokinetics of the contraceptive steroids ethinylestradiol and levonorgestrel in healthy premenopausal women. METHODS: Healthy female volunteers (N = 24) received 2 single doses of a combined oral contraceptive containing ethinylestradiol 30 µg and levonorgestrel 150 µg, either alone (reference) or preceded by treatment with flibanserin 100 mg once daily for 14 days (test). The 2 treatments were given in randomized order, with a 4-week washout period following the last administration of the first treatment. Plasma concentrations of ethinylestradiol and levonorgestrel were measured over 48 hours after dosing for the determination of pharmacokinetic parameters; the primary end points were Cmax and AUC0-∞ of ethinylestradiol and levonorgestrel. FINDINGS: Of the 24 women enrolled (mean age, 38.0 years), 23 completed the study. Mean (SD) Cmax and AUC0-∞ values of ethinylestradiol were 66.7 (16.3) pg/mL and 693 (268) pg · h/mL, respectively, following the oral contraceptive alone, and 72.7 (25.5) pg/mL and 740 (235) pg · h/mL, respectively, when the oral contraceptive was preceded by flibanserin. In both cases, the 90% CIs of the reference/test ratios of Cmax and AUC0-∞ were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of ethinylestradiol. Similarly, the mean (SD) Cmax and AUC0-∞ values of levonorgestrel were 5.0 (1.6) ng/mL and 52.2 (18.7) ng · h/mL, respectively, with the oral contraceptive alone, and 5.0 (1.6) ng/mL and 53.3 (20.4) ng · h/mL, respectively, following flibanserin; again, in both cases, the 90% CIs of the reference/test ratios were within the range of 80% to 125%, indicating that flibanserin had no significant effect on the pharmacokinetic properties of levonorgestrel. All adverse events were mild to moderate in intensity (incidence: 12.5% and 70.8% with ethinylestradiol/levonorgestrel treatment alone and following administration of flibanserin, respectively). IMPLICATIONS: Pretreatment with flibanserin 100 mg once daily for 2 weeks did not produce a clinically relevant change in oral contraceptive drug exposure following single-dose administration of ethinylestradiol/levonorgestrel. This finding is relevant to women with hypoactive sexual desire disorder who might prefer oral contraceptives to other forms of birth control. EudraCT No: 2006-006960-46.

Genetic variation in the first-pass metabolism of ethinylestradiol, sex hormone binding globulin levels and venous thrombosis risk.

BACKGROUND: Use of ethinylestradiol, one of the active ingredients in combined oral contraceptives, affects the incidence of venous thrombosis. To explain why some women develop thrombosis when using oral contraceptives and others do not, we hypothesized a role for the first-pass metabolism of ethinylestradiol in the liver. We set out to determine the association between genetic variation in the first-pass metabolism of ethinylestradiol, venous thrombosis risk and the effect on Sex-hormone-binding-globulin (SHBG) levels. METHODS: Premenopausal women were included from two case-control studies: LETS (103 cases; 159 controls) and MEGA (397 cases; 796 controls). Haplotype-tagging SNPs were selected in 11 candidate genes; COMT, CYP1A2, CYP2C9, CYP3A4, CYP3A5, SULT1A1, SULT1E1, UGT1A1, UGT1A3, UGT1A9, UGT2B7. Venous thrombosis risk was expressed as odds ratios (OR) with 95% confidence intervals (CI). For SHBG levels, mean differences with 95%CI were estimated in combined oral contraceptive-using control subjects from the MEGA study. RESULTS: Two copies of haplotype D in the UGT2B7 gene increased venous thrombosis risk (ORLETS: 3.78; ORMEGA: 2.61) as well as SHBG levels (mean difference 27.6nmol/L, 95%CI: -61.7 to 116.9 compared with no copies) in oral contraceptive users and not in non-users. In oral contraceptive users, haplotype A and B in the CYP3A4 gene were associated with venous thrombosis risk, but not in non-users; however, the effect on SHBG levels was not directional with the risk. None of the other haplotypes were associated with venous thrombosis. CONCLUSION: Genetic variation in the UGT2B7 gene may, in part, explain venous thrombosis risk in combined oral contraceptive users.

Treating migraine with contraceptives.

At least 18% of women suffers from migraine. Clinically, there are two main forms of migraine: migraine with aura (MA) and migraine without aura (MO) and more than 50% of MO is strongly correlated to the menstrual cycle. The high prevalence of migraine in females, its correlation with the menstrual cycle and with the use of combined hormonal contraceptives (CHCs) suggest that the estrogen drop is implicated in the pathogenesis of the attacks. Although CHCs may trigger or worsen migraine, their correct use may even prevent or reduce some forms of migraine, like estrogen withdrawal headache. Evidence suggested that stable estrogen levels have a positive effect, minimising or eliminating the estrogenic drop. Several contraceptive strategies may act in this way: extended-cycle CHCs, CHCs with shortened hormone-free interval (HFI), progestogen-only contraceptives, CHCs containing new generation estrogens and estrogen supplementation during the HFI.

Endogenous thrombin potential changes during the first cycle of oral contraceptive use.

OBJECTIVES: Venous thromboembolism (VTE) risk increases within months of combination oral contraceptive (COC) initiation. Because elevated endogenous thrombin potential (ETP) has been found in several studies to be a VTE risk factor, we evaluated the extent of ETP changes during the initial cycle of an ethinyl estradiol (EE) and levonorgestrel (LNG) COC. We also assessed the relationship between ETP changes and systemic EE and LNG concentrations. STUDY DESIGN: Participants provided multiple blood samples during a first 21-day cycle of a 30-mcg EE/150-mcg LNG COC and after a further 7 days without an active COC. Thrombin generation measured with and without addition of activated protein C (APC) yielded ETP+APC and ETP-APC and the normalized APC sensitivity ratio (nAPCsr). EE and LNG pharmacokinetic analyses were conducted over 24 h after the first COC tablet and again at steady state. RESULTS: Thrombin generation was determined in 16 of the 17 women who completed the study. Mean ETP-APC increased steadily to 21% above baseline at 24 h after the 6th COC tablet (COC624; p<.001) and to 28% above baseline at steady state (COC21; p<.001). The percentage increase in mean ETP+APC was considerably more - 54% at COC624 and 79% at steady state. Mean nAPCsr increased by 28% at COC624 and by 41% at steady state. Higher concentrations of EE or LNG were not correlated with greater increases in ETP. CONCLUSIONS: ETP increases during the first COC cycle were substantial. IMPLICATIONS: The early increases in ETP may provide biological support for the rapid increase in VTE risk during initial COC use. The lack of association between this clotting system perturbation and the systemic EE concentration is surprising and deserves further study.

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.

Lack of Pharmacokinetic Interactions Between Macitentan and a Combined Oral Contraceptive in Healthy Female Subjects.

Macitentan, a dual endothelin receptor antagonist used in pulmonary arterial hypertension, induces cytochrome P450 (CYP) 3A at supratherapeutic concentrations in vitro. Most combined oral hormonal contraceptives (OCs) are CYP3A substrates and their efficacy can be affected by CYP3A inducers. This randomized crossover study assessed possible pharmacokinetic (PK) interactions between macitentan and an OC containing ethinyl estradiol and norethindrone (or norethisterone). Twenty-six healthy women received a single oral dose of OC alone (reference) and concomitantly with 10 mg macitentan at steady state (test). No PK interaction was concluded if the 90% confidence intervals (CIs) of geometric mean ratios (GMRs; test/reference) of the peak plasma concentration (Cmax ) and the exposure from 0 to infinity (AUC0 - ∞ ) to the OC components were within the equivalence limits of 0.8 to 1.25. Cmax and AUC0-∞ of the OC were within the equivalence limits. For ethinyl estradiol, GMRs (90%CIs) of Cmax and AUC0-∞ were 0.92 (0.85-0.99) and 0.95 (0.90-0.99). For norethindrone, these values were 1.02 (0.95-1.09) and 1.04 (0.98-1.09), respectively. Overall, study treatments were well tolerated. No major changes from baseline in safety parameters were reported in either treatment. Macitentan does not affect the PK of OCs.

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.

Self-reported and verified compliance in a phase 3 clinical trial of a novel low-dose contraceptive patch and pill.

OBJECTIVE: Pregnancy rates in US contraceptive clinical trials are increasing due to decreased treatment compliance. This study compared compliance with a new low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (CP, Twirla™) with that of a low-dose combination oral contraceptive (COC) in a demographically diverse population. STUDY DESIGN: This analysis was part of an open-label, parallel-group, multicenter phase 3 study that randomized healthy sexually active women (17-40years) to 13cycles of LNG/EE CP or 6cycles of COC, then 7cycles of LNG/EE CP. We defined self-reported compliance as cycles that, according to diaries, show 21days of patch wear without missed days or any patch worn >7days or 21days of pill-taking without missed pill days. We verified compliance by detectable plasma presence of LNG and EE at cycles 2, 6, and 13. RESULTS: Of the intention-to-treat population with diary information (N=1328, mean age 26.4years, 46% minorities, 33% obese), 10.0% of the CP (n=998) versus 21.2% of the COC group (n=330) self-reported noncompliance after 6cycles (p<.001). Laboratory assessments verified 10-14% of participants in both groups as noncompliant. Self-reported perfect use did not vary between obese [body mass index (BMI) ≥30kg/m(2)] versus nonobese (BMI <30kg/m(2)) participants in both groups or when stratified by age, education, or race/ethnicity in the CP group. CONCLUSIONS: Self-reported compliance was significantly greater in the CP than COC group and did not vary by obesity status. Discrepancies between self-reported and verified compliance question reliability of patient diaries. IMPLICATIONS STATEMENT: This paper, based on an analysis of a phase 3 trial, shows that compliance was significantly greater with a new weekly transdermal CP than with a once-daily COC in obese as well as nonobese participants. Discrepancies between self-reported compliance and laboratory-verified compliance raise questions regarding the reliability of patient diaries.

Comparative study of the effects of combined oral contraceptives in hemostatic variables: an observational preliminary study.

Thrombotic risk is associated with the estrogen dose and type of progestin in combined oral contraceptives. Studies published since 1990 showed that third-generation progestins have larger risk to contribute to thrombosis development than the second-generation. However, there are conflicts in the literature regarding the thrombotic risk associated to the drospirenone progestin. So, this study aimed to evaluate the effects of 3 formulations of contraceptives containing ethinylestradiol (EE) (20 and 30 µg) combined with drospirenone versus levonorgestrel combined with EE (30 µg) in hemostatic parameters. This cross-sectional study included 70 healthy women between 18 and 30 years, BMI 19 to 30 kg/m², not pregnant, non-smokers, and users or non-users (control) of contraceptives for a minimum period of 6 months. The following parameters were assessed: prothrombin time (PT), Factor VII, activated partial thromboplastin time (aPTT), Factor XII, fibrinogen, Factor 1 + 2, Protein C, Protein S, antithrombin, D-dimers, and plasminogen activator inhibitor-1. Significant alterations were found in PT, aPTT, fibrinogen, D-dimers, and protein S, all favoring a state of hypercoagulation for contraceptive containing DRSP/20EE. Both contraceptives containing DRSP/30EE and LNG/30EE promoted changes that favor the hypercoagulability in the coagulant variable PT and in the anticoagulant variables Protein S and Protein C, respectively. We suggest that the progestin drospirenone can contribute to an inadequate balance among procoagulant, anticoagulant, and fibrinolytic factors, since that the contraceptive containing the lowest dose of estrogen and drospirenone (DRSP/20EE) caused a higher number of hemostatic changes.

Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein.

Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants.

OBJECTIVE: Drug-drug interactions between canagliflozin, a sodium glucose co-transporter 2 inhibitor approved for the management of type-2 diabetes mellitus, and an oral contraceptive (OC), warfarin, and digoxin were evaluated in three phase 1 studies in healthy participants. METHODS: All studies were open-label; study 1 included a fixed-sequence design, and studies 2 and 3 used a crossover design. Regimens were: study 1: OC (levonorgestrel (150 µg) + ethinyl estradiol (30 µg))/day (day 1), canagliflozin 200 mg/day (days 4 - 8), and canagliflozin with OC (day 9); study 2: canagliflozin 300 mg/day (days 1 - 12) with warfarin 30 mg/day (day 6) in period 1, and only warfarin 30 mg/day (day 1) in period 2, or vice versa; study 3: digoxin alone (0.5 mg/day (day 1) + 0.25 mg/day (days 2 - 7)) in period 1, and with canagliflozin 300 mg/day (days 1 - 7) in period 2, or vice versa. Pharmacokinetics (PK) were assessed at prespecified intervals; OC: days 1 and 9, canagliflozin: days 8 - 9 (study 1); warfarin: days 6 (period 1) and 1 (period 2) (study 2); and digoxin: days 5 - 7 (periods 1 and 2) (study 3). Warfarin's pharmacodynamics (PD; International Normalized Ratio (INR)) was assessed on days 6 (period 1) and 1 (period 2). RESULTS: Canagliflozin increased the plasma exposure of OC (maximum plasma concentration (Cmax): 22%, area under the curve (AUC): 6%) and digoxin (Cmax: 36%, AUC: 20%); but did not alter warfarin'€™s PK and PD. No clinically relevant safety findings (including hypoglycemia) were noted. CONCLUSION: Canagliflozin can be coadministered with OC, warfarin, or digoxin without dose adjustments. All treatments were well-tolerated.

Correcting oral contraceptive pharmacokinetic alterations due to obesity: a randomized controlled trial.

OBJECTIVE: To determine if increasing the hormone dose or eliminating the hormone-free interval improves key pharmacokinetic (PK) alterations caused by obesity during oral contraceptive (OC) use. STUDY DESIGN: Obese [body mass index (BMI)≥30 kg/m(2)], ovulatory, otherwise healthy, women received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) dosed cyclically (21 days active pills with 7-day placebo week) for two cycles and then were randomized for two additional cycles to the following: continuous cycling (CC, a dose neutral arm using the same OC with no hormone-free interval) or increased dose (ID, a dose escalation arm using an OC containing 30 mcg EE/150 mcg LNG cyclically). During Cycles 2, 3 and 4, outpatient visits were performed to assess maximum serum concentration (Cmax), area under the curve (AUC0-∞) and time to steady state as well as pharmacodynamics. These key PK parameters were calculated and compared within groups between baseline and treatment cycles. RESULTS: A total of 31 women enrolled and completed the study (CC group, n=16; ID group, n=15). Demographics were similar between groups [mean BMI: CC, 38 kg/m(2) (S.D. 5.1); ID, 41 kg/m(2) (S.D. 7.6)]. At baseline, the key LNG PK parameters were no different between groups; average time to reach steady state was 12 days in both groups; Cmax were CC: 3.82±1.28 ng/mL and ID: 3.13±0.87 ng/mL; and AUC0-∞ were CC: 267±115 h ng/mL and ID: 199±75 h ng/mL. Following randomization, the CC group maintained steady-state serum levels whereas the ID group had a significantly higher Cmax (p<.001) but again required 12 days to achieve steady state. However, AUC was not significantly different between CC (412±255 h ng/mL) and ID (283±130 h ng/mL). Forty-five percent (14/31) of the study population had evidence of an active follicle-like structure prior to randomization and afterwards this decreased to 9% (3/31). CONCLUSION: Both increasing the OC dose and continuous dosing appear to counteract the impact of obesity on key OC PK parameters. IMPLICATIONS: Obesity adversely affects the pharmacokinetics of very low dose OC pills. Although the impact of these changes on OC efficacy is still under debate, PK parameters can be normalized in obese users by continuous dosing or increasing to a low-dose pill.

Pharmacokinetic and pharmacodynamic interactions between the hepatitis C virus protease inhibitor, boceprevir, and the oral contraceptive ethinyl estradiol/norethindrone.

PURPOSE: The purpose of this study was to examine drug interactions between boceprevir, a hepatitis C virus NS3/4A protease inhibitor, and a combined oral contraceptive containing ethinyl estradiol (EE) and norethindrone (NE). METHODS: A single-center, open-label study was conducted in 20 healthy female volunteers. In three consecutive 28-day treatment periods, subjects received EE/NE (0.035 mg/1 mg; 21 days on, 7 days off). During period 3, subjects also received boceprevir (800 mg three times daily) for 28 days. RESULTS: Coadministration of boceprevir with EE/NE did not affect NE AUC0-24 but slightly reduced NE C max. Geometric mean ratios (GMRs) for NE AUC0-24 and C max with EE/NE alone and EE/NE plus boceprevir were 0.96 (90% confidence interval (CI), 0.87-1.06) and 0.83 (90% CI, 0.76-0.90). Coadministration of boceprevir with EE/NE reduced EE AUC0-24 and C max by 26 and 21%, with GMRs of 0.74 (90% CI, 0.68-0.80) and 0.79 (90% CI, 0.75-0.84). Boceprevir had no effect on mid-cycle luteinizing hormone (LH), follicle-stimulating hormone (FSH), or sex hormone-binding globulin levels, and progesterone concentrations remained <1 ng/ml during the luteal phase. Adverse events reported in this study were consistent with the well-established safety profile of boceprevir. CONCLUSION: Serum progesterone, LH, and FSH levels indicate that ovulation was suppressed during coadministration of boceprevir with EE/NE. Coadministration of boceprevir with combined oral contraceptives containing EE and ≥1 mg of NE is therefore unlikely to alter contraceptive effectiveness. The ovulation suppression activity of oral contraceptives containing lower doses of NE, and of other forms of hormonal contraception during coadministration with boceprevir, has not been established.

A comparison of the pharmacokinetic profile of an ascending-dose, extended-regimen combined oral contraceptive to those of other extended regimens.

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.