RESUMO
BACKGROUND AND OBJECTIVES: Nintedanib is a tyrosine kinase inhibitor approved for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD), idiopathic pulmonary fibrosis, and other chronic fibrosing ILDs with a progressive phenotype. As nintedanib may cause foetal harm, patients taking nintedanib should avoid pregnancy. The objective of this study was to investigate the effect of nintedanib co-administration on the pharmacokinetics of Microgynon (ethinylestradiol and levonorgestrel) in female patients with SSc-ILD. METHODS: This was an open-label, two-period, fixed-sequence, drug-drug interaction study. Female patients with SSc and ≥ 10% extent of fibrotic ILD on a high-resolution computed tomography scan were eligible to participate. In Period 1, patients received one Microgynon tablet (ethinylestradiol 30 µg and levonorgestrel 150 µg) ≥ 3 days before the first administration of nintedanib in Period 2. In Period 2, patients received one Microgynon tablet following intake of nintedanib 150 mg twice daily for ≥ 10 consecutive days. The primary pharmacokinetic endpoints were the areas under the plasma concentration-time curve of ethinylestradiol and levonorgestrel over the time interval from 0 to the last quantifiable data point (AUC0-tz) and the maximum measured concentrations of ethinylestradiol and levonorgestrel in plasma (Cmax). The secondary pharmacokinetic endpoint was the area under the plasma concentration-time curve of ethinylestradiol and levonorgestrel over the time interval from 0 extrapolated to infinity (AUC0-∞). The relative exposures of ethinylestradiol and levonorgestrel when administered alone and in combination with nintedanib were assessed using an ANOVA model. RESULTS: Seventeen patients were treated. Pharmacokinetic data from 15 patients were analysed. Plasma concentration-time profiles of ethinylestradiol and levonorgestrel were similar following administration of Microgynon before and after administration of nintedanib for ≥ 10 consecutive days. Adjusted geometric mean (gMean) ratios [90% confidence intervals (CIs)] for AUC0âtz (101.4% [92.8, 110.7]) and AUC0â∞ (101.2% [94.0, 109.1]) indicated that there was no difference in total ethinylestradiol exposure when Microgynon was administered before or after administration of nintedanib. The adjusted gMean ratio for Cmax of ethinylestradiol (116.7% [90% CI 107.6, 126.5]) indicated an increase in peak exposure in the presence of nintedanib. Adjusted gMean ratios [90% CIs] for AUC0-tz (96.4% [91.5, 101.6]) and Cmax (100.9% [89.9, 113.2]) indicated that there was no difference in total or peak levonorgestrel exposure when Microgynon was administered before or after administration of nintedanib. The adjusted gMean ratio for AUC0â∞ of levonorgestrel indicated a decrease in total exposure in the presence of nintedanib (88.1% [90% CI 80.0, 97.0]). CONCLUSION: Pharmacokinetic data indicate that there is no relevant effect of nintedanib on plasma exposure to ethinylestradiol and levonorgestrel in female patients with SSc-ILD. TRIAL REGISTRATION: Clinicaltrials.gov NCT03675581.
Assuntos
Antineoplásicos/farmacologia , Contraceptivos Hormonais/farmacocinética , Etinilestradiol/farmacocinética , Indóis/farmacologia , Levanogestrel/farmacocinética , Doenças Pulmonares Intersticiais , Escleroderma Sistêmico , Área Sob a Curva , Contraceptivos Hormonais/sangue , Combinação de Medicamentos , Interações Medicamentosas , Etinilestradiol/sangue , Europa (Continente) , Feminino , Humanos , Levanogestrel/sangue , Pessoa de Meia-Idade , Estados UnidosRESUMO
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.
Assuntos
Contraceptivos Hormonais/farmacocinética , Anticoncepcionais Orais Combinados/farmacocinética , Levanogestrel/administração & dosagem , Levanogestrel/farmacocinética , Peso Corporal , Contraceptivos Hormonais/administração & dosagem , Contraceptivos Hormonais/sangue , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/sangue , Feminino , Humanos , Dispositivos Intrauterinos Medicados , Levanogestrel/sangueRESUMO
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 â¼19% 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.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/administração & dosagem , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacocinética , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/farmacocinética , Levanogestrel/farmacocinética , Administração Oral , Área Sob a Curva , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/sangue , Anticoncepcionais Orais Combinados/sangue , Esquema de Medicação , Combinação de Medicamentos , Interações Medicamentosas , Etinilestradiol/administração & dosagem , Etinilestradiol/sangue , Feminino , Voluntários Saudáveis , Humanos , Levanogestrel/administração & dosagem , Levanogestrel/sangue , Pessoa de Meia-Idade , Transtornos de Enxaqueca/prevenção & controleRESUMO
Poor patient adherence to oral contraceptives is the predominant cause of failure of these therapies, leading to unplanned pregnancies that can negatively affect female health worldwide. To improve patient adherence, we developed an oral contraceptive that is administered once a month. Here, we describe the design and report in vivo characterization of a levonorgestrel-releasing gastric resident dosage form in pigs.
Assuntos
Anticoncepcionais Orais/administração & dosagem , Administração Oral , Animais , Anticoncepcionais Orais/sangue , Anticoncepcionais Orais/farmacocinética , Formas de Dosagem , Esquema de Medicação , Liberação Controlada de Fármacos , Feminino , Levanogestrel/administração & dosagem , Levanogestrel/sangue , Levanogestrel/farmacocinética , SuínosRESUMO
Lack of adherence to medication dosing schedules is a significant cause of morbidity and mortality with large associated financial costs. This is especially true for contraceptive hormones, which provide almost perfect prevention of pregnancy when used correctly, but have significant failure rates in typical use, due largely to poor adherence. To increase medication acceptability and adherence, we introduce pharmaceutical jewelry, in which a transdermal patch is incorporated into jewelry worn on skin. To demonstrate the approach, we incorporated transdermal patches containing the contraceptive hormone levonorgestrel (LNG) into an earring, a ring, a necklace, and a wrist watch. Transdermal delivery of LNG from earring patches across porcine skin ex vivo achieved a steady state flux of 1.7⯵g/cm2·h. Pharmacokinetic analysis in hairless rats yielded LNG delivery rates that maintained serum LNG levels near 1500â¯pg/ml throughout the 1-week patch application period, which is well above the human contraceptive threshold concentration of 200â¯pg/ml. When patches were applied cyclically for 16â¯h on and 8â¯h off to simulate earring removal at night, serum LNG concentrations dipped during off periods, but remained well above the human contraceptive threshold. Earring patches were well tolerated by the rats. We conclude that pharmaceutical jewelry can provide a novel method of drug delivery, especially for contraceptive hormones, that has the potential to improve acceptability and increase medication adherence.
Assuntos
Anticoncepcionais Femininos/administração & dosagem , Sistemas de Liberação de Medicamentos , Joias , Levanogestrel/administração & dosagem , Adesivo Transdérmico , Animais , Anticoncepcionais Femininos/sangue , Anticoncepcionais Femininos/farmacocinética , Levanogestrel/sangue , Levanogestrel/farmacocinética , Ratos Pelados , Pele/metabolismo , Absorção Cutânea , SuínosRESUMO
OBJECTIVES: We explored levonorgestrel (LNG) concentrations, bleeding patterns and endometrial thickness in women with epilepsy (WWE) initiating an LNG-intrauterine device (IUD) co-administered with antiepileptic drugs (AEDs). STUDY DESIGN: This pilot study included 20 WWE ages 18 to 45 years with well-controlled seizures and stable AED regimens initiating a 52-mg LNG-IUD (20 mcg/d initial release). We collected blood and measured endometrial thickness before IUD placement and 21 days, 3 months and 6 months thereafter. Participants recorded bleeding/spotting daily. We measured total LNG (radioimmunoassay), serum hormone binding globulin (SHBG, immunoassay) and calculated the free LNG index. We compared total LNG, free LNG index, SHBG and endometrial thickness over time using a linear mixed-effects model. RESULTS: Total LNG, free LNG index and SBHG levels remained stable from day 21 throughout. Endometrial thickness decreased from a median of 5.9 mm [interquartile range (IQR) 4.6-7.5] at day 21 to 3.3mm (2.8-4.9) by month 6 (p=0.02). Bleeding and spotting days decreased from a median of 16 (IQR 13-23) in month 1 to 6.5 (IQR 4-8.5) in month 6 regardless of AED regimen. CONCLUSION: Like women without epilepsy, WWE initiating the LNG-IUD experience stable total LNG concentrations and decreasing endometrial thickness and bleeding over the first 6 months of use. IMPLICATIONS: Like women without epilepsy, WWE using antiepileptic drugs can expect a stable LNG concentration and decreasing bleeding during the first 6 months of LNG-IUD use. Our data can be useful for guidance of WWE considering use the LNG-IUD.
Assuntos
Anticonvulsivantes/uso terapêutico , Contraceptivos Hormonais/sangue , Endométrio/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Levanogestrel/sangue , Adulto , Contraceptivos Hormonais/administração & dosagem , Feminino , Humanos , Dispositivos Intrauterinos Medicados , Levanogestrel/administração & dosagem , Projetos Piloto , Adulto JovemRESUMO
To compare the pharmacokinetics (PK) of the progestin levonorgestrel for various routes of administration, an integrated population PK analysis was performed. This analysis integrated data from 10 clinical pharmacology studies and resulted in a single, comprehensive population PK model (and its applications) describing the PK of levonorgestrel and its variability for 6 levonorgestrel-containing contraceptives: 3 intrauterine systems (IUSs; levonorgestrel [LNG]-IUS 20 [Mirena® ], LNG-IUS 12 [Kyleena® ], and LNG-IUS 8 [Jaydess® /Skyla® ]); 2 oral contraceptives (the progestin-only pill [Microlut® /Norgeston® ] and the combined oral contraceptive [Miranova® ]); and a subdermal implant (Jadelle® ). The levonorgestrel-containing contraceptives administered orally or as an implant act mainly via their systemic (unbound) levonorgestrel exposure, whereas levonorgestrel administered via an IUS is released directly into the uterine cavity, resulting in lower systemic levonorgestrel concentrations. The integrated population PK analysis revealed that the combined oral contraceptive led to the highest levonorgestrel exposure, followed by the progestin-only pill and the implant, which led to similar levonorgestrel exposure, and the IUSs, which led to the lowest levonorgestrel exposure (in decreasing order: LNG-IUS 20, LNG-IUS 12, and LNG-IUS 8). The difference was even more distinct at the end of the indicated duration of use of 3 years (LNG-IUS 8) and 5 years (LNG-IUS 20 and LNG-IUS 12). Comparing the 3 IUSs and the implant, in vivo release rates were highest for the implant, followed by LNG-IUS 20, then LNG-IUS 12, and were lowest for LNG-IUS 8. This is in line with the comparison of the total levonorgestrel concentrations.
Assuntos
Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Levanogestrel/administração & dosagem , Levanogestrel/farmacocinética , Administração Oral , Combinação Albuterol e Ipratrópio , Anticoncepcionais Femininos/sangue , Vias de Administração de Medicamentos , Implantes de Medicamento , Liberação Controlada de Fármacos , Feminino , Humanos , Dispositivos Intrauterinos , Levanogestrel/sangueRESUMO
A specific and sensitive high-performance liquid chromatography-tandem mass spectrometry method that could be used to determine the concentration of levonorgestrel (LNG) in beagle dog plasma was developed. Specifically, terfenadine was used as the internal standard (IS). The separation was achieved on a Kinetex-C18 110A column (3 × 30 mm i.d., 2.6 um, Phenomenex) and a gradient mobile phase consists of methanol (0.1% formic acid) and water (0.1% formic acid) was used. The flow rate was 0.8 mL/min and the injection volume was 10 µL. The detection was performed on a triple-quadruple tandem mass spectrometer by multiple reaction monitoring mode via electrospray ionization. Quantitative analysis was carried out at m/z 313.0 â 108.9 and m/z 472.6 â 436.2 for LNG and IS respectively. This method demonstrated the linearity of LNG over a concentration range of 0.5-50 ng/mL with a coefficient correlation (r) of 0.9973. The lower limit of quantification was 0.5 ng/mL. The intra- and inter-assay precisions were 2.9 and 11.2%, with an accuracy range from 94.8 to 108.4%. The stability data indicated that sample preparation and storage process had little effect on the concentration of LNG QC sample. The validated method was successfully applied to study the pharmacokinetics of LNG in beagle dog after vaginal administration of intravaginal ring.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dispositivos Anticoncepcionais Femininos , Levanogestrel/sangue , Espectrometria de Massas em Tandem/métodos , Administração Intravaginal , Animais , Cães , Estabilidade de Medicamentos , Feminino , Levanogestrel/administração & dosagem , Levanogestrel/farmacocinética , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Levonorgestrel (LNG) is a synthetic progestin that is available in oral contraceptive tablets, a subdermal implant, and an intrauterine system for contraception. LNG pharmacokinetics are a pivotal determinant of contraceptive efficacy and essential in assessing drug-drug interactions influencing LNG exposure following different routes of LNG administration. A highly sensitive LC-MS/MS method was developed and validated to quantify levonorgestrel in human plasma. Liquid-liquid extraction was utilized with a sample volume of 500⯵L to extract levonorgestrel from plasma. Chromatographic separation of LNG was achieved with a Fortis™ C18 (3⯵m: 100â¯mmâ¯×â¯2.1â¯mm) reverse phase analytical column. The mobile phases consisted of de-ionized water plus 0.1% NH4OH (100:0.1%, v/v) (A), and methanol plus 0.1% NH4OH (100:0.1%, v/v) (B) delivered as a gradient at a flow rate of 400⯵L/min. Detection of LNG and internal standard (D-(-)-norgestrel-d7) was achieved using positive polarity mode monitoring at 313.2-245.2â¯amu and 320.1-251.2â¯amu, respectively. The assay was linear over the calibration range of 49.6 to 1500â¯pg/mL. This method was used to quantify plasma LNG released by subdermal implant in support of a drug interaction study among women with HIV receiving efavirenz- or nevirapine-based antiretroviral therapy.
Assuntos
Cromatografia Líquida/métodos , Anticoncepcionais Femininos/sangue , Levanogestrel/sangue , Espectrometria de Massas em Tandem/métodos , Anticoncepcionais Femininos/química , Anticoncepcionais Femininos/farmacocinética , Implantes de Medicamento , Feminino , Infecções por HIV , Humanos , Levanogestrel/química , Levanogestrel/farmacocinética , Modelos Lineares , Extração Líquido-Líquido , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
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.
Assuntos
Benzimidazóis/farmacologia , Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/farmacocinética , Levanogestrel/farmacocinética , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Adulto , Benzimidazóis/efeitos adversos , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Combinados/sangue , Estudos Cross-Over , Combinação de Medicamentos , Interações Medicamentosas , Etinilestradiol/efeitos adversos , Etinilestradiol/sangue , Feminino , Humanos , Levanogestrel/efeitos adversos , Levanogestrel/sangue , Pessoa de Meia-Idade , Agonistas do Receptor 5-HT1 de Serotonina/efeitos adversos , Antagonistas do Receptor 5-HT2 de Serotonina/efeitos adversosRESUMO
OBJECTIVE: The objective was to assess the extent of concordance between self-reported contraceptive use and the presence of contraceptive progestins in serum. STUDY DESIGN: We evaluated self-reported contraceptive use by using radioimmunoassay to examine baseline serum levels of medroxyprogesterone acetate (MPA) and levonorgestrel (LNG) among 97 Malawian women enrolling in a contraceptive trial. RESULTS: Twelve percent (12/97) of study participants who reported no hormonal contraceptive use in the previous 6months had either MPA or LNG detected in their serum. CONCLUSIONS: The observed discordance between self-report and detection of exogenous hormones in serum indicates that caution is warranted when drawing conclusions based on self-reported contraceptive use.
Assuntos
Comportamento Contraceptivo/estatística & dados numéricos , Anticoncepcionais Femininos/sangue , Levanogestrel/sangue , Acetato de Medroxiprogesterona/sangue , Autorrelato , Adulto , Feminino , Humanos , Malaui , Radioimunoensaio , Revelação da VerdadeRESUMO
BACKGROUND AND OBJECTIVES: The quality of cervical mucus (CM) among the levonorgestrel-releasing intrauterine system (LNG-IUS) users is controversial. The objectives were to assess CM compared to the levels of oestradiol (E2) and the frequency of cycles with luteal activity among users of the LNG-IUS. MATERIALS AND METHODS: In total, 224 LNG-IUS users for between two months and five years were recruited at a Brazilian family planning clinic. For the cross-sectional part of the study, we enrolled 175 LNG-IUS users at 2, 6 12, 24, 36, 48, and 60 months after insertion (25 women in each group), and we performed one evaluation. For the prospective part of the study, we enrolled 49 LNG-IUS users at the same lengths of use after insertion (7 women in each group), and we evaluated these women once a week for five consecutive weeks. . RESULTS: Mean (± SEM) CM scores of all evaluations among women with single and weekly evaluations were between 3.3 ± 0.9 and 8.5 ± 0.3, respectively independently of the length of use of the LNG-IUS. Mean E2 values ranged from 45.5 ± 6.8 to 472.5 ± 34.7 pg/ml and the maximum ovarian follicle diameter on the days of evaluation varied from 14.0 ± 1.3 to 31.2 ± 0.4 mm. CONCLUSIONS: The mean CM score of all evaluations, independent of the length of use of the LNG-IUS and normal levels of serum E2, was below 10 was according to the WHO is inadequate for sperm penetration.
Assuntos
Muco do Colo Uterino/fisiologia , Anticoncepcionais Femininos/administração & dosagem , Dispositivos Intrauterinos Medicados , Levanogestrel/administração & dosagem , Adulto , Brasil , Anticoncepcionais Femininos/sangue , Estudos Transversais , Estradiol/sangue , Feminino , Humanos , Levanogestrel/sangue , Folículo Ovariano/fisiologia , Estudos Prospectivos , Fatores de TempoRESUMO
BACKGROUND: Levonorgestrel (LNG) is a commonly used emergency contraceptive which can effect sex hormone levels in female blood. The objective of this study was to develop and validate a specific and sensitive LC-MS/MS method for monitoring endogenous sex hormone levels (17ß-estradiol and progesterone) in female plasma after administration of LNG. Results & methodology: The method was developed, optimized and validated according to the EMA guideline. Assay validation met all the criteria, including good linearity in the range of 0.1-20 ng/ml for 17ß-estradiol, as well as 0.2-30 ng/ml for LNG and progesterone. CONCLUSION: The method has been preliminarily applied to explore the variation trend of sex hormone levels in healthy Chinese female volunteers' plasma after oral administration of 1.5 mg LNG tablet. With LNG absorption into plasma, progesterone and estradiol levels descended rapidly, and maintained at low levels in the onset time.
Assuntos
Cromatografia Líquida/métodos , Anticoncepcionais Femininos/sangue , Estradiol/sangue , Levanogestrel/sangue , Progesterona/sangue , Espectrometria de Massas em Tandem/métodos , Anticoncepcionais Femininos/administração & dosagem , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Levanogestrel/administração & dosagem , Limite de DetecçãoRESUMO
OBJECTIVE: To determine if differences exist in the pharmacokinetics (PK) of levonorgestrel-based emergency contraception (LNG-EC) in obese and normal body mass index (BMI) users and test whether doubling the dose of LNG-EC in obese women increases total and free (active) LNG serum concentrations. STUDY DESIGN: Healthy, reproductive-age women with obese and normal BMIs received 1.5mg LNG orally (ECx1) and then in a subsequent menstrual cycle, the obese group also received 3mg LNG (ECx2). Dosing occurred during the follicular phase. Total and free LNG PK parameters were obtained via serum samples through an indwelling catheter at 0, 0.5, 1, 1.5, 2, and 2.5h. The primary outcome was the difference in total and free LNG concentration maximum (Cmax) between ECx1 and ECx2 in the obese group. RESULTS: A total of 10 women enrolled and completed the study (normal BMI=5, median 22.8kg/m(2), range 20.8-23.7; obese BMI=5, 39.5kg/m(2), range 35.9-46.7). The total LNG Cmax for obese subjects following ECx1 (5.57±2.48ng/mL) was significantly lower than the level observed in normal BMI women (10.30±2.47, p=.027). Notably, ECx2 increased the Cmax significantly (10.52±2.76, p=.002); approximating the level in normal BMI subjects receiving ECx1. Free LNG Cmax followed a similar pattern. CONCLUSION: Obesity adversely impacts both the total and free Cmax levels of LNG EC and this likely explains its lack of efficacy in obese women. Doubling the dose appears to correct the obesity-related PK changes but additional research is needed to determine if this also improves EC effectiveness in obese women. IMPLICATIONS: This study demonstrates that obesity interferes with the pharmacokinetics of LNG EC, and that doubling the dose may be an effective strategy to improve its efficacy in obese women.
Assuntos
Anticoncepção Pós-Coito/métodos , Anticoncepcionais Orais Sintéticos/administração & dosagem , Anticoncepcionais Orais Sintéticos/farmacocinética , Levanogestrel/administração & dosagem , Levanogestrel/farmacocinética , Obesidade/sangue , Adolescente , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Anticoncepcionais Orais Sintéticos/sangue , Feminino , Humanos , Levanogestrel/sangue , Ciclo Menstrual/efeitos dos fármacos , Oregon , Estudos Prospectivos , Adulto JovemRESUMO
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.
Assuntos
Anticoncepcionais Orais Hormonais/farmacocinética , Combinação de Medicamentos , Etinilestradiol/administração & dosagem , Etinilestradiol/farmacocinética , Voluntários Saudáveis , Levanogestrel/administração & dosagem , Levanogestrel/farmacocinética , Adulto , Povo Asiático , China , Anticoncepcionais Orais Hormonais/administração & dosagem , Anticoncepcionais Orais Hormonais/sangue , Relação Dose-Resposta a Droga , Etinilestradiol/sangue , Feminino , Humanos , Levanogestrel/sangue , Adulto JovemRESUMO
BACKGROUND: Levonorgestrel subdermal implants are preferred contraceptives with an expected failure rate of <1% over 5 years. We assessed the effect of efavirenz- or nevirapine-based antiretroviral therapy (ART) coadministration on levonorgestrel pharmacokinetics. METHODS: This nonrandomized, parallel group, pharmacokinetic evaluation was conducted in three groups of human immunodeficiency virus-infected Ugandan women: ART-naive (n = 17), efavirenz-based ART (n = 20), and nevirapine-based ART (n = 20). Levonorgestrel implants were inserted at baseline in all women. Blood was collected at 1, 4, 12, 24, 36, and 48 weeks. The primary endpoint was week 24 levonorgestrel concentrations, compared between the ART-naive group and each ART group by geometric mean ratio (GMR) with 90% confidence interval (CI). Secondary endpoints included week 48 levonorgestrel concentrations and unintended pregnancies. RESULTS: Week 24 geometric mean levonorgestrel concentrations were 528, 280, and 710 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.53; 90% CI, .50, .55 and nevirapine: ART-naive GMR, 1.35; 90% CI, 1.29, 1.43). Week 48 levonorgestrel concentrations were 580, 247, and 664 pg/mL in the ART-naive, efavirenz, and nevirapine groups, respectively (efavirenz: ART-naive GMR, 0.43; 90% CI, .42, .44 and nevirapine: ART-naive GMR, 1.14; 90% CI, 1.14, 1.16). Three pregnancies (3/20, 15%) occurred in the efavirenz group between weeks 36 and 48. No pregnancies occurred in the ART-naive or nevirapine groups. CONCLUSIONS: Within 1 year of combined use, levonorgestrel exposure was markedly reduced in participants who received efavirenz-based ART, accompanied by contraceptive failures. In contrast, nevirapine-based ART did not adversely affect levonorgestrel exposure or efficacy. CLINICAL TRIALS REGISTRATION: NCT01789879.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Benzoxazinas/uso terapêutico , Anticoncepcionais Femininos/farmacocinética , Infecções por HIV/tratamento farmacológico , Levanogestrel/farmacocinética , Gravidez não Planejada , Adolescente , Adulto , Alcinos , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/efeitos adversos , Anticoncepcionais Femininos/sangue , Ciclopropanos , Interações Medicamentosas , Feminino , Infecções por HIV/etnologia , HIV-1/efeitos dos fármacos , Humanos , Levanogestrel/administração & dosagem , Levanogestrel/efeitos adversos , Levanogestrel/sangue , Nevirapina/uso terapêutico , Gravidez , Inibidores da Transcriptase Reversa/uso terapêutico , Fatores de Tempo , UgandaRESUMO
The aquatic environment is polluted with thousands of chemicals. It is currently unclear which of these pose a significant threat to aquatic biota. The typical exposure scenario is now represented by a widespread blanket of contamination composed of myriads of individual pollutants-each typically present at a low concentration. The synthetic steroids, 17α-ethinylestradiol and levonorgestrel, have been widely reported to be present in the aquatic environment in the low ng to sub-ng/l range. They are widely used in contraceptive formulations, both individually and in combination. Our research employed the fathead minnow (Pimephales promelas) 21 day 'pair-breeding' assay to assess reproductive output when pairs of fish were exposed to the single chemicals at low environmentally relevant concentrations, and then to a binary mixture of them. A variety of endpoints were assessed, including egg production, which was inhibited in a concentration-dependent manner by both the individual chemicals and the mixture. Significant, sex specific effects were also seen with both chemicals, at differing levels of biological organisation. Plasma concentrations of EE2 and levonorgestrel were predicted and in the case of levonorgestrel measured, and compared with the human therapeutic plasma concentrations (Read-Across approach) to support the interpretation of the results. A novel quantitative method was developed for the data analysis, which ensured a suitable endpoint for the comparative mixture assessment. This approach compares the reproductive performance from individual pairs of fish during chemical exposure to its pre-treatment performance. The responses from the empirical mixture study were compared to predictions derived from the single substance data. We hypothesised combined responses which were best described by the concept of concentration addition, and found no clear indications against this additivity expectation. However, the effect profiles support the current knowledge that both compounds act in different ways to reduce egg production in fish, and suggest that probably response addition (also called Independent action) is the more appropriate mixture model in this case.
Assuntos
Cyprinidae/fisiologia , Etinilestradiol/toxicidade , Levanogestrel/toxicidade , Reprodução/efeitos dos fármacos , Animais , Bioensaio , Etinilestradiol/sangue , Feminino , Levanogestrel/sangue , Masculino , Poluentes Químicos da Água/toxicidadeRESUMO
Rapid, sensitive, selective and accurate LC/MS/MS method was developed for quantitative determination of levonorgestrel (LNG) in rat plasma and further validated for specificity, linearity, accuracy, precision, sensitivity, matrix effect, recovery efficiency and stability. Liquid-liquid extraction procedure using hexane:ethyl acetate mixture at 80:20 v:v ratio was employed to efficiently extract LNG from rat plasma. Reversed phase Luna column C18(2) (50×2.0mm i.d., 3µM) installed on a AB SCIEX Triple Quad™ 4500 LC/MS/MS system was used to perform chromatographic separation. LNG was identified within 2min with high specificity. Linear calibration curve was drawn within 0.5-50ng·mL(-1) concentration range. The developed method was validated for intra-day and inter-day accuracy and precision whose values fell in the acceptable limits. Matrix effect was found to be minimal. Recovery efficiency at three quality control (QC) concentrations 0.5 (low), 5 (medium) and 50 (high) ng·mL(-1) was found to be >90%. Stability of LNG at various stages of experiment including storage, extraction and analysis was evaluated using QC samples, and the results showed that LNG was stable at all the conditions. This validated method was successfully used to study the pharmacokinetics of LNG in rats after SubQ injection, providing its applicability in relevant preclinical studies.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Anticoncepcionais/sangue , Levanogestrel/sangue , Progestinas/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Anticoncepcionais/farmacocinética , Feminino , Levanogestrel/farmacocinética , Plasma/química , Progestinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Sensibilidade e EspecificidadeRESUMO
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.