RESUMO
The wide array of polydimethylsiloxane (PDMS) variants available on the market, coupled with the intricate combination of additives in silicone polymers, and the incomplete understanding of drug release behavior make formulation development of levonorgestrel intrauterine systems (LNG-IUSs) formidable. Accordingly, the objectives of this work were to investigate the impact of excipients on formulation attributes and in vitro performance of LNG-IUSs, elucidate drug release mechanisms, and thereby improve product understanding. LNG-IUSs with a wide range of additives and fillers were prepared, and in vitro drug release testing was conducted for up to 12 months. Incorporating various additives and/or fillers (silica, silicone resins, silicone oil, PEG, etc.) altered the crystallization kinetics of the crosslinked polymer, the viscosity, and the microstructure. In addition, drug-excipient interactions can occur. Interestingly, additives which increased matrix hydrophobicity and hindered PDMS crystallization facilitated dissolution and permeation of the lipophilic LNG. The influence of additives and lubricants on the mechanical properties of LNG-IUSs were also evaluated. PDMS chemical substitution and molecular weight were deemed to be most critical polymer attributes to the in vitro performance of LNG-IUSs. Drugs with varying physicochemical characteristics were used to prepare IUSs, modeling of the release kinetics was performed, and correlations between release properties and the various physicochemical attributes of the model drugs were established. Strong correlations between first order release rate constants and both drug solubility and Log P underpin the partition and diffusion-based release mechanisms in LNG-IUSs. This is the first comprehensive report to provide a mechanistic understanding of material-property-performance relationships for IUSs. This work offers an evidence-based approach to rational excipient selection and tailoring of drug release to achieve target daily release rates in vivo. The novel insights gained through this research could be helpful for supporting development of brand and generic IUS products as well as their regulatory assessment.
Assuntos
Dimetilpolisiloxanos , Liberação Controlada de Fármacos , Excipientes , Levanogestrel , Levanogestrel/química , Levanogestrel/administração & dosagem , Levanogestrel/farmacocinética , Excipientes/química , Dimetilpolisiloxanos/química , Dispositivos Intrauterinos Medicados , Cristalização , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/química , Anticoncepcionais Femininos/farmacocinética , ViscosidadeRESUMO
OBJECTIVES: To assess the pharmacokinetics and pharmacodynamics of the etonogestrel (ENG) contraceptive implant when inserted at an alternative scapular site. STUDY DESIGN: We conducted a pilot study of healthy, reproductive-age females who underwent subdermal insertion of an ENG implant over the inferior edge of the nondominant scapula (scapular insertion). We measured serum ENG levels over 1 year at nine time points. Participants completed questionnaires on insertion site and bleeding side effects. We collected photographs and video recordings of insertion and removal techniques. RESULTS: We enrolled five participants (as prespecified), their median age was 26.0 years (range: 19.6-30.3), and median body mass index was 25.0 kg/m2 (range: 22.0-28.0). All serum ENG concentrations remained >90 pg/mL and were within the range of published data for arm insertion of ENG implant at all time points. The mean serum ENG level was 511.7 pg/mL (±168.2) at 1 week and 136.6 pg/mL (±21.8) at 12 months. During the first week after insertion, four of five participants noted insertion site pain with a median pain score of 2 (range 1-3), but all noted resolution by week two. Participants reported variable bleeding patterns consistent with standard ENG implant placement. At the end of the study, all participants reported satisfaction with the implant and would recommend scapular insertion to a friend. CONCLUSIONS: Scapular insertion of the ENG contraceptive implant has similar pharmacokinetics to arm insertion over 1 year of use. This novel, alternative site was well tolerated and demonstrated similar bleeding side effects to standard arm insertion. IMPLICATIONS: Subdermal scapular insertion of the etonogestrel contraceptive implant demonstrated similar pharmacokinetics to arm insertion over 1 year of use. Our pilot data support scapular insertion as an alternative site for ENG contraceptive implants, which could be beneficial for certain patient populations.
Assuntos
Anticoncepcionais Femininos , Desogestrel , Implantes de Medicamento , Escápula , Humanos , Feminino , Desogestrel/administração & dosagem , Desogestrel/farmacocinética , Projetos Piloto , Adulto , Anticoncepcionais Femininos/farmacocinética , Anticoncepcionais Femininos/administração & dosagem , Adulto Jovem , Contraceptivos Hormonais/administração & dosagem , Contraceptivos Hormonais/farmacocinéticaRESUMO
OBJECTIVES: To measure plasma concentrations of medroxyprogesterone acetate (MPA) in users with epilepsy treated with antiseizure medications and compare these to MPA concentrations in those without epilepsy. STUDY DESIGN: For this multisite cross-sectional study, we obtained a single blood sample from those with epilepsy treated with various antiseizure medications (n = 18) within the week before their next depot medroxyprogesterone injection. Among the participants without epilepsy (n = 20), 10 similarly were scheduled within the week prior to the next injection, and 10 were scheduled at earlier intervals to attempt to balance the time intervals between groups. MPA concentrations were determined by a validated assay. RESULTS: MPA concentrations were similar among those with epilepsy and controls and between groups with and without the use of enzyme-inducing medications. The lowest MPA concentrations, under 0.07 ng/mL, were observed among two of eight using enzyme-inducing antiseizure medications, one of 10 using noninducing medications, and one of 19 controls had concentrations below 0.2 ng/mL. CONCLUSIONS: In this exploratory study, lower MPA concentrations in some participants using enzyme-inducing antiseizure medications suggest a potential interaction that could reduce depot medroxyprogesterone efficacy.
Assuntos
Anticonvulsivantes , Epilepsia , Acetato de Medroxiprogesterona , Humanos , Acetato de Medroxiprogesterona/administração & dosagem , Acetato de Medroxiprogesterona/farmacocinética , Acetato de Medroxiprogesterona/sangue , Feminino , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Estudos Transversais , Adulto , Epilepsia/tratamento farmacológico , Epilepsia/sangue , Adulto Jovem , Preparações de Ação Retardada , Adolescente , Contraceptivos Hormonais/administração & dosagem , Contraceptivos Hormonais/farmacocinética , Pessoa de Meia-Idade , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Anticoncepcionais Femininos/sangueRESUMO
An intrauterine system (IUS) can be implanted in the uterus and deliver drug directly at the site of pharmacological action. Mirena was the first FDA-approved levonorgestrel (LNG) releasing IUS without an approved generic form. Its 5-year application duration presents challenges for bioequivalence (BE) assessment using the conventional in vivo studies with pharmacokinetic and/or comparative clinical endpoints. Conventionally, along with other conditions, BE could be established if the 90% confidence interval (CI) of the ratio of geometric means of residual LNG at the end of 5 years is within the BE limits of 80.00% and 125.00%. Modeling and simulation were conducted to identify a shortened BE study duration and its corresponding BE acceptance limit that can be used as a surrogate for the conventional limit for a 5-year study. Simulation results suggest that having the 90% CI of the residual LNG 12 months post insertion within 95.00-105.26% would ensure that residual LNG amount at 5 years to be within 80.00-125.00%. This modeling and simulation practice leads to the current BE recommendation: if a test IUS is made of the same material in the same concentration and has the same physical dimensions as the Mirena, its BE could be established by showing (1) comparative physicochemical and mechanical properties; (2) comparative in vitro drug release behavior for 5 years; and (3) performance in a comparative short-term in vivo study and BE based on 90% confidence interval of test and reference ratio of residual LNG to be within 95.00-105.26% at month 12.
Assuntos
Anticoncepcionais Femininos , Dispositivos Intrauterinos Medicados , Anticoncepcionais Femininos/farmacocinética , Feminino , Humanos , Levanogestrel/farmacocinética , Equivalência Terapêutica , Fatores de TempoRESUMO
OBJECTIVE: To assess the variability of repeated measurements of serum etonogestrel concentration among contraceptive implant users. STUDY DESIGN: We measured 3 consecutive serum etonogestrel concentrations, drawn weekly, in women using etonogestrel implants for 12 to 36 months. We used a repeated measures test to evaluate differences. RESULTS: Among 20 participants, repeat serum etonogestrel concentrations did not differ from initial measurements (Friedman's test, p = 0.95). Mean serum etonogestrel concentrations had similar 95% confidence intervals at each time point: (134.09, 201.46), (135.08, 237.46), and (132.66, 192.45). CONCLUSION: We confirm that single-time measurements of serum etonogestrel concentration are acceptable pharmacokinetic outcomes for etonogestrel implant studies. IMPLICATIONS: Pharmacokinetic studies of the etonogestrel contraceptive implant assume single-time measurements are stable steady-state estimates based on small studies using older analysis methods. Our repeated measures study using modern liquid-chromatography mass-spectrometry analysis methods provides updated support for single-time pharmacokinetic measurements among etonogestrel implant users.
Assuntos
Anticoncepcionais Femininos , Anticoncepcionais Femininos/farmacocinética , Desogestrel , Implantes de Medicamento/farmacocinética , Feminino , HumanosRESUMO
PROBLEM: Injectable hormonal contraceptives (IHC) have been associated with altered mucosal and systemic milieu which might increase HIV risk, but most studies have focused on DMPA and not NET-EN, despite the growing popularity and lower HIV risk associated with the latter in observational studies. METHOD OF STUDY: We used high-performance liquid chromatography in combination with tandem triple quadrupole mass spectrometry (HPLC-LC-MS/MS) to measure steroid hormones in plasma samples of CAPRISA004 study participants. Concentrations of 48 cytokines were measured in the cervicovaginal lavage (CVL) and plasma, and their expression was compared between participants with detectable NET-EN (n = 201) versus non-detectable IHC (n = 90). Each log10 cytokine concentration was tested as an outcome in linear-mixed models, with NET-EN detection as the main explanatory variable. Multivariable models were adjusted for potential confounders. RESULTS: In bivariate analysis, detectable NET-EN was associated with reduced cervicovaginal M-CSF (P = 0.008), GM-CSF (P = 0.025) and G-CSF (P = 0.039), and elevated levels MIF (P = 0.008), IL-18 (P = 0.011), RANTES (P = 0.005) and IL-1Rα (P < 0.001). Lower G-CSF (P = 0.011) and elevated IL-1Rα (P = 0.008) remained significant in adjusted models. Multivariable analyses of plasma samples obtained from NET-EN-detectable women showed a significant increase in IP-10 (P = 0.026) and reductions in TNF-ß (P = 0.037), RANTES (P = 0.009), and M-CSF (P < 0.001). While similar growth factor reduction in CVL was noted for both DMPA and NET-EN, similar trends were not observed for endogenous progesterone. CONCLUSIONS: Detectable NET-EN was associated with reduced growth factors in the plasma and genital tract; particularly G-CSF and M-CSF. Our results suggest that while NET-EN is not inflammatory, it may have important immunological effects.
Assuntos
Anticoncepcionais Femininos , Citocinas/imunologia , Noretindrona , Vagina/imunologia , Adolescente , Adulto , Cromatografia Líquida , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Feminino , Humanos , Noretindrona/administração & dosagem , Noretindrona/farmacocinética , África do Sul , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate after a single subcutaneous injection in the abdomen of 150 or 300 mg Depo-Provera and compare results to two injections of Depo-SubQ Provera 104 given 3 months apart. DESIGN: Partially randomized, multicenter, parallel-group study. SETTING: Research unit. PATIENT(S): Forty-two women of reproductive age with confirmed ovulatory cycle and body mass index of 18-35 kg/m2. INTERVENTION(S): Women received a single subcutaneous injection of 150 mg (n = 24) or 300 mg (n = 9) of Depo-Provera or two injections of Depo-SubQ Provera 104 (n = 9). MAIN OUTCOME MEASURE(S): Suppression of ovulation as measured by progesterone, serum medroxyprogesterone acetate concentrations, and estimated pharmacokinetics parameters. RESULT(S): No ovulations were observed during 7 months after a single injection of 150 or 300 mg Depo-Provera. The 150 mg group had a similar Cmax as observed over two injection cycles of Depo-SubQ Provera 104 and a similar 6-month trough concentration as the 3-month trough of Depo-SubQ Provera 104. CONCLUSION(S): Our pharmacodynamics and pharmacokinetics data provide proof of concept that Depo-Provera (150 mg) may be an effective contraceptive method when injected subcutaneously every 6 months, with up to a 4-week grace period for reinjections. CLINICAL TRIAL REGISTRATION NUMBER: NCT02456584.
Assuntos
Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Acetato de Medroxiprogesterona/administração & dosagem , Acetato de Medroxiprogesterona/farmacocinética , Ovulação/efeitos dos fármacos , Ovulação/metabolismo , Adulto , Feminino , Humanos , Injeções SubcutâneasRESUMO
OBJECTIVE: To compare plasma etonogestrel concentrations sampled from the contralateral- versus ipsilateral-to-implant arm. STUDY DESIGN: Sub-analysis of a cross-sectional study in Botswana in 33 participants who provided contralateral and ipsilateral blood samples. RESULTS: Plasma etonogestrel concentrations in contralateral and ipsilateral specimens were highly correlated (correlation coefficient = 0.99; p < 0.0001). Bland-Altman analysis of agreement showed that etonogestrel levels were on average 5.9 pg/mL higher (2.1%) in ipsilateral compared to contralateral specimens (95% confidence interval: -4.1, 15.9 pg/mL). CONCLUSIONS: We found no meaningful differences in plasma etonogestrel concentrations between samples taken from the contralateral- versus ipsilateral-to-implant arm. IMPLICATIONS: Our data suggest that etonogestrel plasma concentrations are unlikely to be meaningfully different between samples drawn from the ipsilateral- versus the contralateral-to-implant arms in etonogestrel contraceptive implant users.
Assuntos
Anticoncepcionais Femininos/sangue , Desogestrel/sangue , Implantes de Medicamento/administração & dosagem , Braço , Botsuana , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Estudos Transversais , Desogestrel/administração & dosagem , Desogestrel/farmacocinética , Implantes de Medicamento/farmacocinética , Feminino , HumanosRESUMO
OBJECTIVE: In AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions. METHODS: In A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 µg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed. RESULTS: The 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (P = 3.2 × 10), decreased plasma concentrations of etonogestrel (P = 1.7 × 10), and decreased ethinyl estradiol (P = 6.7 × 10). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers. CONCLUSION: CYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Sulfato de Atazanavir/uso terapêutico , Benzoxazinas/uso terapêutico , Anticoncepcionais Femininos/sangue , Contraceptivos Hormonais/sangue , Ritonavir/uso terapêutico , Adulto , Alcinos , Sulfato de Atazanavir/farmacocinética , Benzoxazinas/farmacocinética , Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Contraceptivos Hormonais/administração & dosagem , Contraceptivos Hormonais/farmacocinética , Dispositivos Anticoncepcionais Femininos , Ciclopropanos , Citocromo P-450 CYP2B6/genética , Desogestrel/sangue , Desogestrel/farmacocinética , Interações Medicamentosas , Etinilestradiol/sangue , Etinilestradiol/farmacocinética , Feminino , Estudos de Associação Genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Humanos , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Ritonavir/farmacocinética , VaginaRESUMO
Long-acting injectable contraceptives have been associated with mucosal immune changes and increased HIV acquisition, but studies have often been hampered by the inaccuracy of self-reported data, unknown timing of injection, and interactions with mucosal transmission co-factors. We used mass spectrometry to quantify the plasma concentrations of injectable contraceptives in women from the CAPRISA004 study (n = 664), with parallel quantification of 48 cytokines and >500 host proteins in cervicovaginal lavage. Higher DMPA levels were associated with reduced CVL concentrations of GCSF, MCSF, IL-16, CTACK, LIF, IL-1α, and SCGF-ß in adjusted linear mixed models. Dose-dependent relationships between DMPA concentration and genital cytokines were frequently observed. Unsupervised clustering of host proteins by DMPA concentration suggest that women with low DMPA had increases in proteins associated with mucosal fluid function, growth factors, and keratinization. Although DMPA was not broadly pro-inflammatory, DMPA was associated with increased IP-10 in HSV-2 seropositive and older women. DMPA-cytokine associations frequently differed by vaginal microbiome; in non-Lactobacillus-dominant women, DMPA was associated with elevated IL-8, MCP-1, and IP-10 concentrations. These data confirm a direct, concentration-dependant effect of DMPA on functionally important immune factors within the vaginal compartment. The biological effects of DMPA may vary depending on age, HSV-2 status, and vaginal microbiome composition.
Assuntos
Colo do Útero/efeitos dos fármacos , Colo do Útero/metabolismo , Anticoncepcionais Femininos/farmacocinética , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Vagina/efeitos dos fármacos , Vagina/metabolismo , Adulto , Biomarcadores , Colo do Útero/microbiologia , Cromatografia Líquida , Anticoncepcionais Femininos/administração & dosagem , Citocinas/biossíntese , Monitoramento de Medicamentos , Feminino , Humanos , Microbiota , Mucosa/imunologia , Mucosa/metabolismo , Mucosa/microbiologia , África do Sul , Espectrometria de Massas em Tandem , Vagina/microbiologia , Adulto JovemRESUMO
OBJECTIVE: To compare medroxyprogesterone acetate (MPA) concentrations between HIV-positive women on antiretroviral therapy (ART) and HIV-negative women initiating depot medroxyprogesterone (DMPA) injectable. STUDY DESIGN: Secondary analysis of 28 HIV-positive women on non-nucleoside reverse transcriptase inhibitor-containing ART regimens and 10 HIV-negative women randomized to initiate DMPA in a clinical trial of progestin contraception in Malawi. RESULTS: MPA concentrations were significantly lower among HIV-positive women on ART, compared with HIV-negative women, at week 4 and week 13 (p=.03 for both), but not at day 3 or week 26 post-DMPA initiation. CONCLUSIONS: Antiretroviral medications may affect MPA metabolism in HIV-positive African women.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Anticoncepcionais Femininos/farmacocinética , Infecções por HIV/tratamento farmacológico , Acetato de Medroxiprogesterona/farmacocinética , Progestinas/uso terapêutico , Adulto , Anticoncepção/métodos , Anticoncepcionais Femininos/uso terapêutico , Preparações de Ação Retardada , Feminino , Humanos , Malaui , Acetato de Medroxiprogesterona/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: To evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz (EFV)-containing or nevirapine (NVP)-containing antiretroviral therapy (ART). DESIGN: We analyzed stored samples from women self-reporting implant use in the Partners PrEP Study. METHODS: Plasma samples collected every 6 months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared with pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on EFV and NVP to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on EFV, NVP, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations. RESULTS: Our analysis included 11 women who initiated EFV, 13 who initiated NVP, and 36 who remained ART-naive. In the EFV group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 [90% confidence intervals (0.31, 0.49); Pâ<â0.001] and the etonogestrel aGMR was 0.51 (0.34, 0.76; Pâ=â0.006) compared with the control group. No difference was observed in the NVP group compared with controls [levonorgestrel 0.93 (0.74, 1.18); Pâ=â0.64; etonogestrel 1.07 (0.77, 1.50); Pâ=â0.73]. Possession of four allele variants were found to result in further reductions in progestin concentrations among those receiving EFV. CONCLUSION: Concomitant use of EFV significantly reduces levonorgestrel or etonogestrel concentrations by 61 and 49%, respectively, compared with no ART use. We also report allelic variants in hepatic enzymes that influenced the extent of the observed drug-interaction between progestins and EFV.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Desogestrel/farmacocinética , Antagonismo de Drogas , Levanogestrel/farmacocinética , Adulto , Alcinos , Anticoncepcionais Femininos/administração & dosagem , Ciclopropanos , Desogestrel/administração & dosagem , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Quênia , Levanogestrel/administração & dosagem , Modelos Lineares , Nevirapina/administração & dosagem , Testes Farmacogenômicos , UgandaRESUMO
OBJECTIVE: To determine whether serum etonogestrel concentrations in contraceptive implant users are associated with certain individual patient characteristics. STUDY DESIGN: We enrolled reproductive-age women using etonogestrel contraceptive implants between 12-36 months duration and measured a single serum etonogestrel concentration. Participants also completed a questionnaire about demographics. RESULTS: We enrolled 350 participants; median age was 22.5 years (range 18.0-39.1), median months of implant use was 26.0 (range 12.0-36.0), and median body mass index was 25.7 kg/m2 (range 18.5-52.0). Our study population was primarily white/Caucasian (46.6% [163/350]) and Hispanic/Latina ethnicity (51.4% [180/350]). The median serum etonogestrel concentration was 137.4 pg/ml and etonogestrel concentrations varied 12.4 fold in the population (range 55.8-695.1 pg/ml). Using forward stepwise linear regression, months of implant use (ß=-1.74, p<.001) and body mass index (ß=-3.10, p<.001) were both significantly associated with decreased serum etonogestrel concentration with Black/African American race as a positive effect modifier (ß=18.24, p=.099); R-squared for the model=0.13. CONCLUSIONS: Individuals demonstrated a wide variability in serum etonogestrel concentrations, which can potentially affect side-effect profiles and efficacy. Increasing body mass index and longer duration of implant use were associated with small decreases in serum etonogestrel concentrations, while self-reported Black/African American race was associated with a non-significant increase. Despite these findings, most of etonogestrel variability was unaccounted for, suggesting that other clinical, pharmacologic, and genetic factors contributing to variability in etonogestrel concentrations remain to be determined. IMPLICATIONS: Although increases in body mass index are associated with lower etonogestrel levels in contraceptive implant users, the majority of women will maintain serum concentrations that consistently suppress ovulation. Furthermore, certain patient characteristics can only explain a small portion (13%) of the variability in serum etonogestrel levels among contraceptive implant users.
Assuntos
Índice de Massa Corporal , Anticoncepcionais Femininos/sangue , Anticoncepcionais Femininos/farmacocinética , Desogestrel/sangue , Desogestrel/farmacocinética , Adolescente , Adulto , Implantes de Medicamento/farmacocinética , Etnicidade , Feminino , Humanos , Modelos Lineares , Fatores de Tempo , População Branca , Adulto JovemRESUMO
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
OBJECTIVE: Endogenous and exogenous contraceptive hormones may affect mucosal pharmacokinetics (PKs) of topical antiretrovirals such as tenofovir. We present PK data from healthy women using tenofovir vaginal gel, at baseline (follicular and luteal phases) and after oral contraceptive pill (OCP) or depot medroxyprogesterone acetate (DMPA) use. METHODS: CONRAD A10-114 was a prospective, interventional, open-label, parallel study. We enrolled 74 women and 60 completed the study (32 and 28 who selected OCPs or DMPA, respectively). Participants used 2 doses of tenofovir gel separated by 2 hours, without intercourse, and were examined 3 or 11 hours after the last dose. We assessed pharmacokinetics in plasma, cervicovaginal (CV) aspirate, and vaginal tissue. RESULTS: In general, there were no significant differences in mucosal tenofovir and tenofovir diphosphate concentrations (P > 0.23) in the follicular and luteal phases, except for lower mean tenofovir tissue concentrations (P < 0.01) in the follicular phase. Tenofovir concentrations significantly decreased in CV aspirate (P < 0.01) after contraceptive use, but overall remained very high (>10 ng/mL). Mean tissue tenofovir diphosphate increased to 6229 fmol/mg after DMPA use compared with 3693 and 1460 fmol/mg in the follicular and luteal phases, respectively (P < 0.01). The molecular conversion of tenofovir into tenofovir diphosphate was more effective in DMPA users (molecular ratio of 2.02 versus 0.65 luteal phase, P < 0.01). CONCLUSIONS: Both menstrual cycle phase and exogenous hormones affect topical tenofovir mucosal and systemic PKs. However, high levels of tenofovir and tenofovir diphosphate were observed in the CV mucosa in the presence or absence of OCPs and DMPA, with tissue levels exceeding benchmarks of predicted mucosal anti-HIV efficacy (tenofovir >1.00 ng/mL in CV aspirate and tenofovir diphosphate >1000 fmol/mg).
Assuntos
Fármacos Anti-HIV/farmacocinética , Anticoncepcionais Femininos/farmacocinética , Infecções por HIV/prevenção & controle , Acetato de Medroxiprogesterona/farmacocinética , Tenofovir/farmacocinética , Cremes, Espumas e Géis Vaginais/farmacocinética , Administração Intravaginal , Adulto , Fármacos Anti-HIV/administração & dosagem , Anticoncepcionais Femininos/administração & dosagem , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Acetato de Medroxiprogesterona/administração & dosagem , Ciclo Menstrual/efeitos dos fármacos , Pessoa de Meia-Idade , Estudos Prospectivos , Tenofovir/administração & dosagem , Resultado do Tratamento , Cremes, Espumas e Géis Vaginais/administração & dosagem , 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
Potential drug interactions with hormonal contraceptives are an important public health concern. A public meeting on "Drug Interactions With Hormonal Contraceptives: Public Health and Drug Development Implication" was hosted by the United States Food and Drug Administration (FDA). The meeting endeavored to provide an opportunity for the FDA to seek input from experts on the public health concerns associated with the use of hormonal contraceptives and interacting drugs that might affect efficacy and safety, including pharmacokinetic/pharmacodynamic considerations, in the design of drug interaction studies of hormonal contraceptives for drug development and approaches to translating the results of drug interaction information into informative labeling and communication. The input received could be used to refine FDA's thinking on hormonal contraceptives drug interaction study design and interpretation and labeling communication of drug interaction risk. This meeting benefited from strong and diverse participation from the Center for Drug Evaluation and Research at the FDA, Centers for Disease Control and Prevention, National Institutes of Health, Swedish Medical Products Agency, pharmaceutical industry, and representatives of academia. This report provides a summary of the key discussion based on the presentations and panel discussion.
Assuntos
Anticoncepcionais Femininos/administração & dosagem , Anticoncepcionais Femininos/farmacocinética , Desenvolvimento de Medicamentos , Saúde Pública , United States Food and Drug Administration , Interações Medicamentosas , Humanos , Estados UnidosRESUMO
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.
Assuntos
Antirretrovirais/farmacocinética , Anticoncepcionais Orais Hormonais/farmacocinética , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Anticoncepcionais Femininos/farmacocinética , Anticoncepcionais Femininos/farmacologia , Anticoncepcionais Orais Hormonais/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Dispositivos Intrauterinos Medicados , GravidezRESUMO
OBJECTIVE: To report differences in ovarian stimulation outcomes in women using a levonorgestrel-releasing intrauterine device (LNG-IUD). DESIGN: Retrospective cohort study. SETTING: University-based infertility practice. PATIENT(S): Female patients pursuing either social oocyte cryopreservation or oocyte donation. INTERVENTION(S): Chart review of all female patients presenting from January 1, 2012, to June 30, 2017, for social oocyte cryopreservation or oocyte donation. Demographic data, cycle performance data, and the presence or absence of an LNG-IUD at the time of ovarian stimulation were compared. MAIN OUTCOME MEASURE(S): Total oocyte yield and total mature oocyte yield. Secondary measures included clinical pregnancy rate and live birth rate in recipients of donor oocytes. RESULT(S): Univariate analysis of predicted oocyte yield and mature oocyte yield showed no significant difference between subjects with and without an LNG. When controlling for history of recent hormonal contraceptive use, initial antral follicle count (AFC), age, body mass index (BMI), gonadotropin dose, and stimulation day/protocol, no significant differences were seen in total oocyte yield or mature oocyte yield in the presence or absence of an LNG-IUD. Univariate analysis of the effect of LNG-IUDs on the predicted clinical pregnancy rate and live birth rate did not significantly differ for oocyte recipients. Controlling for history of recent hormonal contraceptive use, initial AFC, age, BMI, gonadotropin dose, and stimulation day/protocol also showed no significant differences in the predicted clinical pregnancy rate and live birth rate. CONCLUSION(S): LNG-IUDs do not affect cycle performance in women undergoing ovarian stimulation cycles.