A Drug-Drug Interaction Study to Investigate the Effect of Nintedanib on the Pharmacokinetics of Microgynon (Ethinylestradiol and Levonorgestrel) in Female Patients with Systemic Sclerosis-Associated Interstitial Lung Disease.

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 AUC0‒tz (101.4% [92.8, 110.7]) and AUC0‒∞ (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 AUC0‒∞ 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.

An exploratory study on the association of lifestyle factors with serum etonogestrel concentrations among contraceptive implant users.

PURPOSE: To explore how diet and exercise habits associate with serum etonogestrel concentrations among contraceptive implant users. MATERIALS AND METHODS: We conducted a secondary analysis of healthy, reproductive-age women using etonogestrel implants. This study was registered on ClinicalTrials.gov, NCT03092037. We assessed diet and exercise habits with two validated surveys: Healthy Eating Vital Signs and the Stanford Brief Activity Survey. Participants previously had their serum etonogestrel concentrations measured using a validated liquid-chromatography mass-spectrometry assay. We then used linear modelling to test for associations between survey responses and serum etonogestrel concentrations. RESULTS: Among 129 participants, diet and exercise habits had no significant associations with serum etonogestrel concentrations (p = 0.22-0.72), with inconsistent effects found for increased caloric intake and sedentary lifestyle. CONCLUSION: This exploratory study found no significant effect of diet or exercise habits on steady-state pharmacokinetics among contraceptive implant users. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT03092037.

Combined hormonal contraception and COVID-19.

Aim: This article reviews the possibility of using combined hormonal contraception during the COVID-19 pandemic. Methods: narrative reviewResults: The factors that protect women from the severity of the disease are analysed, as well as the risk factors for the use of this type of contraception, especially related to the increased risk of a thrombotic event in patients affected by the disease. Finally, the information available on the guidelines for action in patients with COVID-19 using combined hormonal contraception is collected.Conclusions: We can continue to prescribe and use hormonal methods with EE.

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.

Pharmacogenetic interactions between antiretroviral drugs and vaginally administered hormonal contraceptives.

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.

Relationship Between Etonogestrel Concentrations and Bleeding Patterns in Contraceptive Implant Users.

OBJECTIVE: To estimate whether serum etonogestrel concentrations influence bleeding patterns and related side effects in contraceptive implant users. METHODS: We conducted a prospective cross-sectional study with healthy, reproductive-aged women using etonogestrel implants for 12-36 months. Participants completed a brief questionnaire to assess their current bleeding pattern and any experience of abnormal bleeding with the implant. We then measured serum etonogestrel concentrations. We also reviewed the charts of participants to determine whether a prescription for oral contraceptive pills was ever given for treatment of implant-related bothersome bleeding. We performed multivariable logistic regression to test for associations between serum etonogestrel concentrations and both bleeding patterns and related side effects. RESULTS: We enrolled 350 women, and 59.4% reported having experienced abnormal bleeding with the contraceptive implant. Only 14.9% of participants reported amenorrhea and 37.7% reported monthly periods. Among participants with reviewable medical records (n=253), roughly 20% had received a prescription for oral contraceptive pills during implant use. Increasing serum etonogestrel concentrations were significantly associated with increasing odds of reporting abnormal bleeding (adjusted odds ratio [aOR] 1.005, P=.015) and increasing odds of having received an oral contraceptive pill prescription (aOR 1.008, P=.002). For every 100 pg/mL increase in serum etonogestrel concentration, contraceptive implant users in this study had 1.6 times the odds of reporting abnormal bleeding and 2.3 times the odds of having received a prescription as treatment for bothersome bleeding. CONCLUSION: We found both objective and subjective evidence that higher levels of progestin from the contraceptive implant were associated with bleeding side effects experienced by women in this study. Pharmacologic variation may influence the side effects women experience with a variety of hormonal contraceptive methods, in turn affecting patient satisfaction and discontinuation rates.

A pilot study of levonorgestrel concentrations and bleeding patterns in women with epilepsy using a levonorgestrel IUD and treated with antiepileptic drugs.

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.

HIV risk associated with serum medroxyprogesterone acetate levels among women in East and southern Africa.

BACKGROUND: Some observational studies have found increased HIV risk associated with self-reported use of injectable depot medroxyprogesterone acetate. Testing blood samples for medroxyprogesterone acetate (MPA), the progestin in depot medroxyprogesterone acetate, permits validation of self-reported data, and exploration of whether potential HIV risk is correlated with MPA levels, which are highest soon after injection. METHODS: We conducted a case-control study testing archived serum from women who participated in three longitudinal studies of HIV prevention in East and southern Africa. Case samples, from women who acquired HIV, were from visits that occurred at or immediately prior to the first evidence of HIV infection. Secondary analyses restricted to case samples collected within 15 and 30 days of the estimated date of HIV infection. Matched control samples were from women who remained HIV uninfected. We used multivariable conditional logistic regression to compare exogenous hormone levels, quantified through mass spectrometry, among cases and controls. RESULTS: When restricted to cases with samples collected within 15 days or less of estimated date of HIV infection, MPA detection was more frequent among women who acquired HIV (adjusted odds ratio = 2.75, 95% confidence interval 1.22-6.19). In this subset, the increase in HIV risk was only among samples with MPA detected at a low level of 0.02-0.50 ng/ml: 36.7% of cases and 9.4% of controls, adjusted odds ratio = 6.03, 95% confidence interval 2.50-14.54. CONCLUSION: Detection of MPA at low levels close to the estimated time of HIV acquisition was significantly more frequent among women who acquired HIV. Studies are needed that explore biological mechanisms elicited by any MPA level and HIV risk.