Levonorgestrel

Fotherby, K.

doi:10.2165/00003088-199528030-00003

Cited by 72 publications

(23 citation statements)

References 58 publications

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“…With EE inhibiting the cytochrome p450 enzyme system in the liver and increasing binding proteins (SHBG) during chronic EE exposure, we expected and found a decrease in the total clearance of LNG and an increase in LNG volume of distribution in both BMI groups from the beginning versus the end of the hormone-free interval [15,16,17,19]. However, the obese group had a significantly lower clearance than the normal BMI group at the beginning of the hormone-free interval even with similar levels of binding proteins (SHBG).…”

Section: Discussionmentioning

confidence: 99%

Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic–pituitary–ovarian activity

et al. 2009

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Objective-This study was conducted to determine whether increased body mass index (BMI) affects oral contraceptive (OC) pharmacokinetics and suppression of hypothalamic-pituitary-ovarian (HPO) axis activity.Study design-Ovulatory reproductive-age women of normal (< 25 kg/m 2 ; n = 10) and obese (> 30 kg/m 2 ; n = 10) BMI received OCs for two cycles (prospective cohort). Subjects were admitted for two 48-h inpatient stays at the beginning and end of the hormone-free interval. Ethinyl estradiol (EE) and levonorgestrel (LNG) levels were evaluated during both inpatient stays. Gonadotropin pulsatility (FSH and LH) was measured during the second inpatient stay. Estradiol (E 2 ) and progesterone (P) were measured daily during inpatient stays and twice per week in Cycle 2.Results-BMI was greater in the obese, compared to the normal BMI group [37.3 kg/m 2 (SD 6.0) versus 21.9 kg/m 2 (SD 1.6); p < 0.05]. The LNG half-life was significantly longer in the obese group (52.1 ± 29.4 h versus 25.6 ± 9.3 h, p < 0.05) which correlated with a lower maximum LNG concentration on Cycle 2, Day 1 [1.9 ng/mL (SD 0.5) versus 2.5 ng/mL (SD 0.7)] and a longer time to reach steady-state (10 versus 5 days), in obese women. There were no significant differences in volume of distribution between groups. LH pulse parameters did not differ statistically between groups but trended towards greater HPO activity in the obese group. Additionally, more obese (6/10 versus 3/10 normal BMI, p > 0.05) women exhibited E 2 levels consistent with development of a dominant follicle, and P levels consistent with ovulation (2/10 versus 1/10) during Cycle 2.Conclusions-Compared to women of normal BMI, obese women exhibit differences in OC pharmacokinetics that are associated with greater HPO activity.

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Section: Discussionmentioning

confidence: 99%

Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic–pituitary–ovarian activity

et al. 2009

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“…Changes in sex hormone binding globulin (SHBG) and enzyme inhibition caused by EE indeed produce differences in serum concentrations of total LNG between single- and multiple-dose studies [2,7–9]. Additional factors creating complexities may include the radioimmunoassay (RIA) being used, products, dosages, duration of blood sampling and types of subjects.…”

Section: Introductionmentioning

confidence: 99%

Perspectives on variability in pharmacokinetics of an oral contraceptive product

Jusko

2017

Contraception

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The early literature and reviews have described the pharmacokinetics (PK) of oral contraceptive (OC) compounds such as ethinyl estradiol (EE) and levonorgestrel (LNG) in women as subject to large intersubject variability. This was partly due to the use of diverse radioimmunoassays, limited sampling periods and an incomplete understanding of single- vs. multiple-dose kinetics and the role of EE in causing both inhibition of hepatic metabolism along with induction of sex hormone binding globulin. Over the past two decades, LNG and EE have been used as target drugs for the assessment of possible drug interactions upon introduction of many new therapeutic agents. This has resulted in at least 17 publications that describe the PK of LNG and EE in women using various 150 mcg/30 mcg products under fairly standard multiple-dose conditions. A review of these studies indicates only moderate variability in the Cmax and area under the curve both within and across these studies. There is impressive similarity in these drug exposure indices found in studies carried out with several products by investigators at numerous sites and countries.

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“…However, the commonly referred to therapeutic concentration for LNG (0.4 ng/ml), is non-empirically derived from normal BMI women treated with an LNG-only formulation (Norplant® implant) [12]. Unlike Norplant, OCs include EE, a potent inducer of sex hormone-binding globulin (SHBG) which strongly binds LNG [13–15]. While LNG-only methods decrease plasma SHBG levels by ~50% from baseline, OCs increase SHBG by ~50% [13–15].…”

Section: Discussionmentioning

confidence: 99%

“…Unlike Norplant, OCs include EE, a potent inducer of sex hormone-binding globulin (SHBG) which strongly binds LNG [13–15]. While LNG-only methods decrease plasma SHBG levels by ~50% from baseline, OCs increase SHBG by ~50% [13–15]. The role of obesity is complicated, as obesity is associated with a decrease in SHBG levels but also with alterations in drug transport [16].…”

Section: Discussionmentioning

confidence: 99%

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

Edelman¹,

Cherala²,

Munar³

et al. 2014

Contraception

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Objective To determine if increasing the hormone dose or eliminating the hormone-free interval improves key pharmacokinetic (PK) alterations caused by obesity during oral contraceptive (OC) use. Study design Obese (BMI ≥ 30 kg/m2), ovulatory, otherwise healthy, women received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) dosed cyclically (21 days active pills with 7-day placebo week) for two cycles and then were randomized for two additional cycles to: Continuous Cycling [CC, a dose neutral arm using the same OC with no hormone-free interval] or Increased Dose [ID, a dose escalation arm using an OC containing 30 mcg EE/150 mcg LNG cyclically]. During Cycle 2, 3, and 4, outpatient visits were performed to assess maximum serum concentration (Cmax), area under the curve (AUC0-∞), and time to steady state as well as pharmacodynamics. These key PK parameters were calculated and compared within groups between baseline and treatment cycles. Results A total of 31 women enrolled and completed the study (CC group n = 16; ID group n = 15). Demographics were similar between groups [mean BMI: CC 38kg/m2 (SD 5.1), ID 41kg/m2 (SD 7.6)]. At baseline, the key LNG PK parameters were no different between groups; average time to reach steady-state was 12 days in both groups; Cmax were CC: 3.82 ± 1.28 ng/mL and ID: 3.13 ± 0.87 ng/mL; and AUC0-∞ were CC: 267 ± 115 hr*ng/mL and ID: 199±75 hr*ng/mL. Following randomization, the CC group maintained steady-state serum levels whereas the ID group had a significantly higher Cmax (p< 0.001) but again required 12 days to achieve steady-state. However, AUC was not significantly different between CC (412 ± 255 hr*ng/mL) and ID (283 ± 130 hr*ng/mL). Forty-five percent (14/31) of the study population had evidence of an active follicle-like structure prior to randomization and afterwards this decreased to 9% (3/31). Conclusion Both increasing the OC dose and continuous dosing appear to counteract the impact of obesity on key OC PK parameters.

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Levonorgestrel

Cited by 72 publications

References 58 publications

Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic–pituitary–ovarian activity

Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic–pituitary–ovarian activity

Perspectives on variability in pharmacokinetics of an oral contraceptive product

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

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