Pharmacokinetics of single and multiple doses of ethinyl estradiol and levonorgestrel in relation to smoking

Kanarkowski, R; Tornatore, Kathleen M.; D'Ambrosio, R; Gardner, Mark; Jusko, William J.

doi:10.1038/clpt.1988.7

Cited by 33 publications

(12 citation statements)

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“…These correlations are comparable to correlations for the immunosuppressive drug tacrolimus in stable solid organ transplantation patients for whom these correlations are used clinically to assess systemic exposure in order to prevent rejection and side effects [18, 19]. These correlations are comparable to the relationship shown between LNG trough values and AUC in a prior study on the effect of smoking on LNG absorption [20]. Additionally, using steady-state data from a previous PK study of the same OC formulation in normal-weight and obese women [21], we found that the C 24 trough values were highly correlated with the AUC values for both normal weight (r = 0.96; 95% CI [0.87, 0.99]; n = 13) and obese women (r = 0.98; 95% CI [0.94, 0.99]; n = 15), and the relationship was the same in both groups.…”

Section: Discussionsupporting

confidence: 68%

Estimating systemic exposure to levonorgestrel from an oral contraceptive

et al. 2017

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Objective The gold standard for measuring oral contraceptive (OC) pharmacokinetics is the 24-hour steady-state area-under-the-curve (AUC). We conducted this study to assess whether limited sampling at steady state or measurements following use of one or two OCs could provide an adequate proxy in epidemiological studies for the progestin 24-hour steady-state AUC of a particular OC. Study Design We conducted a 13-sample, 24-hour pharmacokinetic study on both day 1 and day 21 of the first cycle of a monophasic OC containing 30 μg ethinyl estradiol and 150 μg levonorgestrel (LNG) in 17 normal-weight healthy white women, and a single-dose 9-sample study of the same OC after a one-month washout. We compared the 13-sample steady-state results with several steady-state and single-dose results calculated using parsimonious sampling schemes. Results The 13-sample steady-state 24-hour LNG AUC was highly correlated with the steady-state 24-hour trough value (r = 0.95; 95% CI [0.85, 0.98]) and with the steady-state 6, 8, 12 and 16-hour values (0.92 ≤ r ≤ 0.95). The trough values after one or two doses were moderately correlated with the steady-state 24-hour AUC value (r = 0.70; 95% CI [0.27, 0.90] and 0.77; 95% CI [0.40, 0.92], respectively). Conclusions Single time-point concentrations at steady-state and after administration of one or two OCs gave highly to moderately correlated estimates of steady-state LNG AUC. Using such measures could facilitate prospective pharmaco-epidemiologic studies of the OC and its side effects.

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Section: Discussionsupporting

confidence: 68%

Estimating systemic exposure to levonorgestrel from an oral contraceptive

et al. 2017

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“…1, the 24-h steady-state time frame may not permit sufficient accuracy for assessing t 1/2 values that exceed 12 h. One study [28] extended blood sampling out to 48 h after one cycle of daily dosing of 20 mcg EE and 100 mcg LNG and found the t 1/2 of EE of about 16 h and that of LNG averaging 25.6±9.3 h, similar to the values in the tables. Our multiple-dose studies with 50 mcg EE and 250 mcg LNG tablets produced similar t 1/2 values as well [8]. However, the terminal half-life reflects only part of the time course of drug exposure or AUC.…”

Section: Literature Assessmentmentioning

confidence: 56%

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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“…Its pharmacokinetics has been described in detail in terms of absolute bio availability [7,8], bioequivalence [9], influence by eth nic groups [10] and smoking habits [11], From time to time reviews were published [12,13] and drug-to-drug interactions were described [14].…”

Section: Discussionmentioning

confidence: 99%

Comparison of Serum Ethinyl Estradiol, Sex-Hormone-Binding Globulin, Corticoid-Binding Globulin and Cortisol Levels in Women Using Two Low-Dose Combined Oral Contraceptives

Hümpel¹,

Täuber²,

Kuhnz³

et al. 1990

Horm Res

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The study included 69 women taking a desogestrel (n = 30)- or gestodene (n = 39)-containing low-dose combined oral contraceptive for at least 3 months. Group size was calculated to detect a difference in mean values of 80% of 1 standard deviation (α = 0.05, β = 0.1). Seven serum samples were obtained up to 4 h, and 1 sample 24 h, after drug intake on 1 day between the 10th and the 21st day of the cycle. The concentrations of sex-hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and cortisol were measured in a 0- to 4-hour serum pool by radioimmunoassay. Ethinyl estradiol (EE₂) levels were analyzed in single and pooled samples using anti-EE₂-6β-carboxymethyloxime-bovine serum albumin antiserum. The area under the curves (AUC) up to 4 and 24 h and C_maxand t_max were evaluated. Statistical analysis (analysis of covariance) did not reveal a dependence of values on duration of treatment or day of cycle. Both treatments resulted in almost identical values for all parameters evaluated. The mean levels of SHBG, CBG and cortisol were in the range of 186-226nmol/l, 89-93 mg/l and 280- 281 µg/l, respectively. Mean maximum EE₂ levels of 106-129 pg/ml were found 1.6-1.8 h after pill intake and AUC0-4 h accounted for 329-374 pg·h·ml^-1. The recently reported differences in serum EE₂ and CBG levels between two groups of 11 women each treated with desogestrel- and gestodene-containing pills, respectively, could not be confirmed.

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Pharmacokinetics of single and multiple doses of ethinyl estradiol and levonorgestrel in relation to smoking

Cited by 33 publications

References 0 publications

Estimating systemic exposure to levonorgestrel from an oral contraceptive

Estimating systemic exposure to levonorgestrel from an oral contraceptive

Perspectives on variability in pharmacokinetics of an oral contraceptive product

Comparison of Serum Ethinyl Estradiol, Sex-Hormone-Binding Globulin, Corticoid-Binding Globulin and Cortisol Levels in Women Using Two Low-Dose Combined Oral Contraceptives

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