Elsevier

Contraception

Volume 66, Issue 1, July 2002, Pages 73-76
Contraception

Original research article
Pharmacokinetics of levonorgestrel 0.75 mg tablets

https://doi.org/10.1016/S0010-7824(02)00321-9Get rights and content

Abstract

This study examined plasma levonorgestrel (LNG) concentrations and pharmacokinetics following oral administration of a single LNG 0.75 mg tablet. Sixteen healthy female volunteers 19–44 years old enrolled in the study. Serial blood samples were drawn over 72 h after dosing in a fasting state. A gas chromatographic, negative ionization mass spectrometric detection analytical method was used to determine plasma LNG concentrations. The observed mean peak plasma LNG concentration was 14.1 ± 7.9 ng/mL (range 6.7–39.0 ng/mL). The mean time of peak concentration was 1.63 ± 0.74 h (range 1–4 h). The plasma LNG concentration versus time profiles were subjected to noncompartmental pharmacokinetic analysis for the purposes of determining half-lives, apparent oral clearances (Cl/F), apparent volumes of distribution after oral administration (V/F), and mean residence time (MRT). Half-lives calculated from the terminal decline in plasma LNG concentrations ranged from 16.2 h to 32.3 h (mean = 24.4 ± 5.3 h). The Cl/F was 7.06 ± 2.69 L/h, V/F was 260 ± 129 L, and MRT was 27.8 ± 5.2 h. LNG was well tolerated; there were no serious adverse events during the study.

Introduction

Levonorgestrel (LNG) is a synthetic progestin used as a progestin-only emergency contraceptive and, when administered at lower doses either alone or in combination with an estrogen, as an oral contraceptive. LNG possesses strong progestational and anti-ovulatory activities with no estrogenic effects. Norgestrel was first synthesized in the 1950s as a racemic mixture (d- and l-enantiomers). LNG is the biologically active levorotatory enantiomer, formerly known as d-norgestrel. While the racemate was first clinically evaluated and still continues to be marketed in some countries, LNG is customarily used in contraception products. LNG has also been the progestogen of choice for inclusion in drug delivery systems such as implants, intrauterine devices, and intravaginal rings.

Considerable pharmacokinetic and therapeutic information is available for LNG. Because LNG does not undergo significant first-pass metabolism in the intestine or liver [1], [2], [3], it may be expected to display less intersubject variation and less propensity for drug interactions. However, large intersubject and intrasubject variations in the relation of plasma LNG concentration to dose are noted [4], [5]. Individual terminal half-lives of LNG have been reported to range from 4 to 54 h [6] The oral bioavailability of LNG is greater than 90%, but has been reported to be dependent on the dosage form and affected by concomitant administration of estrogen [4], [6], [7], [8].

The purpose of this investigation was to determine LNG pharmacokinetics following the oral administration of the most widely used commercially available tablet containing 0.75 mg of LNG. Two 0.75 mg tablets, taken 12 h apart, is the present internationally accepted dosage for safe and effective use of LNG as an emergency contraceptive

Section snippets

Subjects

Sixteen female subjects with an age range of 19–44 years (28 ± 9 years) and weight range of 50.8–79.2 kg (65.3 ± 9.9 kg) enrolled in the study. All subjects were considered healthy with no remarkable medical histories. Of the 16 subjects, 9 were White, 6 were African American, and 1 was an Asian/Pacific Islander. The enrollment criteria excluded subjects who were pregnant, postmenopausal, presently using steroidal contraception, or who had taken a prescription drug within two weeks of entering

Results

All 16 subjects completed the study as designed. A semi-log plot of mean ± SD LNG plasma concentrations as a function of time is shown in Fig. 1. Plasma concentrations appeared to decline in a multi-exponential fashion after the time of peak concentration. From mean and individual data, the fall in LNG plasma concentrations 12–14 h after dosing could be described by mono-exponential decline.

Individual LNG pharmacokinetic parameter values obtained by noncompartmental methods are presented in

Discussion

In this study, the mean half-life was 24.4 h, with values ranging from 16.2 h to 32.3 h. The prolonged half-life of LNG and the resultant maintenance of high plasma concentrations of LNG through 20 h post-dosing observed in the present study questions the necessity for strict adherence to the recommended 12-h dosing interval when the tablets are used for emergency contraception.

Whereas an inadequate duration of sampling times beyond 24 h may have led to inaccurate estimates of half-lives and

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This study was supported by a grant from the CONRAD Program, Arlington, VA.

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