Tazarotene Does Not Affect the Pharmacokinetics and Efficacy of a Norethindrone/Ethinylestradiol Oral Contraceptive
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Clin Pharmacokinet 2004; 43 (10): 673-684 0312-5963/04/0010-0673/$31.00/0 © 2004 Adis Data Information BV. All rights reserved.
Tazarotene Does Not Affect the Pharmacokinetics and Efficacy of a Norethindrone/Ethinylestradiol Oral Contraceptive Zhiling Yu, Dale Yu, Patricia S. Walker and Diane D-S Tang-Liu Allergan Inc., Irvine, California, USA
Abstract
Objective: To determine the pharmacokinetic and pharmacodynamic interaction between oral tazarotene and an oral contraceptive containing norethindrone 1mg and ethinylestradiol 0.035mg (Ortho-Novum® 1/35). Design: Two separate open-label, parallel-group, single-centre, pharmacokinetic and pharmacodynamic interaction studies. Participants and methods: Twenty-seven healthy women (age 20–55 years) completed Study I, with a duration of 64 days during three consecutive menstrual cycles. Ortho-Novum® 1/35 was taken once daily from study day 0 (first cycle day 1) to day 61 (third cycle day 6), and oral tazarotene 1.1mg was coadministered daily from study day 34 (second cycle day 7) to day 61. Twenty-nine healthy women (age 20–44 years) completed Study II, with a duration of 75 days during three consecutive menstrual cycles. Ortho-Novum® 1/35 was taken once daily from study day 0 (first cycle day 1) to day 74 (third cycle day 19), and oral tazarotene 6mg was coadministered daily from study day 48 (second cycle day 21) to day 74. In both studies, the pharmacokinetics of tazarotenic acid on study day 61 (third cycle day 6) were evaluated from plasma tazarotenic acid concentrations. Pharmacokinetic parameters of plasma norethindrone and ethinylestradiol were compared before and after tazarotene administration (cycle day 6 of the second and third cycles, respectively). Serum luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations were compared before and after tazarotene administration (cycle days 2, 4 and 6 of the second and third cycles, respectively). In Study II, serum progesterone concentrations were also determined on cycle days 18 and 20 of the second and third cycles. Tazarotenic acid was determined by liquid chromatography-tandem mass spectrometry. Ethinylestradiol and norethindrone were determined by gas chromatography-mass spectrometry. LH and FSH were assayed by microparticle enzyme immunoassay in Study I and by double-antibody radioimmunoassay in Study II. Progesterone was determined by solid-phase radioimmunoassay. Results: In Study I (tazarotene 1.1mg), the area under the plasma concentration-time curve from zero to 24 hours (AUC24) and the peak concentration in plasma (Cmax) for tazarotenic acid were 121 ± 27 μg • h/L and 28.9 ± 9.4 μg/L (mean ± SD), respectively. In Study II (tazarotene 6mg), AUC24 and Cmax for tazarotenic acid were 379 ± 78 μg • h/L and 111 ± 37 μg/L (mean ± SD), respectively. In both studies, for both norethindrone and ethinylestradiol, the 90%
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CIs of AUC24 and Cmax on cycle day 6 before and after tazarotene administration were within the 80–125% boundary. In Study I, the 90% CIs of serum FSH and LH c
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