Pharmacokinetics of levonorgestrel and etonogestrel in rat or minipig following intravenous, subcutaneous, or intradermal administration
Creators: name: Ko, Paul J.
name: Milad, Mark A.
name: Radulovic, Louis L.
name: Gibson, Don M.
Publisher: name: Taylor & Francis
Year: 2022
Subjects: subject: Biochemistry
subject: Cell Biology
subject: 59999 Environmental Sciences not elsewhere classified
subject: FOS: Earth and related environmental sciences
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: Immunology
subject: FOS: Clinical medicine
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: Cancer
subject: 111714 Mental Health
subject: FOS: Health sciences

description: The objective of these studies was to determine the pharmacokinetics of levonorgestrel and etonogestrel in Sprague-Dawley rat or Göttingen minipig following various administration routes.Four sequential crossover studies were conducted: Study 1 administered levonorgestrel 30 µg intravenously and intradermally in four minipigs; Study 2 administered levonorgestrel 30 µg intravenously in 12 rats; Study 3 administered levonorgestrel 60 µg intravenously and subcutaneously in 12 rats; and Study 4 administered etonogestrel 30 µg intravenously in 12 rats. Samples were quantified using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were estimated via noncompartmental analysis.<i>C</i><sub>max</sub> and AUC<sub>inf</sub> for etonogestrel and levonorgestrel were similar following 30 µg intravenous bolus in rats, suggesting comparable pharmacokinetics. Levonorgestrel exposure was dose-proportional in rats, based on two-fold higher AUC<sub>inf</sub> following levonorgestrel 60 versus 30 µg. The bioavailability of intradermal and subcutaneous levonorgestrel was 97.7% (Study 1) and 90.3% (Study 3), respectively. The minipig levonorgestrel clearance was 21.5 L/hr, which was about 20-fold higher than both the rat levonorgestrel (range: 0.985–1.45 L/hr) and etonogestrel clearance (range: 0.803–0.968 L/hr).These studies contribute to the gap in knowledge of nonclinical levonorgestrel and etonogestrel pharmacokinetics, which is necessary for the ongoing development of long-acting reversible contraceptives. The objective of these studies was to determine the pharmacokinetics of levonorgestrel and etonogestrel in Sprague-Dawley rat or Göttingen minipig following various administration routes. Four sequential crossover studies were conducted: Study 1 administered levonorgestrel 30 µg intravenously and intradermally in four minipigs; Study 2 administered levonorgestrel 30 µg intravenously in 12 rats; Study 3 administered levonorgestrel 60 µg intravenously and subcutaneously in 12 rats; and Study 4 administered etonogestrel 30 µg intravenously in 12 rats. Samples were quantified using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were estimated via noncompartmental analysis. <i>C</i><sub>max</sub> and AUC<sub>inf</sub> for etonogestrel and levonorgestrel were similar following 30 µg intravenous bolus in rats, suggesting comparable pharmacokinetics. Levonorgestrel exposure was dose-proportional in rats, based on two-fold higher AUC<sub>inf</sub> following levonorgestrel 60 versus 30 µg. The bioavailability of intradermal and subcutaneous levonorgestrel was 97.7% (Study 1) and 90.3% (Study 3), respectively. The minipig levonorgestrel clearance was 21.5 L/hr, which was about 20-fold higher than both the rat levonorgestrel (range: 0.985–1.45 L/hr) and etonogestrel clearance (range: 0.803–0.968 L/hr). These studies contribute to the gap in knowledge of nonclinical levonorgestrel and etonogestrel pharmacokinetics, which is necessary for the ongoing development of long-acting reversible contraceptives.