Pharmacokinetics of levonorgestrel and etonogestrel in rat or minipig following intravenous, subcutaneous, or intradermal administration.

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.Cmax and AUCinf 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 AUCinf 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.

Bioequivalence assessment of a pregabalin capsule and oral solution in fasted healthy volunteers: a randomized, crossover study.

OBJECTIVE: To determine the oral bioavailability of a pregabalin capsule relative to a pregabalin solution. METHODS: This was an open-label, randomized, crossover study in 12 healthy volunteers. Pharmacokinetics were compared for a 100-mg capsule and a 100-mg capsule dissolved in water, administered fasted. RESULTS: Mean Cmax and AUC0-∞ for the capsule were within 2% of those for the solution (3.8 vs. 3.7 µg/ml and 26.7 vs. 27.0 µg×h/ml, respectively). The 90% confidence intervals for the ratios of Cmax and AUC0-∞ fell fully within 80 - 125%. CONCLUSIONS: A 100-mg pregabalin capsule is bioequivalent to a pregabalin solution (100-mg capsule dissolved in water).

Clinical pharmacokinetics of pregabalin in healthy volunteers.

Pregabalin has shown clinical efficacy for treatment of neuropathic pain syndromes, partial seizures, and anxiety disorders. Five studies in healthy volunteers are performed to investigate single- and multiple-dose pharmacokinetics of pregabalin. Pregabalin is rapidly absorbed following oral administration, with peak plasma concentrations occurring between 0.7 and 1.3 hours. Pregabalin oral bioavailability is approximately 90% and is independent of dose and frequency of administration. Food reduces the rate of pregabalin absorption, resulting in lower and delayed maximum plasma concentrations, yet the extent of drug absorption is unaffected, suggesting that pregabalin may be administered without regard to meals. Pregabalin elimination half-life is approximately 6 hours and steady state is achieved within 1 to 2 days of repeated administration. Corrected for oral bioavailability, pregabalin plasma clearance is essentially equivalent to renal clearance, indicating that pregabalin undergoes negligible nonrenal elimination. Pregabalin demonstrates desirable, predictable pharmacokinetic properties that suggest ease of use. Because pregabalin is eliminated renally, renal function affects its pharmacokinetics.

Activity profile of pregabalin in rodent models of epilepsy and ataxia.

Pregabalin (Lyrica) is a novel amino acid compound that binds with high affinity to the alpha2-delta (alpha2-delta) auxiliary protein of voltage-gated calcium channels. In vivo, it potently prevents seizures, pain-related behaviors and has anxiolytic-like activity in rodent models. The present studies were performed to determine the profile of pregabalin anticonvulsant activity in a variety of mouse and rat models. In the high-intensity electroshock test, pregabalin potently inhibited tonic extensor seizures in rats (ED50 = 1.8 mg/kg, PO), and low-intensity electroshock seizures in mice. It prevented tonic extensor seizures in the DBA/2 audiogenic mouse model (ED50 = 2.7 mg/kg, PO). Its time course of action against electroshock induced seizures in rats roughly followed the pharmacokinetics of radiolabeled drug in the brain compartment. At higher dosages (ED50 1= 31 mg/kg, PO), pregabalin prevented clonic seizures from pentylenetetrazole in mice. In a kindled rat model of partial seizures, pregabalin prevented stages 4-5 behavioral seizures (lowest effective dose = 10 mg/kg, IP), and also reduced the duration of electrographic seizures. Pregabalin was not active to prevent spontaneous absence-like seizures in the Genetic Absence Epilepsy in Rats from Strasbourg (GAERS) inbred Wistar rat strain. Pregabalin caused ataxia and decreased spontaneous locomotor activity at dosages 10-30-fold higher than those active to prevent seizures. These findings suggest that pregabalin has an anticonvulsant mechanism different from the prototype antiepileptic drugs and similar to that of gabapentin except with increased potency and bioavailability. In summary, our results show that pregabalin has several properties that favor treatment of partial seizures in humans.