Influence of avosentan (SPP3OI) on the pharmacokinetics of a second generation oral contraceptive containing ethinylestradiol and levonorgestrel in healthy female volunteers.
BACKGROUND
Avosentan (SPP301) is a potent and highly selective ETA receptor blocker and is clinically investigated in diabetic nephropathy. This study was designed to evaluate whether avosentan influences the pharmacokinetics of steroid oral contraceptives.


METHODS
During a run-in phase, 16 healthy females received an oral contraceptive containing ethinylestradiol 0.03 mg and levonorgestrel 0.15 mg for the first 21 days of a minimum of one menstrual cycle. In a subsequent double-blind, randomized two menstrual cycle crossover treatment phase, subjects received either avosentan 25 mg or placebo once daily concomitantly with the oral contraceptive. Serum ethinylestradiol and plasma levonorgestrel concentrations were measured on Days 14 and 15 of the two treatment periods for the evaluation of the 24-hour kinetic parameters, and an additional sample was collected on Day 21 to determine their trough concentrations. Serum progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels as well as plasma avosentan and Ro 68-5925 levels were determined on Days 13, 14, 15 and 21 of each cycle of the treatment phase.


RESULTS
Avosentan had a statistically significant lowering effect of 9 - 15% on the ethinylestradiol serum concentration levels. The 90% confidence intervals of the pharmacokinetic parameters did not include 1 or exceeded the 0.8 - 1.25 acceptance range for lack of interaction. The plasma concentration-time curves and pharmacokinetic parameters of levonor-gestrel were not statistically different during concomitant treatment with either avosentan or placebo. Compared to placebo, avosentan lowered the serum concentrations of progesterone statistically significantly by about 8% and increased slightly the LH and FSH serum concentrations. Safety and tolerability patterns were comparable during avosentan and placebo administration.


CONCLUSIONS
Because of the effect of avosentan on the concentration levels of ethinylestradiol and progesterone, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during avosentan treatment.
Dieterle
W
W
Drug Disposition Consultants, Lörrach, Germany.
Mann
J
J
D000328:Adult; D019540:Area Under Curve; D003278:Contraceptives, Oral, Hormonal / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D065128:Endothelin Receptor Antagonists; D004997:Ethinyl Estradiol / Q000097:blood / Q000493:pharmacokinetics*; D005076:Exanthema / Q000139:chemically induced; D005151:Facial Injuries / Q000139:chemically induced; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006261:Headache / Q000139:chemically induced; D006801:Humans; D016912:Levonorgestrel / Q000097:blood / Q000493:pharmacokinetics*; D007986:Luteinizing Hormone / Q000097:blood; D008875:Middle Aged; D015394:Molecular Structure; D011374:Progesterone / Q000097:blood; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D012220:Rhinitis / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
D003278:Contraceptives, Oral, Hormonal; D004338:Drug Combinations; D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D011743:Pyrimidines; C519554:Ro 68-5925; D004997:Ethinyl Estradiol; D011374:Progesterone; D016912:Levonorgestrel; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; C484919:Avosentan