The low and variable bioavailability of cyclosporine has been attributed to poor absorption. However, recent studies have suggested that intestinal first-pass metabolism exerts a significant effect on bioavailability. We describe theory and methods to differentiate the contribution from oral absorption and intestinal and hepatic metabolism to overall cyclosporine bioavailability. Analysis of data from previous studies in our laboratories shows that in the absence of intestinal metabolism, cyclosporine absorption from its presently available dosage form averages at least 65% +/- 12% in healthy volunteers and 77% +/- 19% in kidney transplant patients. Analysis also suggests that the extraction ratio for cyclosporine in the gut is approximately twice the hepatic extraction and that cyclosporine absorption does not present a problem, with an average of 86% of the drug absorbed intact from its commercially available product in healthy volunteers. The boundary condition analysis described should have broad application in the differentiation of factors responsible for poor bioavailability.

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These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of methylphenidate) into clinical application (the selection of a new drug delivery pattern for methylphenidate). This approach produced a new product (OROS-methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy (10-12 hours) after a single administration in the morning.

Dapoxetine is a serotonin transporter inhibitor currently in development for the treatment of premature ejaculation. This randomized, 2-sequence, 2-treatment crossover study assessed the single- and multiple-dose pharmacokinetics of dapoxetine following once-daily administration of dapoxetine 30 mg and 60 mg to healthy male volunteers. Dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations reached approximately 1 hour after dosing; plasma concentrations after single doses of dapoxetine decreased rapidly to approximately 5% of peak concentrations by 24 hours. Elimination was biphasic, with an initial half-life of approximately 1.4 hours and a terminal half-life of approximately 20 hours. Dapoxetine showed time-invariant pharmacokinetics and dose proportionality between doses, and its pharmacokinetics was unaffected by multiple dosing. The pharmacokinetics of dapoxetine metabolites, desmethyldapoxetine and dapoxetine-N-oxide, was similarly unaffected by multiple dosing. There were no serious adverse events; the most commonly reported adverse events were diarrhea, dizziness, and nausea.