The pharmacokinetics and pharmacodynamics of recombinant human interferon-beta (rHuIFN-beta 1a) were assessed following administration to 12 healthy male volunteers. Each subject received, in a double-blind, balanced, random-order, crossover sequence, single doses of 6 MIU of rHuIFN-beta 1a (Rebif) i.v., i.m., and s.c. or matching placebo on four occasions separated by washout periods of 1 week. Blood samples were collected at preset times for the measurement of serum IFN-beta levels and of intracellular 2'-5'-oligoadenylate synthetase levels. Blood pressure, sitting heart rate, respiratory rate, oral body temperature, and tolerance were monitored regularly. All administrations of rHuIFN-beta 1a were well tolerated, although about half of the subjects had a flu-like syndrome, as expected. After i.v. bolus injection, the pharmacokinetics of rHuIFN-beta 1a were well described by a classic two-compartment model. Mean total clearance of rHuIFN-beta 1a was about 100 L.h-1. The distribution half-life was 5 min, and the terminal half-life was approximately 5 h. After i.m. or s.c. injection, serum IFN-beta profiles were rather flat, and about one sixth of the administered dose was available systemically. Extent and duration of clinical and biologic effects were independent of the route of administration and of the IFN-beta serum levels. Biologic pharmacodynamic effects persisted even when IFN-beta serum levels had returned to baseline and were still significantly elevated 3 days after a single dose. Because of the independence of the extent and duration of clinical and biologic pharmacodynamic effects from the route of administration and from the IFN-beta serum levels, the s.c route of administration is preferred in indications in which primarily an immunomodulatory action is sought. Predominantly antiviral and antiproliferative activity is enhanced by the i.v. route to provide adequate drug levels at the site of pathology, although its application is limited on practical grounds.

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A pharmacodynamic analysis of the input-response relationship between the gonadotropin-releasing hormone antagonist antide and luteinizing hormone (LH) and testosterone concentrations is presented. A control compartmental model is developed using pharmacokinetic and pharmacodynamic data from experiments in which different short intravenous antide infusions were given to healthy male volunteers. Because of the control interdependence between serum LH and testosterone a separation principle similar to one we have used previously to analyze physiological pharmacokinetic data is used for model exploration: testosterone and LH are first modeled separately, conditioning on the other observed response. This reveals that the LH effect on testosterone depends on previous LH exposure and that LH depends not on current but on previous testosterone exposure, resulting in an LH overshoot after antide-induced suppression. Both submodels are combined into one global model, which in addition includes a model for testosterone circadian variation. This model describes the data well and can be used to predict responses for some nonstudied antide dosages. However, the sensitivity of predictions to model assumptions limits the range of valid extrapolation, and this, too, is illustrated.

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