Pharmacodynamics, pharmacokinetics and safety profile of the new platelet-activating factor antagonist apafant in man.
Platelet-activating factor (PAF) is a unique phospholipid mediator with multifunctional properties. Evidence generated in experimental studies suggests that PAF plays a pathogenetic role in anaphylactic, inflammatory and immunogenic reactions. Apafant (WEB 2086, CAS 105219-56-5), a novel synthetic PAF receptor antagonist, was administered to a total of 101 healthy volunteers within 5 studies to investigate its pharmacologic activity, pharmacokinetic behaviour and safety profile. Pharmacologic activity was monitored by inhibition of 5 x 10(-8) mol/l PAF-induced platelet aggregation ex vivo. The following treatment schedules were studied: oral single dose 1.25 to 400 mg; oral multiple dose 100 mg t.i.d. over 7 days; i.v. infusion 0.5 to 50 mg (over 30 min); inhalative administration up to 1.0 mg. PAF induced platelet aggregation was virtually completely inhibited by single oral doses of 20 mg upwards, throughout during the multiple oral dose study, at all dose levels tested in the i.v. study and (significantly but not completely) at 0.5 and 1.0 mg in the inhalative study. Following oral administrations (capsules) apafant is absorbed rapidly (tmax 1 to 2 h), there is linear pharmacokinetics for the mean plasma concentrations of apafant measured by RIA as well as for the areas under the curve (AUCs). Approximately 60% of apafant is bound to plasma protein, the mean volume of distribution is 28 l, about 44% of an oral dose is excreted in the urine, the mean renal clearance is 192 ml/min. No accumulation of the drug occurred in volunteers with normal kidney function. No clinically relevant drug related adverse events or changes in laboratory or vital parameters such as blood pressure, heart rate, respiratory rate and ECG were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
Brecht
H M
HM
Department of Medicine, Boehringer Ingelheim KG, Rhein, Germany.
Adamus
W S
WS
Heuer
H O
HO
Birke
F W
FW
Kempe
E R
ER
D000328:Adult; D001381:Azepines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001772:Blood Cell Count; D001774:Blood Chemical Analysis; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010980:Platelet Membrane Glycoproteins; D011485:Protein Binding; D011897:Random Allocation; D011956:Receptors, Cell Surface / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D001381:Azepines; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086