The phosphodiesterase 5 inhibitor sildenafil is a potential therapeutic option in the treatment of persistent pulmonary hypertension of the newborn (PPHN) and neonatal hypoxemia. In this open-label trial, 36 term neonates with PPHN or hypoxemia were administered intravenous sildenafil for up to 7 days starting within 72 h of birth. A mixed-effects pharmacokinetic model that included two-compartment disposition of sildenafil and its metabolite and an effect of postnatal age on sildenafil clearance was used to describe plasma concentration-time data of parent and metabolite. Allometrically scaled sildenafil clearance increased threefold from the first day after birth to values similar to those in adults by the first week. Volume of distribution of sildenafil in neonates was fourfold higher than in adults, resulting in a longer terminal half-life in neonates (48-56 h) compared to adults. Increase in sildenafil clearance in the early postnatal period likely reflects maturation of CYP-mediated N-demethylation.

Aims This study constituted the first administration of the oral platelet inhibitor, sibrafiban, to humans. The aim was to investigate the pharmacokinetics and pharmacodynamics of Ro 44-3888, the active principle of sibrafiban, after single ascending oral doses of sibrafiban. Particular emphasis was placed on intersubject variability of the pharmacokinetic and pharmacodynamic parameters of Ro 44-3888. Methods The study consisted of three parts. Part I was an open ascending-dose study to determine target effect ranges of sibrafiban. Part II, a double-blind, placebocontrolled, parallel-group study, addressed the intersubject variability of pharmacokinetic and pharmacodynamic parameters of the active principle at a sibrafiban dose achieving an intermediate effect. Part III was a double-blind, placebo-controlled, ascending-dose design covering the complete plasma concentration vs pharmacodynamic response curve of sibrafiban. Results At sibrafiban doses between 5 mg and 12 mg, the pharmacokinetics of free Ro 44-3888 in plasma were linear whereas those of total Ro 44-3888 were nonlinear because of the saturable binding to the glycoprotein IIb-IIIa receptor. Saturation of the GP IIb-IIIa receptor was reached at plasma concentrations of 15.9 ng ml −1 . At sibrafiban doses up to 2 mg, ADP-induced platelet aggregation was inhibited by 50%, whereas the inhibition of TRAP-induced platelet aggregation was about 20-30%. At the higher doses, ADP-induced platelet aggregation was almost completely inhibited while a clear dose-response could be observed with TRAP-induced inhibition of platelet aggregation at sibrafiban doses of 5 to 12 mg. Ivy bleeding time increased very steeply with dose with a significant prolongation observed at doses of 5 to 7 mg of sibrafiban (5-7 min, >30 min in one case). At a sibrafiban dose of 12 mg, the stopping criterion for dose escalation ( prolongation of the Ivy bleeding time >30 min in three out of four subjects per dose group) was reached. The interindividual coefficients of variation of the integrated pharmacokinetic and pharmacodynamic parameters (AUC and AUE) were below 20%, thus lying well within the pre-set level of acceptance. Conclusions With a low intersubject variability of its pharmacokinetic and pharmacodynamic parameters, linear pharmacokinetics and pharmacodynamic effects closely related to its plasma concentrations, Ro 44-3888 has good pharmacological prerequisites for a well controllable therapy of secondary prevention of arterial thrombosis in patients with acute coronary syndrome.

Aims The purpose of this clinical study was to evaluate the effects of a ticlopidine/aspirin combination on the pharmacokinetics and pharmacodynamics of sibra®ban and the tolerability of the combination therapy Methods Thirty-eight healthy male volunteers were randomized to receive one of the following treatments for 7 days: sibra®ban (n=12), ticlopidine/aspirin (n=12), or the combination treatment sibra®ban/ticlopidine/aspirin (n=14). Concentrations of the active metabolite of sibra®ban, Ro 44±3888, in plasma and urine were determined by column-switching liquid chromatography combined with tandem mass spectrometry. The pharmacodynamics of sibra®ban and ticlopidine/aspirin were examined by measuring the inhibition of ADP-or collagen-induced platelet aggregation. Results The addition of ticlopidine/aspirin to sibra®ban did not signi®cantly alter the pharmacokinetic parameters of Ro 44±3888. the geometric mean ratio for AUC(0,12h) was 110 (95% CI 0.82, 1.22). Separately, sibra®ban and ticlopidine/ aspirin inhibited ADP-and collagen-induced platelet aggregation and the effects of the two treatments were additive. For example, the average inhibition of ADP-induced platelet aggregation over 12 h was 42% in the sibra®ban treated group, 55% in the ticlopidine/aspirin group and 69% in the sibra®ban/ticlopidine group. The bleeding time was prolonged in the treatments with ticlopidine/aspirin (8.1 min) and sibra®ban/ticlopidine/aspirin (8.6 min) compared with sibra®ban alone (3.5 min). Conclusions This study shows a signi®cant pharmacodynamic interaction between sibra®ban and ticlopidine/aspirin. Consequently, the simultaneous administration of sibra®ban and ticlopidine/aspirin should be carefully monitored to ensure the patient's coverage with an antiplatelet drug without exposure to an excessive bleeding risk.

AIMS To characterize the pharmacokinetics of sildenafil and its active metabolite in newborns with PPHN. METHODS In this open‐label, dose‐escalation trial, 35 neonates diagnosed with PPHN were administered sildenafil within 72 hours of birth. Subjects received a continuous i.v. infusion for up to 7 days. Mixed‐effects pharmacokinetic models implemented in NONMEM, and parameterized in terms of clearance (CL), inter‐compartmental clearance (Q), and volumes of distribution (V1, V2) were used to describe parent and metabolite plasma concentration‐time data simultaneously. Covariates effects on model parameters were evaluated. RESULTS The final model included 2‐compartment disposition of both parent and metabolite with post‐natal age as a covariate on sildenafil CL and weight as a covariate on V1 of metabolite. Mean parameter estimates for sildenafil from the final pharmacokinetic model were: θCL = 0.81 L/hr, θage = 0.63, V1 = 11.1 L, Q = 0.13 L/hr, and V2 = 5.17 L. Interindividual variability (IIV) in CL and V1 were 61% and 41%, respectively. Mean sildenafil CL therefore increased from 0.81 L/hr at 1 day to 2.77 L/hr at 7 days after birth. Mean parameter estimates for metabolite were: CL = 3.88 L/hr, θV1 = 2.78 L, θwt = 2.53, Q = 3.65 L/hr, and V2 = 32.5 L. CONCLUSIONS Sildenafil CL in neonates after 7 days was similar to allometrically scaled adult values, consistent with the maturation of hepatic CYP3A4. Volume of distribution of sildenafil in neonates was approximately 3‐4 fold higher than that in adults. Clinical Pharmacology & Therapeutics (2005) 79, P46–P46; doi: