The pharmacokinetics of traxoprodil were quite different in the two phenotypes. In extensive metabolisers, the oral bioavailability was nonlinear and dose-dependent, while in poor metabolisers, oral bioavailability appeared to be linear and dose-independent. Based on the pharmacokinetics in extensive and poor metabolisers, the nonlinear oral bioavailability in extensive metabolisers may be attributed to saturation of hepatic first-pass CYP2D6 metabolism. Thus, at a high oral dose, the impact of CYP2D6 metabolism on traxoprodil pharmacokinetics is minimal.
Background Pharmacodynamic effects of opiate antagonists and agonists such as naltrexone (NTX) and fentanyl (FE) have been documented in separate studies and various populations. However, no data are available for a direct comparison in the same group of subjects. Methods NTX 50mg QD and a matched placebo were compared in a randomized double‐blind crossover study conducted in a research hospital setting. NTX was administered for 3 days to 16 healthy males. ACTH, cortisol, FSH, LH, PRL and pupillary diameter (PD) were measured on Day 1. On Day 3, blockade of agonist‐induced effects was tested by use of an IV bolus of FE. Results On Day 1, NTX induced an increase in LH, ACTH and cortisol (p<0.01 each; 90%CI ratio[1.29–1.91],[1.42–2.40],[1.26–2.06]). No effect was observed on FSH, PRL and PD. On Day 3, NTX was associated with a blockade of the following FE effects: increase in ACTH (p<0.0001,[0.15–0.59]), cortisol (p=0.01,[0.38–0.81]) and PRL (p<0.0001,[0.12–0.22]) and reduction in PD (p<0.0001,[2.47–3.32]). NTX did not influence pain perception during the cold pressor test performed after FE. Conclusion Blockade of FE‐induced changes in PRL and PD were the most significant treatment effects observed. In contrast to FE‐induced decreases in ACTH/cortisol reported in stressed or surgical patients, an increase was observed in healthy volunteers. This effect was blocked by NTX. Clinical Pharmacology & Therapeutics (2005) 77, P28–P28; doi:
Purpose A placebo‐ and positive‐controlled (Moxifloxacin, M 400 mg), double‐blind, 6‐way crossover study evaluated the effects of single oral therapeutic and supratherapeutic doses of vardenafil (V 10, 80 mg), and sildenafil (S 50, 400 mg) on QT/QTcF duration. Methods 59 healthy men (mean age 53) received at least one dose of study medication. Six replicate 12‐lead digital ECGs were recorded at 3 time points pre‐dose and at 5 time points post‐dose (up to 4 hrs) to cover the time course of maximum exposure of S, V and metabolites. Plasma concentrations (Cp) of V, S and M were measured at the same time points. The QTcF‐Cp data for V and S were analyzed using NONMEM. Interoccasion variability (IOV) in baseline QTc response across sessions was included in the model. Results: A direct effect Emax model best described the QTcF‐Cp data for V and S. Emax and inter‐individual variability (IIV) in EC50 were modelled to be the same for V and S. Evaluation of the PK/PD model using posterior predictive check showed good predictive performance. (See Table) Conclusion According to the PK/PD model, V and S showed similar maximal QTcF prolongation. Clinical Pharmacology & Therapeutics (2004) 75, P89–P89; doi: Parameter Population Mean (%CV) IIV E0 (msec)387 (0.4)3.2Emax (msec)8.29 (6.1)25.2EC50V (ng/mL)2.44 (34.4)120.4EC50s (ng/mL)59.2 (33.6)120.4IOV on E0 (%CV)1.80 (7.7)Residual Variability, (msec)4.00 (7.0)
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