Compared with controls, average AUC(0-24 h) values for carvedilol were approximately 40% and 50% higher on study Days 1 and 9 in patients with renal insufficiency, primarily due to higher R-carvedilol concentrations with only a small change (<20%) in S-carvedilol concentrations, the isomer possessing beta-blocking activity. These changes in pharmacokinetics are modest in view of the large interindividual variability. Carvedilol was well tolerated in both groups. Although the present study cannot provide a final conclusion, based on the results of the present study, no changes in dosing recommendations for carvedilol are warranted in patients with moderate/severe renal insufficiency.
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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