Pharmacokinetic and pharmacodynamic basis for effective argatroban dosing in pediatrics.

The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of argatroban in pediatric patients and derive dosing recommendations. An open-label multicenter trial was conducted in pediatric patients (n = 18 from birth to 16 years). A population modeling approach was used to characterize pharmacokinetics and pharmacodynamics of argatroban in pediatric patients. Simulations were performed to derive a dosing regimen for pediatric patients. The estimated clearance of argatroban in pediatric patients was 2-fold lower than that in healthy adults. Body weight was significant predictor of argatroban clearance. The clearance in a typical 20-kg pediatric patient was 3.1 L/h. In 4 patients with elevated serum bilirubin levels, the estimated clearance was 0.6 L/h. Effect on activated plasma thromboplastin time (aPTT) was found to be concentration dependent. Simulations suggested that a starting dose of 0.75 µg/kg/min in pediatric patients was comparable in performance to 2.0 µg/kg/min approved in adults for attaining target aPTT and risk for bleeding. A dose increment step size of 0.25 µg/kg/min was suitable for titration. The PK/PD of argatroban was reasonably characterized in pediatrics. Plasma concentration-aPTT relationship was used to derive a safe starting dose and titration scheme for the first time in pediatric patients and was incorporated into the US prescribing information for argatroban.

Pharmacokinetic and clinical data supporting the use of fondaparinux 1.5 mg once daily in the prevention of venous thromboembolism in renally impaired patients.

The study aim was to determine the value of fondaparinux at the once-daily 1.5 mg dose in patients with moderate renal impairment (creatinine clearance between 20 and 50 ml/min). Pharmacokinetic simulations were performed using a population pharmacokinetic model based on data obtained in 756 patients undergoing major orthopedic surgery. The efficacy (venous thromboembolism) and safety (major bleeding) of 1.5 mg fondaparinux were determined by analyzing the available data obtained in all thromboprophylaxis trials using this dosage. The predicted steady-state exposure [area under the plasma concentration-time curve from 0 to 24 h (AUC0-24)] to fondaparinux between patients with moderate renal impairment receiving 1.5 mg and patients with normal renal function receiving 2.5 mg was similar. In four phase II trials (two trials versus placebo, one versus enoxaparin and one without comparator), 353 patients undergoing total hip or knee replacement (10.8% with moderate renal impairment) received fondaparinux 1.5 mg. The overall rate of venous thromboembolism and major bleeding was 10.4 and 0.3%. Fondaparinux 1.5 mg was significantly more effective than placebo (P < 0.01) and was as effective as, and tended to be safer (P = 0.05) than, twice-daily 30 mg enoxaparin. The effect was maintained in patients with moderate renal impairment. The once-daily administration of 1.5 mg fondaparinux in patients with moderate renal impairment resulted in a predicted exposure to the drug similar to that achieved with 2.5 mg in patients with normal renal function. This dosage regimen showed a favorable efficacy/safety clinical profile and should be appropriate in preventing venous thromboembolism in patients with moderate renal impairment.

Population pharmacokinetics of S(-)-carvedilol in healthy volunteers after administration of the immediate-release (IR) and the new controlled-release (CR) dosage forms of the racemate.

Carvedilol is a beta(1)-, beta(2)-, and alpha(1)-adrenoreceptor blocker indicated for treatment of hypertension and mild-to-severe congestive heart failure. The objective of this study was to develop and evaluate a single population model that describes S(-)-carvedilol pharmacokinetics from both the immediate-release (IR) and the new controlled-release dosage forms of the racemate. Carvedilol IR data (1270 measurements) were obtained from 2 open-label studies (50 mg/25 mg Q12 hours for 2 doses). Carvedilol CR data (2058 measurements) were obtained from an open-label, nonrandomized, dose-rising (10, 20, 40, and 80 mg), 4-period balanced crossover study. All data were simultaneously analyzed using NONMEM V. Leverage analysis and internal evaluations were conducted for the final model. A 2-compartment model with first-order absorption and elimination provided the best fit. The model included different absorption rates (KAs) for the CR and IR morning (IR(AM)) and evening (IR(PM)) doses; incorporating change-points at certain times. Estimates of KAs indicated that the absorption was slower at equivalent times and extended for CR relative to IR carvedilol. Oral clearance of S(-)-carvedilol was 149 L/h. The IR(PM) and the CR doses had bioavailability (F(rel)) of 0.80 and 0.76, respectively, relative to the IR(AM) dose. The inter-subject variability in KAs was lower for the CR dosage form than the original IR dosage form. Estimation of interoccasion variability on KAs and F(rel) for the CR dosage form improved the fit. The model performed well in simulation and leverage analysis indicated its robustness. The model will be a useful tool for future simulation studies.

Pharmacokinetics and pharmacodynamics of argatroban in combination with a platelet glycoprotein IIB/IIIA receptor antagonist in patients undergoing percutaneous coronary intervention.

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of argatroban, administered in combination with a platelet glycoprotein IIb/IIIa receptor antagonist, was characterized in patients undergoing percutaneous coronary intervention (PCI). Plasma argatroban and activated clotting times (ACTs) were assessed periprocedurally in 152 patients administered argatroban (250- or 300-microg/kg bolus, then 15-microg/kg/min infusion) in combination with abciximab or eptifibatide during PCI. The PK and PK-PD models were developed utilizing a sequential population approach in NONMEM. Population PK estimates for clearance, central volume, and peripheral volume were 22.0 L/h, 11.0 L, and 13.0 L, respectively (coefficients of variation [CVs]

Evaluation of vardenafil and sildenafil on cardiac repolarization.

This novel study evaluated the effects of vardenafil and sildenafil on QT and corrected QT (QTc) duration using a model that minimizes experimental error to obtain the most accurate assessment of observed QTc effects. A placebo-controlled and positive-controlled, period-balanced, double-blinded, 6-way crossover study evaluated therapeutic and supratherapeutic oral doses of vardenafil (10 and 80 mg, respectively) and sildenafil (50 and 400 mg, respectively), therapeutic doses of moxifloxacin (400 mg), and a placebo in 58 healthy men (mean age 53 years), with dosing every 3 days. Six replicate, 12-lead, digital electrocardiograms (ECGs) were recorded at 3 time points before and 5 time points after dosing to cover the time course of maximum exposure to study drugs and their metabolites. An independent laboratory blindly analyzed approximately 17,000 ECGs. For the placebo, mean change in QTcF (Fridericia) duration 1 hour after dose (approximate Tmax of vardenafil and sildenafil) was 0 ms (+/-0.7 SD). QT/QTc variability was small across regimens, indicating statistically powerful results. Moxifloxacin demonstrated an expected 8-ms mean change and was the only drug to prolong absolute QT. Placebo-corrected mean changes in QTcF duration (90% confidence interval) at 1 hour after dose were 8 ms (range 6 to 9) for vardenafil 10 mg and 6 ms (range 5 to 8) for sildenafil 50 mg. QTci (linear and nonlinear per patient) yielded similar trends: 4 ms (range 3 to 6) for vardenafil 10 mg and 4 ms (range 2 to 5) for sildenafil 50 mg. Dose response demonstrated very shallow QTc relations for study drugs. Therapeutic and supratherapeutic doses produced only small increases in the QTcF interval, which were considered to be clinically irrelevant. This well-controlled, statistically powerful study in middle-aged men demonstrated that vardenafil and sildenafil produced no increase of absolute QT and only similar, small increases of the QTc interval, with a shallow dose-response curve. The study design and conduct may serve as a guide for future QT assessment of new drugs.