Duane Boyle

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.

Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: An open-label, safety, efficacy, and pharmacokinetic study†

An increasing number of pediatric patients suffer from thrombotic events necessitating anticoagulation therapy including heparins. Some such patients develop heparin‐induced thrombocytopenia (HIT) and thus require alternative anticoagulation. As such, studies evaluating the safety, efficacy, and dosing of alternative anticoagulants are required.

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‐μg/kg bolus, then 15‐μg/ 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] ≤ 10%). By covariate analysis, clearance increased linearly with body weight. Plasma argatroban and ACT effect were well described using a sigmoidal Emax model. For argatroban in combination with platelet glycoprotein IIb/IIIa receptor blockade in patients undergoing PCI, population PK parameters are consistent with values reported for argatroban in healthy subjects. A predictable relationship exists between argatroban concentration and effect in this setting.

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 β1-, β1-, and α1-adrenoreceptor blocker indicated for treatment of hypertension and mild-tosevere congestive heart failure. The objective of this study was to develop and evaluate a single population model that describesS(−)-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 (IRAM) and evening (IRPM) 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 ofS(−)-carvedilol was 149 L/h. The IRPM and the CR doses had bioavailability (Frel) of 0.80 and 0.76, respectively, relative to the IRAM 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 Frel 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.

A definitive study of the effects of PDE-5 inhibitors on cardiac repolarization in middle-age males

Patients with erectile dysfunction may use PDE5 inhibitors such as vardenafil (V) and sildenafil (S), which alter the hERG channel of transfected cells only at suprapharmacologic nonclinical concentrations. This study evaluated effects of therapeutic and supratherapeutic doses of V and S on QT/QTc duration. A placebo‐ and active‐control (moxifloxacin, M, at therapeutic dose), period balanced, double blinded, 6 way crossover study evaluated single oral doses of V 10 mg, V 80 mg, S 50 mg, S 400 mg, M 400 mg and placebo in 58 healthy men (mean age 53) with doses separated by 3 days. Six replicate 12‐lead digital ECGs were recorded at 3 time points prior to and 5 time points post dose to cover the full exposure of drugs and metabolites. An independent lab blindly analyzed the ECGs. PK blood samples were drawn at the same 5 time points post dose. For placebo, mean change in QTcF (Fridericia) duration from baseline at 1 hour post dose (approximate Tmax of V and S) was 0 msec (+/‐ 0.7 SD). QT and QTc variability was small across regimens, indicating statistically powerful results due to large sample size and number (17,000) of ECGs. M demonstrated an expected 8 msec mean change and was the only drug to prolong absolute QT. Placebo‐corrected values of mean change from baseline at 1 hour post‐dose for each regimen are shown below. QT corrected using linear and nonlinear methods and each individuals QT/HR data (QTci) yielded similar trends of drug effect on QTc. PK/PD modeling demonstrated a very shallow QTc‐concentration relationship for V and S. Therapeutic and supratherapeutic doses of V and S produced no increase of absolute QT and similar small increases in QTc interval. We conclude that these findings, and the absence of postmarketing reports of torsades de pointes with S, indicate that small increases in QTc for V and S are clinically insignificant. This study design may serve as a guide for future definitive QT assessment. (See Table )

Abstract 1289: Population pharmacokinetics (PK) of the MEK inhibitor GSK1120212 from the first-time-in-human study in patients with solid tumors or lymphoma

Background: GSK1120212 is a reversible, highly selective allosteric inhibitor of MEK1/MEK2. MEK111054, a first-time-in human study (FTIH) is an open-label, multiple-dose, dose escalation trial designed to investigate the safety, PK and pharmacodynamics (PD) of GSK1120212 in patients with solid tumors or lymphoma. A population PK model of GSK1120212 was developed and validated from the dose-escalation part of the FTIH trial. Materials and Methods: GSK1120212 single (0.125-10 mg) and repeat (0.125-4 mg) dose plasma concentrations were obtained from MEK111054 that utilized both continuous and loading dose regimens with daily administration of GSK1120212. Plasma GSK1120212 concentrations were determined using a validated analytical method based on liquid-liquid extraction, followed by HPLC-MS/MS analysis. Population PK analysis was performed on 1373 plasma samples from 55 patients ranging in ages from 35 to 77 years. Population PK analysis was performed using a nonlinear mixed effects modeling method (NONMEM, v. 7.1.0). Concentrations were transformed into the log domain and the residual variability was described by an additive error model. The influence of covariates such as gender, age, weight and BMI on PK parameter estimates was assessed. The final model was validated using a visual predictive check (VPC) of the simulated (n=1000) and observed data. Results: Plasma concentration-time data for GSK1120212 were best described by a two-compartment model with first-order absorption and elimination. The final model also incorporated two sequential absorption rates (KA1 and KA2) with a change point (MTIME) estimated at 0.41 hours post-dose. Final model population mean (%CV) parameter estimates for clearance (CL/F), volume of the central compartment (V2/F), volume of the peripheral compartment (V3/F), and intercompartmental clearance (Q/F) were 6.76 L/hr (7%), 125 L (18%), 746 L (11%), and 114 L, respectively. Interindividual variability ranged from 43 to 88%, interoccassion variability ranged from 8-74%, and the residual variability was 13 ng/mL. Covariates did not influence the pharmacokinetics of GSK1120212. VPC supported the validity of the model and was a good predictor of observed single and repeat dose data in the current study. Conclusion: The population PK model of GSK1120212 in patients with solid tumors or lymphoma provided a description of PK and an understanding of its variability which aided dose selection decisions. Once daily dosing without a loading dose was selected for future studies in order to maintain concentrations above the preclinical antiproliferation IC90. The established population PK model will aid in the development of future population PK/PD assessments with both tumor response and adverse event data. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1289. doi:10.1158/1538-7445.AM2011-1289

PK/PD modeling of QTC duration for vardenafil & sildenafil in healthy volunteers

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.