PK/PD modeling was used to select doses for further development of siltuximab in multicentric CD. The dosing recommendation was also supported by the observed efficacy dose-response relationship. CRP suppression in the subsequent randomized multicentric CD study was in agreement with the modeling predictions.
Viloxazine extended-release capsules (viloxazine ER, Qelbree™) is a novel non-stimulant, recently approved by the U.S. FDA for the treatment of ADHD in pediatrics. Here, we characterize the pharmacokinetics (PK) of viloxazine and its major metabolite 5-HVLX-gluc using a population PK model, and evaluate the impact of 1-4 days of missed viloxazine ER doses on viloxazine PK. Data from four phase 3 trials in pediatric subjects treated with viloxazine ER were used to establish the PK model. Covariate analysis was conducted on the final base model. The impact of 1-4 days of missed doses on steady-state viloxazine PK was evaluated using Monte Carlo simulations. A onecompartmental linear model with first-order absorption and elimination of the parent drug, and first-order metabolite formation and elimination, properly described the population PK of viloxazine and 5-HVLX-gluc. Body weight impacted the systemic exposure of viloxazine and 5-HVLX-gluc. Predicted PK parameters at steady-state in children receiving viloxazine ER were: C max (µg/mL ± standard deviation) at 100 mg = 1.
The objective of this study was to examine the differences in glucose and insulin responses between African-American and Caucasian youths and to determine the associations of between-group differences with sex, body mass index (BMI) and pubertal status using a noncompartmental pharmacokinetic approach. Sixteen African-American and 22 Caucasian healthy adolescents were tested using the frequently sampled intravenous glucose tolerance test. Longitudinal t-tests across each observation revealed that (1) African-American youths have higher insulin concentrations between 4 to 19 min; (2) insulin levels remained similar as subjects were grouped according to sex and pubertal status; (3) for glucose, the only difference was found as it approached steady-state basal level (>100 min) between groups with different BMIs. Linear regression showed that insulin concentrations between 4 to 19 min are associated with BMI in Caucasians. African-American youths were found to have higher insulin responses after glucose stimulation and the insulin concentrations were more related to BMI in Caucasians compared with African-Americans. BMI also has a significant effect on the glucose steady state basal level. The acute insulin response to glucose (AIR(g)) extended to 20 min resulted in a more significant racial difference (p<0.0006) compared with the calculation done over 10 min suggested in the past (p<0.001).
Objective A mechanistic, physiologically-based pharmacokinetic (PK/PD) model was developed to describe the biphasic insulin release and evaluate the racial effects on the glucose– insulin kinetics in response to intravenous glucose. Methods Fifteen African-American and 18 Caucasian children and adolescents between 8 and 18 years of age were enrolled in the study. Intravenous bolus of glucose (250 mg/kg) was administered and blood samples collected at frequent intervals for three hours following the glucose injection. A nonlinear mixed-effect population kinetic analysis with covariate structure was performed using Monolix. Results A significantly higher initial insulin secretion from a readily releasable pool, which is responsible for the first-phase insulin secretion, was detected in African-Americans compared to Caucasians (p < 0.05). Conclusions The proposed kinetic model is able to describe the glucose-stimulated insulin response, account for the first-phase insulin release and identify a racially-based pharmacokinetic difference in insulin’s biphasic secretion behavior. It is hypothesized that the first-phase insulin component may play an important role in the development of type 2 diabetes. The proposed mechanistic model provides a quantitative analysis of the biphasic insulin release that may be useful in the early detection of diabetes.
1365 Introduction Siltuximab (CNTO 328) is a chimeric, murine-human, monoclonal antibody that specifically binds human interleukin (IL)-6 with high affinity. C-reactive protein (CRP) can be a pharmacodynamic (PD) marker of IL-6 bioactivity, i.e., reductions in CRP suggest inhibition of systemic IL-6. A population mechanistic pharmacokinetic (PK)/PD model was developed to describe the relationship between siltuximab serum concentrations and CRP suppression in patients with B-cell non-Hodgkin's lymphoma (NHL), multiple myeloma (MM), or Castleman's disease (CD). Simulation was used to support the dose selection in the CD registration study and future clinical studies. Methods PK/PD data were obtained from a phase 1 clinical study examining multiple dosing regimens of siltuximab administered intravenously in patients with NHL, MM, or CD. Dosing regimens included siltuximab 2.8, 5.5, or 11 mg/kg every 2 weeks; 11 mg/kg every 3 weeks; or 5.5 mg/kg every week. Serial samples to determine serum concentration of siltuximab and serial CRP samples were collected following the first dose. NONMEM 7 was used to simultaneously fit a two-compartment PK model and an inhibitory indirect-response PD model to the observed data. Simulation of 1000 replications was then used to identify siltuximab dosage regimens that would maintain CRP suppression below the lower limit of quantification (LLOQ) of 1 mg/L. Results The mechanistic PK/PD model was able to describe the serum siltuximab and CRP concentration-time profiles. Volume of distribution and systemic clearance rate constant of siltuximab were estimated at 68.42 mL/kg and 0.0584/day, respectively. The PD parameter estimates (Kin and Kout of CRP) were 5.03 mg/L/day and 0.457/day, respectively, and were similar between the three disease types in this study. IC50was estimated at 9.73 μg/mL and was also similar between disease types. For all disease types, simulations showed that siltuximab 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks after the second dose would reduce serum CRP to below the LLOQ throughout the entire treatment period. However, lower dose intensive schedules, including a dose of 5.5 mg/kg every 2 weeks, would not reduce CRP to below the LLOQ at any time point during the treatment period. Conclusion The population PK/PD modeling and simulation support using a siltuximab dose of 11 mg/kg every 3 weeks or 15 mg/kg every 4 weeks in future clinical development studies. This dosing recommendation is supported by the observed efficacy dose-response relationship in patients with CD (J Clin Oncol 2010;28:3701–8). Disclosures: Xie: Johnson & Johnson: Employment, Equity Ownership. Li:Johnson & Johnson: Employment, Equity Ownership. Kurzrock:Johnson & Johnson: Honoraria, Research Funding. van Rhee:Johnson & Johnson: Research Funding. Qin:Johnson & Johnson: Employment, Equity Ownership. Reddy:Johnson & Johnson: Employment, Equity Ownership. Qi:Johnson & Johnson: Employment, Equity Ownership. Davis:Johnson & Johnson: Employment, Equity Ownership. Zhou:Johnson & Johnson: Employment, Equity Ownership. Puchalski:Johnson & Johnson: Employment, Equity Ownership.
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