The appropriateness of the final model was tested using visual predictive check (VPC)
The appropriateness of the final model was tested using visual predictive check (VPC). total of 120 patients provided evaluable pharmacokinetic data with a total of 2,370 serum concentrations. Sifalimumab serum concentrations were determined using a validated colorimetric enzyme-linked immunosorbent Piragliatin assay (ELISA) with a lower limit of quantitation of 1.25?g/mL. Population pharmacokinetic modeling of sifalimumab was performed using a non-linear mixed effects modeling approach with NONMEM VII software. Impact of patient demographics, clinical indices, and biomarkers on pharmacokinetic parameters were explored using a stepwise forward selection and backward elimination approach. The appropriateness of the final model was tested using visual predictive check (VPC). The impact of body WT-based and fixed dosing of sifalimumab was evaluated using a simulation approach. The final population model was utilized for phase IIb dosing projections. Results Sifalimumab pharmacokinetics were best described using a two-compartment linear model with first order elimination. Following intravenous dosing, the typical clearance (CL) and central volume of distribution (and improved the fit significantly. The mean (% between-subject variability) estimates from the base model were as follows: CL?=?0.2?L/day (35?%); are presented as follows (Eqs.?3C6). for a typical/standard patient COG5 were about 176?mL/day, 2.9?L, 2.12?L and 171?mL/day, respectively. The estimates (coefficient of variation) of between-subject variability associated with CL, were 28, 31, 58, and 71?%, respectively. The -shrinkage was estimated to be 4?% (CL), 12?% ({baseline gene signature from 21 genes, baseline steroid use (0?=?no and 1?=?yes), linear clearance, coefficient of variation, inter-compartmental clearance, relative standard error, central volume of distribution, peripheral volume of distribution, baseline body weight Open in a separate window Fig.?1 Final model goodness-of-fit plots for sifalimumab serum concentrations. The (andhorizontalrepresent line of unity Piragliatin and loess fit, respectively The coefficients of body WT effect on CL (anddashed black linesandbeige shaded areasevery 14?days, body weight Predicted Serum Concentrations for Phase IIb Clinical Trial (MI-CP1067; NCT01283139) The final population pharmacokinetic model was used to predict concentrationCtime profiles following 200, 600, and 1,200?mg monthly (with an additional dose at Day 14) dose of Piragliatin sifalimumab in a simulated SLE population of 1,000 patients. The predicted concentration-time profiles (median, 5th, and 95th percentiles) are shown in Fig.?4. The expected steady state pharmacokinetic exposure values following 200, 600, and 1,200?mg monthly (with an additional dose at Day 14) dose of sifalimumab are presented in Table?3. Open in a separate window Fig.?4 Predicted serum concentrations following 200, 600, and 1,200?mg monthly intravenous dosing of sifalimumab (with single loading dose at Day 14) Table?3 Sifalimumab predicted median steady-state parameters following monthly dosing with an additional loading dose on Day 14 area under the concentration-time curve at steady state, peak concentration at steady state, trough concentration at steady state Discussion To improve the understanding of sifalimumab pharmacokinetics, we developed a population pharmacokinetic model to describe serum concentration-time data following various doses of sifalimumab using a nonlinear mixed-effects modeling approach. A further objective was to identify patient/disease characteristics that influence sifalimumab pharmacokinetic parameters. Systematic understanding of the effect of patient/disease covariates would allow more rational insight on the impact of different covariates on pharmacokinetics and the potential for dose individualization for further development of sifalimumab. The elimination and degradation of mAbs occur primarily via two mechanisms: (a) non-specific protein catabolism by the reticuloendothelial system (RES) and (b) specific binding to the target leading to complex internalization (saturable target-mediated clearance) [33, 34]. It is anticipated that sifalimumab, a mAb that binds to IFN-, a soluble target, will exhibit linear pharmacokinetics [35]. In this population analysis, a two-compartment model without target-mediated elimination adequately described sifalimumab concentration-time data. The estimate of CL was about 176?mL/day for a typical individual, which is similar to the phase I study (MI-CP126) and other mAbs [36C42]. Based on population pharmacokinetic modeling, sifalimumab distributes into a central compartment volume ((71?%), which could be a result of.