Estelle Watson (1), Akash Khandelwal (1), Ronald Rosenburg (2) and Roberta Bursi (1)
(1) Pharmacometrics – Global Biometrics, Grünenthal GmbH, Aachen, Germany. (2) Global Clinical Development Strategy, Grünenthal GmbH, Aachen, Germany
Objectives: The aim of this study was to characterise the pharmacokinetics (PK) of Compound X in healthy subjects and subjects receiving Compound X following surgery, following single and multiple intravenous infusions (i.v.).
Methods: A population PK (Pop PK) model was developed using NONMEM (ICON plc v7.2) to characterise the time course of Compound X serum concentrations and its between-subject variability (BSV) derived from i.v. data, obtained from 9 clinical studies (5 healthy volunteer and 2 surgery patient studies) and in total comprised of 370 subjects from which 5764 serum samples were taken. The doses tested ranged from 1 to 80 mg. The stepwise covariate modelling (SCM) module in PsN was used to run the covariate analysis with an inclusion criteria of p <0.05 and a backward exclusion criteria of p<0.01. In total 13 continuous and 3 categorical demographic and physiological covariates were tested. All 16 were tested on clearance (CL) and 4 on the central volume of distribution (Vd). Additionally the LASSO method was also used and compared with the SCM. Validations were performed on the base and final covariate models using goodness of fit, drop in objective function value (OFV) and visual prediction criteria (VPC).
Results: The PK of Compound X following i.v. administration was adequately described using a two compartment model with first order elimination, combined residual error model and a full omega block and was structurally consistent with previously published Pop PK models for oral formulations. Overall the addition of covariates caused minor (<7 %) change in the BSV of Population parameters estimates with eta shrinkage remaining < 15 % in all parameters. In the final model subject status (healthy with short or long infusion or surgery subject) and weight were incorporated in both CL and Vd, while CL additionally incorporated creatinine clearance as covariate.
Conclusions: A Pop PK model was developed using data from i.v. administered Compound X to healthy volunteers and subjects following surgery. The model described adequately the i.v. PK of Compound X. The model will be used in the future to simulate exposures for exposure-adverse event analysis.
Reference: PAGE 24 (2015) Abstr 3584 [www.page-meeting.org/?abstract=3584]
Poster: Methodology - Covariate/Variability Models