Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

International audienceBACKGROUND: HuHMFG1 (AS1402) is a humanised monoclonal antibody that has undergone a phase I trial in metastatic breast cancer. The aim of this study was to characterise the pharmacokinetics (PKs) of HuHMFG1 using a population PK model. METHOD: Data were derived from a phase I study of 26 patients receiving HuHMFG1 at doses ranging from 1 to 16 mg kg(-1). Data were analysed using NONMEM software and covariates were included. A limited sampling strategy (LSS) was developed using training and a validation data set. RESULTS: A linear two-compartment model was shown to be adequate to describe data. Covariate analysis indicated that weight was not related to clearance. An LSS was successfully developed on the basis of the model, in which one sample is collected immediately before the start of an infusion and the second is taken at the end of infusion. CONCLUSION: A two-compartment population PK model successfully describes HuHMFG1 behaviour. The model suggests using a fixed dose of HuHMFG1, which would simplify dosing. The model could be used to optimise dose level and dosing schedule if more data on the correlation between exposure and efficacy become available from future studies. The derived LSS could optimise further PK assessment of this antibody

Comparative pharmacokinetics of rVIII-SingleChain and octocog alfa (Advate^®) in patients with severe haemophilia A

rVIII-SingleChain, a novel recombinant factor VIII (rFVIII), has been designed as a B-domain truncated construct with covalently bonded heavy and light chains, aiming to increase binding affinity to von Willebrand factor (VWF). Preclinical studies confirmed greater affinity for VWF, giving improved pharmacokinetic and pharmacodynamic properties compared with full-length rFVIII. To investigate the pharmacokinetics of rVIII-SingleChain and compare them against those of full-length rFVIII. This study enrolled 27 patients with severe haemophilia A in the AFFINITY clinical trial programme. After a 4-day washout period, all patients received a single infusion of 50 IU kg(-1) octocog alfa (Advate(®) ); after a ≥4-day postinfusion washout period, they received a single infusion of 50 IU kg(-1) rVIII-SingleChain. Blood samples for pharmacokinetic assessments of each product were collected before infusion (predose) and at 0.5, 1, 4, 8, 10, 24, 32, 48 and 72 h postinfusion for both products. rVIII-SingleChain had a longer mean half-life (t1/2 ) (14.5 vs. 13.3 h), lower mean clearance (CL) (2.64 vs. 3.68 mL h(-1) kg(-1) ), higher mean residence time (20.4 vs. 17.1 h) and larger mean AUCinf (2090 vs. 1550 IU?h dL(-1) ) than octocog alfa, respectively. The mean AUCinf after rVIII-SingleChain infusion was ~35% larger than after octocog alfa. A similar pattern was observed for AUC0-last . No serious adverse events or inhibitors were reported. rVIII-SingleChain has a favourable pharmacokinetic profile compared with octocog alfa and was well tolerated. The prolonged t1/2 , larger AUC and reduced CL of rVIII-SingleChain may permit longer dosing intervals, thereby improving patient adherence to prophylactic treatment