Jean-Eric Charoin(1), Philippe Jacqmin(2), Ludger Banken(3), Sian Lennon(4) and Karin Jorga(1)
(1) Clinical Pharmacology, F. Hoffmann-La Roche, Basel; (2) Exprimo Consulting LLP ; (3) Biostatistics, F. Hoffmann-La Roche, Basel; (4) Clinical Pharmacology, F. Hoffmann-La Roche, Welwyn
Objective: To investigate trastuzumab pharmacokinetics and to assess the effect of covariates after long term trastuzumab administration using two different dosing regimens in patients (once weekly and every three weeks).
Material and Methods: Four Phase II/III studies, two with once weekly (loading dose of 4 mg/kg, maintenance dose of 2 mg/kg) and two with every three weeks (loading dose of 8 mg/kg, maintenance dose of 6 mg/kg) administration, were included in the database. In these studies, trough and full concentration-time profiles were collected. In total, 194 patients contributed to 2508 trastuzumab concentrations. A population pharmacokinetic analysis was conducted and individual Empirical Bayesian estimates of trastuzumab clearance, volume and distribution rate constants were estimated. The influence of demographic and clinical characteristics on clearance (CL) and central volume (Vc) were examined using the forwards selection and backwards deletion. For population pharmacokinetic analysis, NONMEM (version V) was used. Simulations were performed with Pharsight Trial Simulator (version 2.1.2). A bootstrap resampling technique (dataset replicated 800 times) was used to estimate confidence interval for the parameters.
Results: A two compartment linear PK model best described the data. Basic population PK parameters were: CL of 0.226 L/day (90% CI was 0.212-0.242), Vc of 3.17 L (90% CI was 3.05-3.32).
Trastuzumab CL increased significantly in patients with higher body weight. The drug regimen had no significant effect on trastuzumab CL and Vc. Based on individual post-hoc estimates, the median steady state AUCs over a period of 3 weeks were 1677 and 1793 mg*day/L, for once weekly and every three weeks regimens, respectively.
Discussion and Conclusion: PK parameter estimates were similar to the ones obtained in a previous population PK analysis performed by Genentech [1]. There was no effect of dosing regimen on trastuzumab PK parameters. The half-life of equilibrium was 26.3 days, which might be the basis for an every three weeks regimen. Trastuzumab CL depended on body weight, which is consistent with the medical practice to adjust the dose on body weight.
Reference:
[1] Washington C.B., Lieberman G., Liu P., Fox J.A., Bruno R. A population pharmacokinetic model for trastuzumab following weekly dosing. Clin. Pharmacol. Ther., 71(2), P12 (abstract MPI-30), 2002.
Reference: PAGE 13 () Abstr 489 [www.page-meeting.org/?abstract=489]
Poster: poster