Gauri G. Rao (1) Neang S. Ly (1) Mohamed A. Kamal (2) Patrick Smith (1, 3) Alan Forrest (1)
(1) University at Buffalo, Buffalo, New York, USA (2) Hoffmann La-Roche, Inc., New York, New York, USA, (3) D3 Medicine, Parsippany, New Jersey, USA
Objectives: Oseltamivir (Tamiflu) is a neuraminidase inhibitor, administered as a phosphate prodrug (OP). The non-toxic and inactive pro-drug, OP is almost completely converted to the active metabolite OC. Our aim was to develop a reduced PK model describing the disposition of OC only, from pediatrics through geriatrics.
Methods: OC plasma concentrations (conc), dosing history and demographic information was pooled from 13 clinical trials for 388 healthy and infected subjects; ages from 1 – 78 yrs and OP doses from 20 – 1,000 mg. Nonlinear mixed-effects modeling was conducted in SADAPT facilitated by SADAPT-TRANS. PK parameters were assumed to be log-normally distributed. Data below the limit of quantification was handled using Beal M3. Model discrimination was done on basis of the objective function and examination of goodness-of-fit plots.
Results: The reduced PK model characterized the OC disposition reasonably well (R2 of 0.970 for individual; 0.799 for POP fitted) compared with a full PK model [1] for OP and OC (R2 of 0.969 for individual; 0.741 for POP fitted). The model was described by a two-compartment (CMT) model with linear clearance. Two transit CMTs accounted for the delay in conversion of OP to OC (transit rate constant, Kt), and OC was absorbed via a first order process (Ka). Residual variability was modeled using the additive plus proportional variance model. Weight, modeled allometrically with a fixed power function (pWt) and CLcr modeled with a fitted power function (pCLcr) , were significant covariates for the apparent OC clearance (CLm/F). The geometric mean (%SE) parameter estimates for OC were Vc/F 19.4L (8.88), Vp/F 190L (4.47), CL/F 15.3L/h (2.31), Kt 0.631h-1(2.54), Ka 1.68 h-1 (8.01), CLd 53.5 (7.04), pWT 0.462(6.64).
Conclusions: The final model described OC PK well and performed as well as the full PK model. This simple model will be useful for PK/PD analysis allowing for better PK/PD parameter estimation with sparser data in future studies.
References:
[1] Kamal et al. Antimicrob. Agents Chemother. 2013, 57(8):3470
Reference: PAGE 23 () Abstr 3048 [www.page-meeting.org/?abstract=3048]
Poster: Drug/Disease modeling - Infection