Pharmacokinetic–pharmacodynamic modelling of the hypoglycaemic effect of pulsatile administration of human insulin in rats

The relationship between the plasma insulin (INS) concentration–time course and plasma glucose concentration–time course during and after pulsatile INS administration to rats was characterized using a pharmacokinetic–pharmacodynamic (PK–PD) model. A total INS dose of 0.5 IU/kg was intravenously injected in 2 to 20 pulses over a 2-h period. Compared with the single bolus administration, the area under the effect-time curve (AUE) increased depending on the number of pulses, and the AUEs for more than four pulses plateaued at a significantly larger value, which was similar to that after the infusion of a total of 0.5 IU/kg of INS over 2 h. No increase in plasma INS concentration occurred after pulsatile administration. Two indirect response models primarily reflecting the receptor-binding process (IR model) or glucose transporter 4 (GLUT4) translocation (GT model) were applied to describe the PK–PD relationship after single intravenous bolus administration of INS. These models could not explain the observed data after pulsatile administration. However, the IR-GT model, which was a combination of the IR and GT models, successfully explained the effects of pulsatile administration and intravenous infusion. These results indicate that the receptor-binding process and GLUT4 translocation are responsible for the change in AUE after pulsatile administration.

Dovitinib (TKI258): Exploration of pharmacokinetics and pharmacodynamics (PK/PD) for dose and regimen consideration.

2603 Background: Dovitinib is a potent oral inhibitor of Receptor Tyrosine Kinases with activity against FGFR, VEGFR and PDGFR. The objectives of this analysis are to describe the PK/PD of dovitinib to characterize the differences between two different dosing regimens, 400 mg once daily (qd) or 500 mg 5 days on, 2 days off (int) in terms of exposure and biomarker response. Methods: PK/PD data from 127 patients receiving dovitinib, 100-600 mg int and 50 – 600 mg qd were available. Duration of therapy was 15 to 859 days. Plasma concentration-time data + sparse biomarker (BM) data were available after the first dose and at steady state (SS). Data was analyzed using non-linear mixed effects modeling to characterize nonlinearities in PK as well as BM response. VEGF, sVEGFR2 and PDGF were described by indirect response models and FGF23 was described using a mechanism based model to characterize acute drop, rebound, tolerance and increase to a new SS over time. Results: Raw data revealed prolonged absorption, linear clearance after the first dose, but dose dependent ↓ in clearance at SS (leading to over-proportional accumulation), and apparent linear clearance at doses below 400 mg qd. ↓ exposure for doses up to 400 mg at SS compared to 1st dose implied auto-induction. The PK was well described by a 1-compartment (CMT) model with 3 transit CMTs to characterize absorption lag. Auto-induction and over-proportional accumulation at SS were modeled as depending on cumulative exposure through a time-dependent process with half-life of 18 h. In our study, median (10th – 90th percentile) Clearance was 30 (17 – 80) L/h on Day 1, and 96 (51 – 185) L/h at SS. The model predicted 36%↑in VEGF, 18% ↓ in sVEGFR2, 82% and 57% ↑in PDGF and FGF23 respectively at SS, for median exposure at a dose of 400 mg qd. Simulations of PK and biomarker responses were performed for different dosing regiments to assess relative safety and target effects. Conclusions: The PK/PD model suggests 400 mg qd may lead to over-proportional accumulation of dovitinib in <5% of subjects while int dosing minimizes this. 500 mg int may be a more tolerable regimen while maintaining adequate PD response, and is being used in the pivotal phase III study for dovitinib in patients with mRCC.