Samira Garonzik1,2, Jerry Nedelman1, Eugene Tan1, Ovidiu Chiparus1 and Margaret Dugan1.
Novartis Pharmaceuticals, University at Buffalo
Objectives: Dovitinib is a potent oral inhibitor of Receptor Tyrosine Kinases (FGFR, VEGFR, PDGFR). It is expected to be effective in patients with tumors with FGF-activated pathways (mutation, amplification or overexpression), especially since FGF is considered a mechanism of resistance to anti-VEGF therapies. The objectives of this analysis were to improve upon an existing PK model [1], and to develop a PD model to describe the response of FGF23 to both dovitinib and VEGF, considered a marker of hypoxia. Inhibition of FGFR has been shown to cause acute FGF23 mRNA decrease, causing serum levels to drop, followed by rebound upon discontinuation of blockade.[2] Continued blockade of angiogenesis leads to increased FGF signaling.[3]
Methods: PK/PD data from 127 patients receiving dovitinib, 50 – 600 mg daily or intermittently over 15 – 859 days was available. Plasma concentration-time data + sparse biomarker (BM) data was available after the first dose and at steady state (SS). Data was modeled to characterize nonlinearities in PK as well as FGF23 response.
Results: Prolonged absorption, linear clearance after the first dose, but dose dependent decrease in clearance beyond day 7 at doses > 400 mg qd (leading to over-proportional accumulation)was observed in the data. The earlier PK model modeled the accumulation as a Michaelis Menten process, implying the greatest potential for accumulation was after the first dose rather than after auto-induction had set in. In the current model, two parallel clearance terms allow for either auto-induction or accumulation to manifest. Both processes depend on cumulative exposure through a single time dependent process. Transit compartments were used to describe absorption lag. Median (10th – 90th percentile) total clearance was 30 (17 – 80) L/h on Day 1, and 96 (51 – 185) L/h at SS. A PD model for FGF23 used a precursor dependent indirect response model to characterize the acute drop and rebound/tolerance. The observed increase of FGF23 levels to a new steady state was modeled as a feedback response to increased VEGF in the system. The model predicted 36% and 57% increase in VEGF and FGF23 respectively at SS, for median exposure at a dose of 400 mg daily. Simulations of PK and BM responses with different dosing regimens quantified relative safety and target effects.
Conclusions: PK/PD model developed described data well. Simulations suggest intermittent dosing may be preferred to minimize over-proportional accumulation.
References:
[1] Wang X, Kay A, Anak O, Angevin E, Escudier B, Zhou W, Feng Y, Dugan M, Schran H. Population Pharmacokinetic/Pharmacodynamic Modeling to Assist Dosing Schedule Selection for Dovitinib. J Clin Pharmacol. 2012 Jan 27. [Epub ahead of print].
[2] Wöhrle S, Bonny O, Beluch N, Gaulis S, Stamm C, Scheibler M, Müller M, Kinzel B, Thuery A, Brueggen J, Hynes NE, Sellers WR, Hofmann F, Graus-Porta D. FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF-23 signaling and regulating FGF-23 expression in bone.J Bone Miner Res. 2011 Oct;26(10):2486-97.
[3] Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008 Jun 15;68(12):4774-82.
Reference: PAGE 21 (2012) Abstr 2462 [www.page-meeting.org/?abstract=2462]
Poster: Other Drug/Disease Modelling