title: Model-based treatment optimization of a novel VEGFR inhibitor.
abstract: OBJECTIVE
  To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK-PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment.
  
  
  METHODS
  A previously developed PK-PD model for lenvatinib (E7080) was updated and parameters were re-estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de-escalation. Additionally, a within-patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred.
  
  
  RESULTS
  Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day⁻¹. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day⁻¹, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%).
  
  
  CONCLUSIONS
  The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE-guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome.
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, the Netherlands. ron.keizer@farmbio.uu.se
authors.forename: Ron J
authors.initials: RJ
authors.lastname: Keizer
authors.forename: Anubha
authors.initials: A
authors.lastname: Gupta
authors.forename: Robert
authors.initials: R
authors.lastname: Shumaker
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008390:Markov Chains; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011507:Proteinuria / Q000139:chemically induced; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000959:Antihypertensive Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D040262:Receptors, Vascular Endothelial Growth Factor; C531958:lenvatinib