title: Predicting the efficacy of an oral paclitaxel formulation (DHP107) through modeling and simulation.
abstract: OBJECTIVE
  DHP107 is an oral paclitaxel under development. The present study characterized the pharmacokinetic properties of DHP107 and predicted the efficacy in comparison to that of intravenous paclitaxel, using modeling and simulation of data from the early phase of clinical development.
  
  
  METHODS
  In the first-in-human study of the pharmacokinetic characteristics of DHP107 and intravenous paclitaxel, patients received DHP107 60 to 600 mg/m(2), followed by intravenous paclitaxel 175 mg/m(2). Using the pharmacokinetic model of DHP107 from the present analysis and from a previously published pharmacodynamic analysis of the association between paclitaxel concentration and neutropenia, phase I clinical trial for DHP107, with a modified Fibonacci dose escalation scheme, were simulated to predict the maximal tolerated dose (MTD). Additional simulations of paclitaxel concentration over time were conducted to compare the efficacy of DHP107 with that of intravenous paclitaxel, based on time over minimum effective concentration.
  
  
  RESULTS
  In the clinical trial simulation, 480 mg/m(2) was the most frequently predicted MTD of DHP107. In the simulations for efficacy, the times over minimum effective concentration with DHP107 at the predicted MTD were greater than those of intravenous paclitaxel in weekly regimens.
  
  
  CONCLUSIONS
  The findings from this analysis suggest the possibility of efficacy of DHP107 in weekly regimens and provides a scientific rationale for further development. Based on findings from modeling and simulation, DHP107 was predicted to be more efficacious compared with intravenous paclitaxel in weekly regimens, and this finding should be confirmed in further clinical trials.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Ulsan University College of Medicine, Ulsan, Republic of Korea.
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Lim
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Ulsan University College of Medicine, Ulsan, Republic of Korea.
authors.forename: Kyun-Seop
authors.initials: KS
authors.lastname: Bae
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Jin-ah
authors.initials: JA
authors.lastname: Jung
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Ulsan University College of Medicine, Ulsan, Republic of Korea.
authors.forename: Yook-Hwan
authors.initials: YH
authors.lastname: Noh
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Ulsan University College of Medicine, Ulsan, Republic of Korea.
authors.forename: Ae-Kyung
authors.initials: AK
authors.lastname: Hwang
authors.affiliation: Department of Product Planning and Development, Daehwa Pharmaceutical Co Ltd, Gangwon-do, Republic of Korea.
authors.forename: Yeong-Woo
authors.initials: YW
authors.lastname: Jo
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Hong
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: KyuPyo
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae-Lyun
authors.initials: JL
authors.lastname: Lee
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Seong Joon
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoon-Koo
authors.initials: YK
authors.lastname: Kang
authors.affiliation: Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: twkimmd@amc.seoul.kr.
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009010:Monte Carlo Method; D009503:Neutropenia / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel
keywords: Cancer; Clinical Trial Simulation; DHP107; NONMEM; paclitaxel