Hyeong-Seok Lim1, Kyun-Seop Bae1, Jin-ah Jung2, Yook-Hwan Noh1, Ae-Kyung Hwang1, Yeong-Woo Jo3, Yong Sang Hong4, KyuPyo Kim4, Jae-Lyun Lee4, Seong Joon Park4, Jeong Eun Kim4, Yoon-Koo Kang4, Tae Won Kim5. 1. Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Ulsan University College of Medicine, Ulsan, Republic of Korea. 2. Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea. 3. Department of Product Planning and Development, Daehwa Pharmaceutical Co Ltd, Gangwon-do, Republic of Korea. 4. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 5. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: twkimmd@amc.seoul.kr.
Abstract
PURPOSE: 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. FINDINGS: 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. IMPLICATIONS: 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.
PURPOSE: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. FINDINGS: 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. IMPLICATIONS: 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: Maarten van Eijk; Huixin Yu; Emilia Sawicki; Vincent A de Weger; Bastiaan Nuijen; Thomas P C Dorlo; Jos H Beijnen; Alwin D R Huitema Journal: Cancer Chemother Pharmacol Date: 2022-07-07 Impact factor: 3.288