Toshiaki Igarashi1, Shinji Kishi2,3, Naoko Hosono3, Takashi Higashi4, Takahiro Iwao5, Ryoichi Yano4,6, Hitoshi Tsukamoto4, Nobuyuki Goto4, Takahiro Yamauchi3, Takanori Ueda3. 1. Department of Pharmacy, University of Fukui Hospital, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Fukui, 910-1193, Japan. igarashi@u-fukui.ac.jp. 2. Department of Health and Nutrition, Faculty of Human Life Studies, Jin-ai University, 3-1-1 Ohde-cho, Echizen, Fukui, 915-8586, Japan. 3. Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Fukui, 910-1193, Japan. 4. Department of Pharmacy, University of Fukui Hospital, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Fukui, 910-1193, Japan. 5. Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan. 6. Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, 4-20-1, Nasahara, Takatsuki, Osaka, 569-1094, Japan.
Abstract
PURPOSE: Vincristine (VCR) is a key drug for treating various malignancies. However, few data are available on the pharmacokinetics of VCR, especially in adult patients. The objective of this study was to clarify the population pharmacokinetics and exposure-response relationships of VCR in adult malignant lymphoma patients. METHODS: Blood samples were collected from patients who were administered R-CHOP-like regimens, and the VCR plasma concentration was determined using liquid chromatography-mass spectrometry. Using NONMEM software, population pharmacokinetic parameters were estimated, and covariates were evaluated. The relationships between the individual parameters and adverse events or therapeutic effects were also investigated. RESULTS: Plasma concentrations were measured in 30 patients. In the final population pharmacokinetics model, body surface area and age were incorporated into clearance as significant covariates. The inter-individual variations in clearance and volume of distribution in the central and third compartments were 17.0, 26.6, and 66.3%, respectively, and the residual variability in the plasma concentration was 23.8%. Although the variability observed in the volume of distribution was large, good predictability was obtained in the individual estimation. The severity of anemia and peripheral neuropathy was correlated with clearance and peak concentration, respectively (adjusted P = 0.040 and 0.024, respectively). In diffuse large B cell lymphoma patients, those with higher area under the curve and dose experienced longer progression-free survival (P = 0.023 and 0.013, respectively). CONCLUSION: The population pharmacokinetics of VCR were evaluated in adult malignant lymphoma patients. VCR pharmacokinetic data could explain in part the adverse events and prognosis of these patients.
PURPOSE:Vincristine (VCR) is a key drug for treating various malignancies. However, few data are available on the pharmacokinetics of VCR, especially in adult patients. The objective of this study was to clarify the population pharmacokinetics and exposure-response relationships of VCR in adult malignant lymphomapatients. METHODS: Blood samples were collected from patients who were administered R-CHOP-like regimens, and the VCR plasma concentration was determined using liquid chromatography-mass spectrometry. Using NONMEM software, population pharmacokinetic parameters were estimated, and covariates were evaluated. The relationships between the individual parameters and adverse events or therapeutic effects were also investigated. RESULTS: Plasma concentrations were measured in 30 patients. In the final population pharmacokinetics model, body surface area and age were incorporated into clearance as significant covariates. The inter-individual variations in clearance and volume of distribution in the central and third compartments were 17.0, 26.6, and 66.3%, respectively, and the residual variability in the plasma concentration was 23.8%. Although the variability observed in the volume of distribution was large, good predictability was obtained in the individual estimation. The severity of anemia and peripheral neuropathy was correlated with clearance and peak concentration, respectively (adjusted P = 0.040 and 0.024, respectively). In diffuse large B cell lymphomapatients, those with higher area under the curve and dose experienced longer progression-free survival (P = 0.023 and 0.013, respectively). CONCLUSION: The population pharmacokinetics of VCR were evaluated in adult malignant lymphomapatients. VCR pharmacokinetic data could explain in part the adverse events and prognosis of these patients.
Entities:
Keywords:
Malignant lymphoma; Pharmacodynamics; Population pharmacokinetics; Vincristine
Authors: Mirjam E van de Velde; Gertjan L Kaspers; Floor C H Abbink; Abraham J Wilhelm; Johannes C F Ket; Marleen H van den Berg Journal: Crit Rev Oncol Hematol Date: 2017-04-06 Impact factor: 6.312
Authors: Jennifer B Dennison; Palaniappan Kulanthaivel; Robert J Barbuch; Jamie L Renbarger; William J Ehlhardt; Stephen D Hall Journal: Drug Metab Dispos Date: 2006-05-05 Impact factor: 3.922
Authors: Jennifer B Dennison; Jamie L Renbarger; David O Walterhouse; David R Jones; Stephen D Hall Journal: Ther Drug Monit Date: 2008-06 Impact factor: 3.681