采用基于铂浓度-时间曲线下目标面积和个体肾小球滤过率的给药策略对患有肿瘤的猫进行卡铂的I期评估。

Phase I evaluation of carboplatin by use of a dosing strategy based on a targeted area under the platinum concentration-versus-time curve and individual glomerular filtration rate in cats with tumors.

作者信息

Bailey Dennis B, Rassnick Kenneth M, Dykes Nathan L, Pendyala Lakshmi

机构信息

Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.

出版信息

Am J Vet Res. 2009 Jun;70(6):770-6. doi: 10.2460/ajvr.70.6.770.

DOI:10.2460/ajvr.70.6.770

PMID:19496668

Abstract

OBJECTIVE

To determine whether a carboplatin dose calculation that is based on a targeted area under the concentration-versus-time curve (AUC(Target)) and individual glomerular filtration rate (GFR) accurately predicts carboplatin-associated myelotoxicoses in tumor-bearing cats, and to determine the maximum tolerated AUC(Target).

ANIMALS

32 cats with tumors.

PROCEDURES

In each cat, plasma clearance of technetium Tc 99m-labeled diethylenetriaminepentaacetic acid was measured to assess GFR. Carboplatin was administered IV. The dose was calculated by use of an equation as follows: Dose = AUC(Target) x 2.6 x GFR x body weight. Initial AUC(Target) was 2.0 min.mg.mL(-1) and was increased in increments of 0.50 min.mg.mL(-1) in cohorts of 3 cats. To assess myelotoxic effects, CBCs were performed weekly for > or = 4 weeks. Following identification of the maximum tolerated AUC(Target), additional cats were treated at that AUC(Target) and plasma platinum concentrations were measured in 6 cats.

RESULTS

The AUC(Target) values ranged from 2.0 to 3.0 min.mg.mL(-1). Neutropenia was the dose-limiting toxicosis, and the maximum tolerated AUC(Target) was 2.75 min.mg.mL(-1). Nineteen cats received this dose of carboplatin; 13 became neutropenic, but only 1 developed severe neutropenia (< 500 neutrophils/microL), and none had neutropenia-associated clinical signs. In the cats that had plasma platinum concentration determined, the difference between AUC(Target) and the measured value ranged from -0.23 to 0.31 min.mg.mL(-1) (median, 0.20 min.mg.mL(-1)).

CONCLUSIONS AND CLINICAL RELEVANCE

In cats, carboplatin-associated myelotoxicoses were accurately and uniformly predicted by use of the proposed dosing strategy. The maximum tolerated AUC(Target) for a single dose of carboplatin was 2.75 min.mg.mL(-1).

摘要

目的

确定基于目标浓度-时间曲线下面积（AUC(Target)）和个体肾小球滤过率（GFR）的卡铂剂量计算方法能否准确预测荷瘤猫的卡铂相关骨髓毒性，并确定最大耐受AUC(Target)。

动物

32只患有肿瘤的猫。

步骤

每只猫均测量99m锝标记的二乙三胺五乙酸的血浆清除率以评估GFR。静脉注射卡铂。剂量通过以下公式计算：剂量 = AUC(Target)×2.6×GFR×体重。初始AUC(Target)为2.0 min·mg·mL⁻¹，在每组3只猫的队列中以0.50 min·mg·mL⁻¹的增量增加。为评估骨髓毒性作用，每周进行全血细胞计数，持续≥4周。确定最大耐受AUC(Target)后，对另外的猫以该AUC(Target)进行治疗，并在6只猫中测量血浆铂浓度。

结果

AUC(Target)值范围为2.0至3.0 min·mg·mL⁻¹。中性粒细胞减少是剂量限制性毒性，最大耐受AUC(Target)为2.75 min·mg·mL⁻¹。19只猫接受了该剂量的卡铂；13只出现中性粒细胞减少，但只有1只出现严重中性粒细胞减少（<500个中性粒细胞/微升），且无一出现与中性粒细胞减少相关的临床症状。在测定血浆铂浓度的猫中，AUC(Target)与测量值之间的差异范围为-0.23至0.31 min·mg·mL⁻¹（中位数为0.20 min·mg·mL⁻¹）。