Population pharmacokinetics of total and unbound plasma cisplatin in adult patients

Abstract

AimsTo investigate the pharmacokinetics of unbound (ultrafilterable) and total plasma platinum using a population approach and to identify patient characteristics that may influence the disposition of the drug. MethodsPharmacokinetic and demographic data were collected from adult patients treated with 30-min daily infusions of cisplatin for various malignancies. Unbound and total platinum concentration-time data were analysed using a nonlinear mixed effects model. ResultsData from 43 patients were available for analysis. A linear two-compar tment model best described total and unbound platinum plasma concentration-time data. The mean population estimates for total and unbound drug were, respectively, 0.68 and 35.5 l h -1 for clearance and 21.1 and 23.4 l for central distribution volume ( V 1 ). Unbound clearance (CL) was dependent on body surface area (BSA) and creatinine clearance, and V 1 was dependent on BSA. The elimination rate constant for plasmabound platinum (modelled as metabolite formation) was 0.014 h -1 . The pharmacokinetic parameter, f m / V m , a measure of the clearance of unbound platinum due to irreversible plasma binding, was related to serum protein concentration and to the inverse of dose per m 2 . The covariate modelling of CL, V 1 and f m / V m improved the intersubject variabilities associated with these parameters. The final pharmacokinetic models were validated using 200 bootstrap samples from the original datasets. ConclusionsThe results support the conventional dose adjustment of cisplatin based on B SA. They also support the need for a dose reduction in case of renal insufficiency.

Cisplatin-based chronotherapy for advanced non-small cell lung cancer patients: a randomized controlled study and its pharmacokinetics analysis

“…Blood samples were drawn from the arm opposite to the infusion site on the second cycle treatment at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, and 72 h after initiation infusion at the last dose of cisplatin [24].…”

“…But unfortunately, the number of literatures about cisplatin-based chronotherapy for treating NSCLC is quite few. Several conventional pharmacokinetics [10][11][12][13][14] and population pharmacokinetics studies [15][16][17][18][19] have been conducted to assess the pharmacokinetic characteristics of cisplatin in patients. In those studies, the interindividual variability in the pharmacokinetic parameters of cisplatin was found to be relatively large, with a coefficient variation of about 30-70 %.…”

Comparison of the effects of cisplatin and a novel platinum polymer conjugate on the production of reactive oxygen species by human neutrophils in vitro

“…These pro-oxidative interactions of cisplatin with neutrophils were evident at concentrations of about 4 mg Pt/mL and upwards, suggesting that these potentially harmful activities may be operative in the therapeutic setting, although only serum levels up to 2.8 mg cisplatin/mL have been documented [Urien and Lokiec, 2004]. These observations are in agreement with other studies that have described cisplatin-mediated augmentation of the production of ROS by murine macrophages [Sodhi and Gupta, 1986;Greetha et al, 1991] and human neutrophils [Yasuda et al, 2000].…”

Pharmacokinetic analysis of capecitabine and cisplatin in combination with trastuzumab in Japanese patients with advanced HER2-positive gastric cancer

“…(Version 8.1 J,TIBCO Software Inc., CA, USA). Similarly, the PK parameter values for cisplatin were compared with those found in previous publications [19][20][21][22].…”