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. 2017 Oct 5;12(10):e0186018.
doi: 10.1371/journal.pone.0186018. eCollection 2017.

Pharmacokinetics and toxicity of subcutaneous administration of carboplatin in poloxamer 407 in a rodent model pilot study

Marije Risselada  1   2 , Keith E Linder  3 , Emily Griffith  1   4 , Brittney V Roberts  5 , Gigi Davidson  6 , William C Zamboni  5 , Kristen M Messenger  7
Affiliations

Pharmacokinetics and toxicity of subcutaneous administration of carboplatin in poloxamer 407 in a rodent model pilot study

Marije Risselada et al. PLoS One. .

Abstract

The objectives of this study were to assess the pharmacokinetics and safety of subcutaneously delivered carboplatin in poloxamer 407 in rats. Carboplatin (5mg/rat) in 0.5ml poloxamer 407 (1.0 ml total volume) was administered subcutaneously in a right subcutaneous perineal incision in all 12 treatment rats. Three control rats received 1.0 ml of poloxamer 407. Total platinum was measured in plasma q24hrs from 0 to 168hrs. Protein-unbound platinum was measured in plasma at 168hrs. After sacrifice on day 7, total platinum was determined in wound bed muscle. Platinum concentrations in all samples were measured by ICP-MS. Wounds were visually assessed daily for 7 days. Perineal tissues (full wound bed including muscle, subcutis, skin) were assessed histologically and scored. Total platinum was detectable in plasma from 24 to 168 hrs. Total plasma platinum AUC and Cmax were 9,165.3 ng/mL•h and 129.4 ng/mL. Day 7 total platinum concentration in muscle was approximately 10-fold higher than total plasma platinum concentration. No unbound platinum was detected in plasma samples at 168 hours. No wound healing complications were detected at any time point, nor was tissue necrosis observed histologically. The results of this study suggest that subcutaneous carboplatin in poloxamer 407 can be used in vivo providing direct tissue exposure to carboplatin without significant local effects or systemic absorption and without wound healing complications.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Plasma carboplatin time curve.
The concentration versus time curve (mean, standard deviation) of the systemically absorbed carboplatin is given as carboplatinplasma (ng/mL) 7 days. ‘●’ indicates the mean of all treatment groups combined.
Fig 2
Fig 2. Concentration of total Pt in plasma and total Pt in muscle at 168 hrs.
The carboplatin concentration (ng/mL) is plotted on the Y-axis in a logarithmic scale. ‘●’ and ‘▼’ represent the Ptplasma (n = 11)and Ptmuscle (n = 6) of every individual rat, respectively.
Fig 3
Fig 3. Histology of the subcutaneous perineal implantation site.
A Shows a photomicrograph of the subcutaneous perineal surgical implantation site of rat from the CP cohort. Minimal necrosis of adipose (score = 1) (arrow) is present adjacent to the implantation site (asterisk). B Shows a photomicrograph of the subcutaneous perineal surgical implantation site of a rat from the CP-μD cohort. Minimal fibrosis (score = 1) (arrows) is present adjacent to the implantation site (asterisk) after receiving carboplatin and poloxamer 407 gel and a μD catheter (C) at the site.
See this image and copyright information in PMC

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