Platinum pharmacokinetics in mice following inhalation of cisplatin dry powders with different release and lung retention properties

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Abstract

Pharmacokinetics of cisplatin administered by the pulmonary route were established in mice using dry powders inhaler (DPI) formulations showing immediate (F1) and controlled release (CR, solid lipid microparticles) in vitro, without (F2) or with PEGylated excipients (F3, F4). Formulation administration was realized using dry powder blends (correspondingly named thereafter F1B to F4B) able to reproducibly deliver particles in vivo using a DP-4M Dry Powder Insufflator™. Their platinum pharmacokinetics were established over 48 h in lungs, total blood and non-target organs vs. IV and endotracheal nebulization (EN). EN and F1B were rapidly distributed from the lungs (t1/2i 2.6 and 5.0 min). F2B was eliminated in ∼1 h (t1/2i 9.0 min). F3B lung retention was sustained for ∼7 h (t1/2i 59.9 min), increasing lung AUC 11-, 4- and 3-fold vs. IV, F1B and F2B. Total blood tmax were higher and AUC and Cmax lower using the pulmonary route vs. IV. Kidney Cmax was reduced 6-, 2- and 3-fold for F1B, F2B and F3B. AUC in kidneys were 2- to 3-fold lower for F1B and F2B vs. IV but comparable for IV vs. F3B, probably because of kidney saturation. PEGylated solid lipid microparticles provided cisplatin particles with interesting lung retention and CR properties.

Introduction

Cisplatin is one of the most potent anticancer drugs. It is used against various cancers (e.g., lung, bladder, brain, cervical, testicular, ovarian, esophageal, gastric, head and neck, osteosarcoma). Its activity lies in its ability to bind with sulfurs, DNA and proteins, causing cell apoptosis (Jamieson and Lippard, 1999). It is administered against small cell and non-small cell lung cancer (SCLC and NSCLC) as part of the “doublet chemotherapy” (e.g., one platinum derivative agent associated with a non-platinum derivative such as taxanes, gemcitabine or pemetrexed for NSCLC). It is prescribed for delivery every 1 to 3 weeks by intravenous (IV) infusion at doses ranging from 30 to 100 mg/m2 of body surface area (NCCN, 2014, NCCN, 2015). Because of its particularly cumulative and irreversible renal toxicity, which is dose-limiting, nephroprotective action such as large water intakes with mannitol and electrolytes is crucial before and after administration (NHS, 2012). Consequently, administration of cisplatin often requires up to 6 to 8 h and day care hospitalization, mobilizing healthcare personnel and increasing health costs and patient discomfort.

The pulmonary route has proven its usefulness in the treatment of various lung diseases (e.g., asthma, chronic obstructive pulmonary disease, pulmonary infections). Inhaled chemotherapy against lung cancer as a local treatment could be proposed as a novel modality for treating patients (Gagnadoux et al., 2008, Zhou et al., 2015). It could be administered as a (neo)adjuvant treatment to surgery or radiotherapy at all stages in SCLC and NSCLC. This would increase drug concentration at the site of action while limiting systemic exposure and the adverse effects frequently observed through parenteral administration, resulting in a higher therapeutic index (Gagnadoux et al., 2008, Zarogoulidis et al., 2012). It could also increase drug concentration locally, in the tumor and its surroundings, particularly in loco-regional lymph nodes. This would help to prevent micrometastasis, the principal cause of cancer resurgence (Kaifi et al., 2010, Kelsey et al., 2009).

Regarding pulmonary drug delivery, dry powder inhalers (DPIs) provide many advantages over nebulizers. These include large inhalation doses of poorly water-soluble drugs in a short administration time, long-term storage stability of formulations and patient-activated inhaler devices that can easily be disposed of, helping to limit environmental and healthcare personnel contamination (de Boer and Hagedoorn, 2015, Friebel and Steckel, 2010). Once inhaled and deposited in the lungs, drug particles are progressively solubilized in lung fluids at a speed rate depending on many parameters. The dissolved part will be available for pharmacological action locally but will also be distributed into the systemic compartment through the blood in the case of permeable drugs. The undissolved part will be subjected to non-absorptive mechanisms and will be progressively eliminated by mucociliary clearance (MCC) and the macrophage phagocytic system (MPS) (Gill et al., 2011). Moreover, too high doses of chemotherapy could lead to high peak concentrations of solubilized drug in the lungs and cause acute pulmonary toxicity, especially with immediate-release (IR) formulations. These issues could be avoided by careful dosage and progressive increase in drug concentration locally through controlled release (CR) delivery systems designed to promote lung retention and avoid clearance mechanisms, especially the MPS (Loira-Pastoriza et al., 2014). The CR of DPI formulations is a challenge in itself: in order to be inhaled, the aerodynamic diameter (dae) must lie in the low micrometer-range (1–5 μm). This generally necessitates reducing the geometric particle size and can in turn increase the burst effect and dissolution rates. More importantly, avoidance of recognition of particles and ensuing phagocytosis by the MPS through surface modification is an even greater challenge. Most DPI formulations developed up to now have been unsuccessful in controlling the pharmacokinetic (PK) profiles of drugs after lung deposition because of low lung retention (Gill et al., 2011, Loira-Pastoriza et al., 2014). Many strategies have also been developed to try to control drug release from inhaled particles, using delivery systems from the nanometer to the micrometer range. Strategies have used liposomes, solid nanoparticles, micelles and polymeric or lipidic biodegradable microspheres (Loira-Pastoriza et al., 2014). Moreover, PEGylation of the particle surface is a well-known and effective approach to limiting macrophage uptake (Patel et al., 2015) and most PEGylated excipients or particles are recognized as safe for inhalation (Klonne et al., 1989).

DPI formulations were developed in a previous study (Levet et al., 2016) in the form of solid lipid microparticles (SLM) embedding cisplatin microcrystals into a biocompatible matrix. The matrix was composed of a highly hydrophobic triglyceride, tristearin (TS), alone or with PEGylated excipients such as alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) or distearoyl phosphoethanolamine polyethylene glycol 2000 (DSPE-mPEG-2000) to modify the particle surface properties. Interesting results were obtained in vitro (Table 1). The particles exhibited dissolution properties, established on the inhalable fraction of particles only and in simulated lung fluid (Son and McConville, 2009), with a low burst-effect and CR over more than 24 h. They also showed a high drug content (≥ 50% w/w) and high fine particle fraction (FPF, expressed as the fraction of particles from the loaded dose with a dae < 5 μm) of up to 52%, which helped to deposit high doses in the lungs (Levet et al., 2016).

Confirmation of the CR abilities in vivo of the DPI formulations produced is essential. These abilities may vary greatly because particles deposited in the lungs are subjected to many other mechanisms than in vitro. For instance, the remaining undissolved particles will also be subjected to MCC and MPS, increasing their elimination rate from the lung.

Preclinical testing of respiratory drugs is often realized on rodents to assess PK, toxicity and efficacy. However, many precautions are required for their administration. First, when using high drug content DPI formulations initially developed for human use, a proper dilution must be realized to meet acceptable doses in rodents. Second, dose-dependent preclinical studies require administration methods and devices that are reliable to deposit said diluted formulations at accurate and reproducible doses in rodent lungs. The DP-4M Dry Powder Insufflator™ (Penn-Century, Inc., Wyndmoor PA, USA) used in this study is an endotracheal device. This necessitates prior anesthesia of the mouse but has many advantages over the other possible systems (e.g., intratracheal devices, nose-only and full-body aerosols). The DP-4M is able to deliver large, accurate doses of powder in mice lungs, helps to limit aerosol propagation and is easily decontaminable, which is of tremendous interest regarding environmental and personnel contamination when using cytostatic/cytotoxic agents. It was demonstrated to be a viable administration method for dose-dependent preclinical studies in a previous work from our lab (Duret et al., 2012a). Finally, thorough investigation of PK and ADME mechanisms, particularly after local administration at low doses and in small animals, require an adaptable and very sensitive quantification method. This method should be able to assess the fate of the drug and of its metabolites in various tissues and at very low quantification thresholds. This was done here by validated methods using electrothermal atomic absorption spectrometry (ETAAS) of platinum.

The aim of this study was therefore to develop a dry powder blend (DPB) for each of the cisplatin DPI formulations developed previously and to verify their reproducibility of delivery in vitro and in vivo using the DP-4M. This was done to ultimately establish the lung retention abilities of formulations and their relative systemic exposure in mice through a PK and distribution study in lung, blood and non-target tissues after a single dose administration. In the following sections, implications regarding the initial formulation compositions were detailed by citing formulations F1 to F4. All further implications regarding the DPBs obtained from these initial formulations (e.g., physico-chemical characterization, in vitro and in vitro emission abilities, pharmacokinetic results) were cited after their corresponding blend F1B to F4B.

Section snippets

Materials

Cisplatin was purchased from Shanghai Jinhe Bio-technology Co., Ltd. (Shanghai, PRC). TS was purchased from Tokyo Chemical Industry Co. Ltd. (Tokyo, Japan), TPGS from Sigma-Aldrich (St. Louis, USA), DSPE-mPEG-2000 from Lipoid (Ludwigshafen, Germany). Pearlitol® 25C mannitol was donated by Roquette Frères (Lestrem, France). l-leucine, Triton™ X-100 and Suprapur© nitric acid were purchased from Merck Millipore (Darmstadt, Germany). Ultrapure Milli-Q® water was obtained from a Purelab Ultra®

Dry diluent characterization

The DP-4M used for dry powder administration to mice is able to deliver powder masses ranging from 0.5 to 4 mg. Duret et al. (2012a) showed that the ideal filling mass was between 2 and 4 mg to obtain an adequate volume of powder to be aerosolized from the sample chamber. This was visible through the drug dose recovery in the mice lungs, which was maximal (between 54 and 85% w/w) using these filling masses and led to delivered powder masses ranging between 1.0 and 2.5 mg in mice. We previously

Conclusion

Inhaled delivery of cisplatin using DPI is an interesting approach. It helps increase cisplatin exposure in the lungs while potentially decreasing toxicities through lower exposure of non-target organs. Cisplatin, because of its low molecular size is readily absorbed through the lung epithelium. The CR of DPI previously achieved in vitro were confirmed in vivo but for a shorter extent relative to in vitro profile and only through PEGylated-excipient-comprising formulations that permitted the

Funding sources

This research received no specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Aknowledgments

The authors thank J-M. Kauffmann (Laboratory of Instrumental Analysis and Bioelectrochemistry of the Faculty of Pharmacy, ULB) for providing the ETAAS apparatus. The authors also thank P. Madau and T. Segato (4MAT, ULB) for the technical analysis using SEM and XRPD, respectively.

References (41)

  • T. Sou et al.

    Investigating the interactions of amino acid components on a mannitol-based spray-dried powder formulation for pulmonary delivery: a design of experiment approach

    Int. J. Pharm.

    (2011)
  • T. Sou et al.

    The effect of amino acid excipients on morphology and solid-state properties of multi-component spray-dried formulations for pulmonary delivery of biomacromolecules

    Eur. J. Pharm. Biopharm.

    (2013)
  • U. Wattendorf et al.

    PEGylation as a tool for the biomedical engineering of surface modified microparticles

    J. Pharm. Sci.

    (2008)
  • N. Wauthoz et al.

    In vivo assessment of temozolomide local delivery for lung cancer inhalation therapy

    Eur. J. Pharm. Sci.

    (2010)
  • X. Yao et al.

    Cisplatin nephrotoxicity: a review

    Am. J. Med. Sci.

    (2007)
  • Q.T. Zhou et al.

    Inhaled formulations and pulmonary drug delivery systems for respiratory infections

    Adv. Drug Deliv. Rev.

    (2015)
  • A.H. de Boer et al.

    The role of disposable inhalers in pulmonary drug delivery

    Expert Opin. Drug Deliv.

    (2015)
  • R.C. DeConti et al.

    Clinical and pharmacological studies with cis-diamminedichloroplatinum (II)

    Cancer Res.

    (1973)
  • C. Duret et al.

    New respirable and fast dissolving itraconazole dry powder composition for the treatment of invasive pulmonary aspergillosis

    Pharm. Res.

    (2012)
  • FDA

    Guidance for Industry, Bioanalytical Method Validation

    (2013)
  • Cited by (0)

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