title: Platinum pharmacokinetics in mice following inhalation of cisplatin dry powders with different release and lung retention properties.
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 F1Bto F4B) able to reproducibly deliver particles in vivo using a DP-4M Dry Powder Insufflator™. Their platinum pharmacokinetics were established over 48h in lungs, total blood and non-target organs vs. IV and endotracheal nebulization (EN). EN and F1Bwere rapidly distributed from the lungs (t1/2i2.6 and 5.0min). F2Bwas eliminated in ∼1h (t1/2i9.0min). F3Blung retention was sustained for ∼7h (t1/2i59.9min), increasing lung AUC 11-, 4- and 3-fold vs. IV, F1Band F2B. Total blood tmaxwere higher and AUC and Cmaxlower using the pulmonary route vs. IV. Kidney Cmaxwas reduced 6-, 2- and 3-fold for F1B, F2Band F3B. AUC in kidneys were 2- to 3-fold lower for F1Band F2Bvs. 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.
authors.affiliation: Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Bd. du Triomphe CP 207, Campus de la Plaine, 1050 Brussels, Belgium. Electronic address: vincent.levet@ulb.ac.be.
authors.forename: Vincent
authors.initials: V
authors.lastname: Levet
authors.affiliation: Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Bd. du Triomphe CP 207, Campus de la Plaine, 1050 Brussels, Belgium.
authors.forename: Romain
authors.initials: R
authors.lastname: Merlos
authors.affiliation: Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Bd. du Triomphe CP 207, Campus de la Plaine, 1050 Brussels, Belgium.
authors.forename: Rémi
authors.initials: R
authors.lastname: Rosière
authors.affiliation: Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Bd. du Triomphe CP 207, Campus de la Plaine, 1050 Brussels, Belgium.
authors.forename: Karim
authors.initials: K
authors.lastname: Amighi
authors.affiliation: Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université libre de Bruxelles (ULB), Bd. du Triomphe CP 207, Campus de la Plaine, 1050 Brussels, Belgium. Electronic address: nawautho@ulb.ac.be.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Wauthoz
mesh_terms: D000280:Administration, Inhalation; D061605:Administration, Intravenous; D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage / Q000737:chemistry; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics; D065546:Drug Liberation; D058995:Dry Powder Inhalers; D005260:Female; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D051379:Mice; D010316:Particle Size; D010984:Platinum / Q000097:blood / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000737:chemistry; D011208:Powders / Q000008:administration & dosage / Q000737:chemistry*; D012212:Rheology
chemical_list: D003692:Delayed-Action Preparations; D011208:Powders; D011092:Polyethylene Glycols; D010984:Platinum; D002945:Cisplatin
keywords: Alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS, PubChem CID:71406); Cisplatin; Cisplatin (PubChem CID:441203); Controlled release; Distearoyl phosphoethanolamine polyethylene glycol 2000, sodium salt (DSPE-mPEG-2000, PubChem CID:86278270); Dry powder for inhalation; Lung cancer chemotherapy; Lung retention; Solid lipid microparticles; Stealth formulation; d-mannitol (PubChem CID: 6251), tristearin (TS, PubChem CID:11146); l-leucine (PubChem CID: 6106)