title: Pharmacokinetics and pharmacodynamics of melphalan in isolated limb infusion for recurrent localized limb malignancy.
abstract: Isolated limb infusion (ILI) is an attractive, less complex alternative to isolated limb perfusion (ILP). It has a lower morbidity in treating localized recurrences and in transit metastases of the limb for tumours such as melanoma, Merkel cell tumour and Kaposi's sarcoma, allowing administration of high concentrations of cytotoxic agent to the affected limb under hypoxic conditions. Melphalan is the preferred cytotoxic agent for the treatment of melanoma by ILP or ILI. We report pharmacokinetic data from 12 patients treated by ILI for tumours of the limb in Brisbane. The kinetics of drug distribution in the limb was calculated using a two-compartment vascular model, where both tissue and infusate act as well-stirred compartments. Analysis of melphalan concentrations in the perfusate during ILI showed good agreement between the values measured and the concentrations predicted by the model. Recirculation and wash-out flow rates, tissue concentrations and the permeability surface area product (PS) were calculated. Correlations between the PS value and the drug concentrations in the perfusate and tissue were supported by the results. These data contribute to a better understanding of the distribution of melphalan during ILI in the limb, and offer the opportunity to optimize the drug regimen for patients undergoing ILI.
authors.affiliation: Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia. M.Roberts@mailbox.uq.edu.au
authors.forename: M S
authors.initials: MS
authors.lastname: Roberts
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wu
authors.forename: G A
authors.initials: GA
authors.lastname: Siebert
authors.forename: Y G
authors.initials: YG
authors.lastname: Anissimov
authors.forename: J F
authors.initials: JF
authors.lastname: Thompson
authors.forename: B M
authors.initials: BM
authors.lastname: Smithers
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007260:Infusion Pumps; D007866:Leg; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008875:Middle Aged; D008954:Models, Biological; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D012514:Sarcoma, Kaposi / Q000188:drug therapy / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan