title: A pharmacokinetic analysis of posaconazole oral suspension in the serum and alveolar compartment of lung transplant recipients.
abstract: Invasive fungal infections cause significant morbidity and mortality after lung transplantation. Fungal prophylaxis following lung transplantation is not standardised, with transplant centres utilising a variety of regimens. Posaconazole is a broad-spectrum antifungal triazole that requires further investigation within the setting of lung transplantation. This prospective, single-centre, observational study explored the pharmacokinetics of posaconazole oral suspension (POS) in the early perioperative period following lung transplantation in 26 patients. Organ recipients were scheduled to receive 400mg POS twice daily for 6 weeks as primary antifungal prophylaxis. Therapeutic drug monitoring (TDM) of serum posaconazole levels was performed in accordance with local clinical protocols. Bronchoalveolar lavage fluid (BALF) was sampled during routine bronchoscopies. Posaconazole levels were measured both in serum and BALF using mass spectrometry. Posaconazole levels were highly variable within lung transplant recipients during the perioperative period and did not achieve 'steady-state'. Serum posaconazole concentrations positively correlated with levels within the BALF (r=0.5527; P=0.0105). Of the 26 patients, 10 failed to complete the study for multiple reasons and so the trial was terminated early. Unlike study findings in stable recipients, serum posaconazole levels rarely achieved steady-state in the perioperative period; however, they do reflect the concentrations within the airways of newly transplanted lungs. The role of POS as primary prophylaxis in the perioperative period is uncertain, but if used TDM may be helpful for determining attainment of therapeutic levels.
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK. Electronic address: louit@doctors.net.uk.
authors.forename: L
authors.initials: L
authors.lastname: Thakuria
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: K
authors.initials: K
authors.lastname: Packwood
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Firouzi
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: P
authors.initials: P
authors.lastname: Rogers
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: S
authors.initials: S
authors.lastname: Soresi
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: K
authors.initials: K
authors.lastname: Habibi-Parker
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: H
authors.initials: H
authors.lastname: Lyster
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: B
authors.initials: B
authors.lastname: Zych
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: D
authors.initials: D
authors.lastname: Garcia-Saez
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: P
authors.initials: P
authors.lastname: Mohite
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: N
authors.initials: N
authors.lastname: Patil
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Sabashnikov
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: M
authors.initials: M
authors.lastname: Capoccia
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: M
authors.initials: M
authors.lastname: Chibvuri
authors.affiliation: MSD Ltd., Hertford Road, Hoddesdon, Herts EN11 9BU, UK.
authors.forename: H
authors.initials: H
authors.lastname: Lamba
authors.affiliation: New House Farm, Purton End, Debden, Saffron Walden, Essex CB11 3JT, UK.
authors.forename: H
authors.initials: H
authors.lastname: Tate
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: M
authors.initials: M
authors.lastname: Carby
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Simon
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: N
authors.initials: N
authors.lastname: Leaver
authors.affiliation: Department of Transplantation, Harefield Hospital, Harefield UB9 6JH, UK.
authors.forename: A
authors.initials: A
authors.lastname: Reed
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D018890:Chemoprevention / Q000379:methods; D005260:Female; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D011446:Prospective Studies; D044967:Serum / Q000737:chemistry*; D013535:Suspensions / Q000008:administration & dosage*; D066027:Transplant Recipients; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D013535:Suspensions; D014230:Triazoles; C101425:posaconazole
keywords: Fungal prophylaxis; Lung transplantation; Pharmacokinetics; Posaconazole oral suspension; Therapeutic drug monitoring