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Posaconazole therapeutic drug monitoring in cystic fibrosis lung transplant patients

Abstract number: P1751

Berge M., Guillemain R., Lefeuvre S., Amrein C., Boussaud V., Chevalier P., Dannaoui E., Billaud E.M.

Invasive aspergillosis represents a major complication in lung transplantation (LTx) particularly in case of cystic fibrosis (CF). Posaconazole (PSZ) is indicated for the curative and prophylactic treatment of invasive fungal infections using respectively 400 mgx2/day and 200 mgx3/day doses. PSZ absorption is saturable, therefore dose increase often needed in CF patients is limited. PSZ half life is long (35 h), resulting in long time to steady state (SS).

Objective: To show that PSZ therapeutic drug monitoring (TDM) in CFLTx allows 1. the achievement of trough concentrations (C0) levels consistent with efficiency (>0.5 mg/L) or at least detectable (>0.2 mg/L); 2. the management of PSZ metabolic drug interactions with immunosuppressants.

Methods: Retrospective and prospective cohort of CFLTx under PSZ between 2006 and 2008 in our centre. Longitudinal collection of both doses and C0 (at SS) data for PSZ and immunosuppressants. TDM by determination of plasma PSZ by LC assay with fluorimetric detection.

Results: 17 CFLTx, aged 26±8 years, received curative (n = 2), preemptive (n = 14) or prophylactic (n = 1) PSZ treatment. Caspofungin was combined to PSZ in 8 patients. The mean treatment duration was 228±197 days, [14–621]. PSZ introduction corresponded to immediate (n = 4), first year (n = 5) or beyond (n = 8) post Tx. 220 PSZ C0 were analyzed. No post Tx time effect on PSZ exposure was observed. The mean PSZ C0 was 0.7±0.5 mg/L, [0.2;1.6] using an average PSZ dose of 1084±310 mg/day, [733;1889], resulting in more than +35% of the recommended dose (p < 0001). In 65% of patients, a dose adjustment was required on day 11 as an average. Such adjustment has been successful in 86% of cases. PSZ was withdrawn (n = 8) because of 7 negative cultures and 1 intravenous route (voriconazole + caspofungin). No particular adverse event (gastrointestinal disorders, headache) has been recorded during PSZ courses. The immunosuppressant tacrolimus dose was tapered by a factor 3 during the coprescription with PSZ.

Conclusion: PSZ TDM was useful to achieve PSZ therapeutic C0 in CFLTx. Despite increase and/or split dose, no C0 > 3 mg/L has been observed. PSZ safety profile was good. Indeed, PSZ acted as a moderate CYP3A4 metabolic inhibitor, justifying a joint TDM of both PSZ and immunosuppressants to manage the immunosuppressants dose adjustment at the introduction or discontinuation of PSZ.

Session Details

Date: 16/05/2009
Time: 00:00-00:00
Session name: 19th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Helsinki, Finland, 16 - 19 May 2009
Presentation type:
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