Pharmacokinetics (PK) of Voriconazole (V) in Lung Transplant Patients (LTP)

B. CAPITANO 1,2, B. A. POTOSKI 1,2, S. HUSAIN 1,2, S. GILBERT 1, D. L. PATERSON 1,2, K. R. MCCURRY 1,2, R. VENKATARAMANAN 2

Author address: 

1 Univ. of Pittsburgh Med. Ctr., Pittsburgh, PA, 2 Univ. of Pittsburgh, Pittsburgh, PA.

Abstract: 

Background: A fixed dose of V is used to prevent aspergillosis in LTP at our institution (6 mg/kg IV q 12h x 2 followed by 200 mg oral twice daily). A large degree of variability in exposure is expected due to the non-linear PK of V, the concomitant use of many drugs and physiological changes in LTP. An association of plasma concentration with efficacy against aspergillosis (> 0.250 μg/ml) and hepatotoxicity (> 5-6 μg/ml) has been suggested. The PK of V achieved with the fixed dose regimen was characterized to quantify total drug exposure in LTP. Methods: Plasma time-concentration profiles were studied over 12h in 5 LTP following the 2nd IV dosing and after a minimum of six oral doses. The half-life (t½), clearance (Cl), area under the curve (AUC0 - 8734;), peak (Cmax) and trough (Cmin,) concentrations were determined using non-compartmental methods. Results: The mean (SD) PK parameters after the IV dose were: t½ 15(6) h, Cmax 6(3) μg/ml, Cmin 2(0.5) μg/ml AUC0 - 8734; 63(33) μg·h/ml and CL 1.8 (0.7) ml/kg/min,. The concentration vs. time profile after oral dosing was essentially flat in 3 LTP, presumably indicating slow dissolution and continuous absorption of V over the dosing interval. The observed Cmax and Cmin ranged from 0.75 to 9.5μg/ml and 0.7 to 7 μg/ml, respectively. The mean (SD) AUC 0-12 hr ss was 42(33) μg·h/ml; range of 9 to 97 μg·h/ml. Conclusions: The PK of V in LTP differed from that previously reported in normal subjects and other populations. A large degree of intrapatient variability between IV and oral PK was noted in all LTP. After identical oral dosing, a ≥ 10 fold interpatient variability in C max, Cmin, and AUCss is suggestive of erratic absorption. The total drug exposure associated with the oral maintenance dose in LTR was twice that reported in healthy volunteers and other patients (mean AUC0-964; of 42 vs 20 μg·h/ml, respectively). These data suggest that the current regimen leads to unpredictable V exposure placing LTP at risk for toxicity.
2004

abstract No: 

A-39-2004

Full conference title: 

44th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 44th