Posaconazole Pharmacokinetics among Lung Transplant Recipients with and without Cystic Fibrosis

R. K. Shields, C. J. Clancy, H. Zhang, R. Venkataramanan, M. H. Nguyen;

Author address: 

Univ. of Pittsburgh, Pittsburgh, PA

Abstract: 

Background. 

Posaconazole (POS) is a promising agent for prevention and treatment of invasive fungal infections among lung transplant recipients (LTR), but there are scant pharmacokinetic (PK) data in this population. We previously showed that POS trough levels >0.5 are associated with successful outcomes following LT. We hypothesized that LTR, in particular those with cystic fibrosis (CF), would have difficulty achieving PK targets.

Methods. 

We conducted a prospective study of POS oral suspension PK among LTR with or without CF. Steady-state (SS; after a minimum of 5 days of therapy) blood samples were obtained at 0, 2, 4, 6, 8, and 12 hours after oral administration. POS levels were determined by a validated HPLC with fluorescence detection assay; calibration curves were linear over 0.02 - 3 µg/mL. Maximum, minimum, and average plasma concentrations were calculated (Cmax, Cmin, Cavg). Area under the curve (AUC) was determined from time 0 to 12h. 

Results. 

20 LTR were enrolled (7 with CF). 60% and 85% were men and white, respectively. POS doses ranged from 600 - 1200mg/day. There was no correlation between dose and level. Median age and weight were lower for CF pts (36 yrs and 57 kg) compared to non-CF pts (61 yrs and 78 kg). Mean time to Cmax was 4.7 hours. Only 20% of pts had Cavg levels >0.5 µg/mL. Mean (standard deviation) Cmax (0.4 [±0.3]), Cmin (0.3[±0.2]), Cavg (0.3 [±0.3], and AUC (3.7 [±3.2]) were lower among CF pts than non-CF pts (1 [±0.8], 0.6 [±0.5], 0.7 [±0.6], and 8.6 [±7.4], respectively) (P=0.04, 0.05, 0.03, and 0.03, respectively). Mean oral clearance (L/h/kg) was 18x higher among CF pts (10.6 ± 18) versus non-CF pts (0.6 ± 0.4; P=0.03). After dose normalization, mean POS AUC for CF pts was decreased by 57% compared to non-CF pts (P=0.06). Trough levels were well correlated with AUC (R2=0.95,P<0.0001); however, significant inter-patient variability was observed for both CF and non-CF pts. 

Conclusions.

POS levels are suboptimal among LTR, particularly those with CF. Trough levels are representative of SS AUC and ideal for therapeutic drug monitoring. Given the challenging PK of POS oral suspension in this population, there is a pressing need to study PK of new formulations.

abstract No: 

A-025
    • ICAAC 55th (2015)