reafter† Cav = time-averaged concentrations (i.e., AUC0-24 hr/24hr)‡ Median (minimum-maximum)
Healthy Volunteers 12 51618
(25) 2151
(25) 2764
(21) 1785
(29) 4
(3-6) 31
(40) 7.5
(26)
Patients 50 37900
(42) 1580
(42) 2090
(38) 1310
(50) 4 (1.3-8.3) - 9.39
(45)
Dose-proportional increases in plasma exposure (AUC) to posaconazole oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg BID to 400 mg BID in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg BID to 600 mg BID in febrile neutropenic patients or those with refractory invasive fungal infections.
The mean (%CV) [min-max] posaconazole oral suspension average steady-state plasma concentrations (Cav) and steady-state pharmacokinetic parameters in patients following administration of 200 mg TID and 400 mg BID of the oral suspension are provided in Table 10.
Table 10: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole Oral Suspension 200 mg TID and 400 mg BID
Dose*
Cav (ng/mL)
AUC† (ng∙hr/mL)
CL/F (L/hr)
V/F (L)
t½ (hr)
Note: Cav based on observed data; other pharmacokinetic parameters based on estimates from population pharmacokinetic analyses
The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.
* Oral suspension administration† AUC (0-24 hr) for 200 mg TID and AUC (0-12 hr) for 400 mg BID‡ HSCT recipients with GVHD§ Not done¶ Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes# Febrile neutropenic patients or patients with refractory invasive fungal infections, Cav n=24
200 mg TID‡ (n=252) 1103 (67)
[21.5-3650] ND§ ND§ ND§ ND§
200 mg TID¶ (n=215) 583 (65)
[89.7-2200] 15,900 (62)
[4100-56,100] 51.2 (54)
[10.7-146] 2425 (39)
[828-5702] 37.2 (39)
[19.1-148]
400 mg BID# (n=23) 723 (86)
[6.70-2256] 9093 (80)
[1564-26,794] 76.1 (78)
[14.9-256] 3088 (84)
[407-13,140] 31.7 (42)
[12.4-67.3]
Absorption: When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with a median Tmax of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 at the 300 mg dose (QD after BID loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54%. The effect of food intake on the oral bioavailability of posaconazole following administration of posaconazole delayed-release tablets is not known. However, since the oral bioavailability of posaconazole is significantly increased when the oral suspension is administered with food or a nutritional supplement (see below), it is also recommended that posaconazole delayed-release tablets be taken with food.
Concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 11).
Table 11
