inactive ingredients: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificial cherry flavor, and purified water.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].
12.2 Pharmacodynamics
Exposure Response Relationship: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), a wide range of plasma exposures to posaconazole was noted. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cav) and prophylactic efficacy (Table 8). A lower Cav may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.
Table 8: Noxafil Oral Suspension Exposure Analysis (Cav) in Prophylaxis Trials
Prophylaxis in AML/MDS*
Prophylaxis in GVHD†
Cav Range (ng/mL)
Treatment Failure‡ (%)
Cav Range (ng/mL)
Treatment Failure‡ (%)
Cav = the average posaconazole concentration when measured at steady state
* Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS† HSCT recipients with GVHD‡ Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections
Quartile 1 90-322 54.7 22-557 44.4
Quartile 2 322-490 37.0 557-915 20.6
Quartile 3 490-734 46.8 915-1563 17.5
Quartile 4 734-2200 27.8 1563-3650 17.5
12.3 Pharmacokinetics
General Pharmacokinetic Characteristics
Noxafil delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of Noxafil delayed-release tablets 300 mg twice daily (BID) on Day 1, then 300 mg once daily (QD) thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 9.
Table 9: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)*
N
AUC0-24 hr
(ng∙hr/mL)
Cav†
(ng/mL)
Cmax
(ng/mL)
Cmin
(ng/mL)
Tmax‡(h)
t1/2
(h)
CL/F
(L/h)
CV = coefficient of variation expressed as a percentage (%CV); AUC0-T = Area under the plasma concentration-time curve from time zero to 24 hr; Cmax = maximum observed concentration; Cmin = minimum observed plasma concentration; Tmax = time of maximum observed concentration; t½ = terminal phase half-life; CL /F = Apparent total body clearance
* 300 mg BID on Day 1, then 300 mg QD the |
