Distribution: Posaconazole has a mean (CV%) volume of distribution of 287 L (24%) in healthy volunteers. Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.

Metabolism: Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.
 
Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically, which affect posaconazole concentrations, is provided in Table 15.
 
Table 15: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers

Coadministered Drug (Postulated Mechanism of Interaction)
 
Coadministered Drug Dose/Schedule
 
Posaconazole Dose/Schedule
 
Effect on Bioavailability of Posaconazole
 
 
Change in Mean
Cmax
(ratio estimate*; 90% CI of the ratio estimate)
 
Change in Mean AUC
(ratio estimate*; 90% CI of the ratio estimate)

* Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC.† The tablet refers to a non-commercial tablet formulation without polymer. 
 
Efavirenz
(UDP-G Induction) 400 mg QD × 10 and 20 days 400 mg (oral suspension) BID × 10 and 20 days ↓45%
(0.55; 0.47-0.66) ↓ 50%
(0.50; 0.43-0.60)
Fosamprenavir (unknown mechanism) 700 mg BID × 10 days 200 mg QD on the 1st day, 200 mg BID on the 2nd day, then 400 mg BID × 8 Days ↓21%
0.79 (0.71-0.89) ↓23%
0.77 (0.68-0.87)
Rifabutin
(UDP-G Induction) 300 mg QD × 17 days 200 mg (tablets) QD × 10 days† ↓ 43%
(0.57; 0.43-0.75) ↓ 49%
(0.51; 0.37-0.71)
Phenytoin
(UDP-G Induction) 200 mg QD × 10 days 200 mg (tablets) QD × 10 days† ↓ 41%
(0.59; 0.44-0.79) ↓ 50%
(0.50; 0.36-0.71)
 
In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 16 [see Contraindications (4) and Drug Interactions (7.1) inc