Pharmacokinetics of a single dose of the antifungal posaconazole as oral suspension in subjects with hepatic impairment

Abstract

Objective:

To evaluate posaconazole pharmacokinetics in subjects with different degrees of hepatic impairment compared with matched healthy subjects.

Research design and methods:

A total of 37 subjects were enrolled in this open-label, single-dose, parallel-group study; 19 with hepatic impairment and 18 healthy subjects with matching demographics. Each subject received a single 400-mg oral dose of posaconazole after a high-fat meal. Blood samples for analysis were taken up to 648 h (∼4 weeks) postdose.

Results:

Compared with maximum plasma concentration (C_max) values in matched subjects with normal hepatic function, values were higher among subjects with moderate hepatic impairment (517 vs. 724 ng/mL) but lower among subjects with severe hepatic impairment (608 vs. 403 ng/mL). No clear trend toward increased or decreased exposure was observed with increasingly severe hepatic impairment, and extensive overlap occurred between normal and hepatically impaired subjects. Therefore, pharmacokinetic variables C_max and area under the curve from time 0 to the time of final quantifiable sample (AUC_tf) values were pooled for subjects with hepatic impairment. Pooled C_max values were similar to the pooled normal groups (607 vs. 605 ng/mL), whereas there was an overall 36% increase in exposure (AUC_tf) for the pooled hepatic impairment group compared with the pooled normal group. Posaconazole was well-tolerated, with six (33%) healthy subjects and six (32%) hepatically impaired subjects reporting adverse events.

Conclusions:

The data from this small single-dose study suggest posaconazole is safe. Furthermore, although limited by the small number of subjects enrolled, the authors feel that dose adjustments are probably not necessary in patients with hepatic impairment; however, physicians should continue to monitor posaconazole use in patients with hepatic impairment.

Key words::

• Antifungal agents
• Liver disease
• Pharmacokinetics
• Posaconazole
• Safety

Transparency

Declaration of funding

Funding for this study came from Schering-Plough Research Institute.

Declaration of financial/other relationships

G.K., E.O., P.P., A.M., J.M., and L.M. have disclosed that they are employees of, and own stock in, Schering-Plough. R.A.P. has disclosed that he is a consultant to Schering-Plough and has received a research grant from Wyeth.

Some peer reviewers receive honoraria from CMRO for their review work. The peer reviewers of this paper have disclosed that they have no relevant financial relationships.

Acknowledgment

The authors thank Darshana Malavade, of SPRI, for her technical help with bioanalytic aspects of this study.