化合物信息

Drug Groups

approved; investigational

Description

Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients.

Indication

For prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised as a result of procedures such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or due to hematologic malignancies with prolonged neutropenia from chemotherapy. Also for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole. Posaconazole is used as an alternative treatment for invasive aspergillosis, Fusarium infections, and zygomycosis in patients who are intolerant of, or whose disease is refractory to, other antifungals.

Pharmacology

Posaconazole is an antifungal agent structurally related to itraconazole. It is a drug derived from itraconzaole through the replacement of the chlorine substituents with flourine in the phenyl ring, as well as hydroxylation of the triazolone side chain. These modifications enhance the potency and spectrum of activity of the drug. Posaconazole can be either fungicial or fungistatic in action.

Toxicity

During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days. No related adverse events were noted by the investigator.

Affected Organisms

Biotransformation

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.

Absorption

Posaconazole is absorbed with a median Tmax of approximately 3 to 5 hours.

Half Life

Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours).

Protein Binding

Posaconazole is highly protein bound (>98%), predominantly to albumin.

Elimination

The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.

Distribution

* 1774 L

Clearance

* 32 L/hr
* 51 L/hr [Single-Dose Suspension Administration of 200 mg, fasted]
* 21 L/hr [Single-Dose Suspension Administration of 200 mg, nonfat meal]
* 14 L/hr [Single-Dose Suspension Administration of 200 mg, high fat meal]
* 91 L/hr [Single-Dose Suspension Administration of 400 mg, fasted]
* 43 L/hr [Single-Dose Suspension Administration of 400 mg with liquid nutritional supplement (14 g fat)]

References

External Links