Introduction

Posaconacole is fat soluble, synthetic triazole antifungal drug with a chemical structure similar to that of itraconazole.  It has the same mechanism of action as all azoles and prevents the formation of ergosterol necessary for the cell walls of fungi.

The first tests showing the potential antifungal activity of posaconazole were presented in 1995 and the drug was approved for use in humans by the FDA in September 2006.

Dose & Delivery

There is currently only one formulation of posaconazole, an oral solution containing numerous ingredients including polysorbate 80 and cherry flavoured.   The drug is better absorbed if it is taken with food because this increases the absorption through the gut wall. 

The normal posaconazole dose is 400mg twice daily; in patients who are not eating 200mg four times daily is preferable.  In patients taking posaconazole prophylaxis the normal dose is 200mg three times a day.  The concentration of the oral suspension is 40mg /ml so 5ml spoon delivers 200mg. 

Fungi the drug is active against.

Posaconazole has an extremely wide spectrum of action.  The fungi whose growth are inhibited by posaconazole and include Aspergillus, Candida, Coccidioides, Histoplasma, Paracoccidioides, Blastomyces, Cryptococcus, Sporothrix, various species of Mucorales (causing Zygomyetes) and numerous other black moulds such as Bipolaris and Exserohilum.  The majority of Aspergillus isolates are killed by posaconazole at clinically relevant concentrations. Acquired resistance to posaconazole does occur in Aspergillus fumigatus and Candida albicans but is otherwise rare.

Typical regimens

Treatment of aspergillosis or zygomycosis, or other rare infection – 400mg twice daily, or 200mg four times daily if not eating. Monitoring of blood levels of posaconazole shows ~10-fold variation in levels, and low levels are associated with failure. Dose escalation to 400mg three times daily might be helpful, if the reason for low levels is not a drug interaction.

For prophylaxis of fungal infection, a dose of 200mg three times daily is preferred.

For oral candidiasis, 200mg once followed by 100mg twice daily.

Metabolism and excretion

Posaconazole is absorbed over three to five hours.  Increasing doses from 200-800mg daily yield proportional increases in exposure.  It takes 7-10 days to reach steady state levels in blood but most people have sufficient concentrations for activity within two days.  Posaconazole has a very large apparent volume of distribution suggesting extensive tissue uptake.  It is also very highly protein bound (>98%).  Posaconazole is metabolised primarily by the liver into glucuronide conjugates.  The elimination half life is typically 35 hours with most of the drug being excreted in the faeces as unchanged drug.

Drug/Drug interactions

Posaconazole has fewer drug drug interactions than itraconazole and voriconazole.  Its levels fall when posaconazole is co-administered with enzyme reducers such as rifampicin, rifabutin, efavirenz, phenytoin, phenobarbitone, carbomazepine and others.  Posaconacole is less well absorbed when it is given in association with proton pump inhibitors (omeprazole, lansoprazole) or H2 receptor antagonists (Cimetidine, ranitidine etc) or for indigestion, gastric or duodenal ulceration.

Posaconazole is a potent inhibitor of CYP3A4. This means that the blood levels of compounds that are metabolised through this system are likely to rise.  Important examples include cyclosporine, tacrolimus and sirolimus, terfenadine, astemizole, and cisapride, ergotamine for migraine, certain statins including simvastatin, lovastatin and atorvastatin, vincristiine or vinblastiine chemotherapy, midazolam, diazepam and other benzodiazapines and some HIV protease inhibitors.  Other drugs have minor interaction including digoxin and sulphonylurea drugs for diabetes and certain calcium channel blockers such as nifedipine and diltiazem.

Side effects

Common side effects include nausea, mild diarrhoea and abdominal discomfort, indigestion and dry mouth.  Liver function tests may also become elevated with the same frequency as with fluconazole.  Skin rashes due to posaconazole are relatively common.  Fever, fatigue and lacking in energy and loss of appetite is also moderately common. 

Numerous other side effects were apparently associated with posaconazole because the drugs were studied in neutropenia and leukaemia therapy.  The frequency of such events in patients only treated with posaconazole without underlying leukaemia is low.  As with all drugs other less common minor or significant side effects may also occur.