Delayed-release Posaconazole Tablets Offer Increased Exposure in a Fasted State
By Caroline A. Lindsay, PharmD
Critical Care Pharmacy Resident, Stanford Hospital & Clinics
Dr. Lindsay reports no financial relationships in this field of study
Posaconazole oral suspension (Noxafil® oral suspension, Merck) has been, for several years, indicated for treatment of orophayngeal candidiasis as well as for prophylaxis of invasive Aspergillus and Candida infections in patients at risk. Posaconazole delayed-release tablets (Noxafil® delayed-release tablets, Merck) were recently FDA-approved for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients 13 years of age and older.
Posaconazole works by inhibiting the fungal cytochrome P450 enzyme lanosterol 14a-demethylase which is the rate-limiting step in ergosterol synthesis. This results in a depletion of ergosterol which weakens the structural integrity of the fungal cell membrane and may also be associated with accumulation of toxic intermediates.
The new delayed-release tablets produce superior drug exposure when compared to the oral suspension when administered to patients under fasted conditions. Table 1 shows the pharmacokinetic parameters under fed and fasted conditions. In summary, under fasted conditions, the tablet form results in an AUC0-4 almost 4 times as high as observed with the oral suspension. Although, with the exception of a slightly higher Cmax, there is no significant difference in exposure between the tablet and oral suspension, the manufacturer nonetheless recommends that posaconazole delayed-release tablets be administered with a meal.
Table 1. Plasma pharmacokinetic parameters of 100 mg posaconazole
|Formulation||AUC0-t (ng*h/mL)||AUC0-∞ (ng*h/mL)||Cmax (ng/mL)||Tmaxb (h)||t1/2 (h)||CL/F (L/h)||
Under fasted conditions
|Oral suspension||2,970 (50)||3,420 (44)||84.0 (62)||4.00 (2.00, 8.00)||29.2 (31)||34.0 (38)||1,450 (54)|
|Tablet||11,400 (26)||11,700 (26)||385 (28)||5.00 (3.00, 6.00)||26.1 (28)||9.16 (29)||345 (45)|
Under fed conditions
|Oral suspension||8,470 (25)||8,570 (24)||243 (18)||6.00 (5.00, 12.0)||25.1 (35)||12.1 (26)||427 (39)|
|Tablet||11,700 (24)||11,900 (23)||327 (23)||8.00 (3.00, 24.00)||23.7 (21)||8.97 (32)||305 (34)|
a Data are means (percent coefficient of variation) for 16 subjects. AUC0 t, area under the curve from time zero to the time of the final quantifiable sample; AUC0 ∞, area under the curve from time zero to infinity; CL/F, apparent total body clearance; Cmax, maximum plasma concentration; CV, coefficient of variation; t1/2, terminal-phase half-life; Tmax, time to Cmax; V/F, apparent volume of distribution b Data are median (min, max)
Dosing of posaconazole delayed-release tablets differs from that of the oral suspension. For fungal prophylaxis, the dose of the delayed-release tablet is 300 mg PO BID on the first day, followed by 300 mg PO daily. Duration of therapy is based on a patient's recovery from immunosuppression.
As with the oral suspension, posaconazole delayed-release tablet is hepatically metabolized, primarily via glucoronidation. It is also a substrate of P-glycoprotein and a strong inhibitor of cytochrome P450 3A4. It is contraindicated for concurrent use with the following agents, as posaconazole will increase the levels of these drugs:
- Sirolimus can result in sirolimus toxicity
- CYP3A4 substrates such as pimozide and quinidine can result in QTc prolongation
- HMG-CoA reductase inhibitors that are metabolized by CYP3A4 can result in rhabdomyolysis
- Ergot alkaloids can result in ergotism
In addition, posaconazole should be used with caution in patients taking calcineurin inhibitors (cyclosporine, tacrolimus) as posaconazole will increase the levels of these agents. Posaconazole has also been shown to prolong the QTc interval and cause Torsades de Pointes. Elevations in liver function tests can also occur, and may require discontinuation of posaconazole. Finally, posaconazole can prolong the hypnotic/sedative effects of midazolam, so patients should be monitored closely.
The most common side effects (>25%) in patients taking posaconazole delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea. Nausea was the most common reason for discontinuation of posaconazole (2%).
In summary, the delayed-release tablet has signicantly improved drug exposure under fasted conditions compared to the oral suspension. The delayed-release tablets should be used instead of the oral suspension, especially for patients unable to eat a full meal.
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