| SydPath Information Sheet | John Ray |
| Posaconazole | |
PreamblePosaconazole is an oral antifungal agent for the treatment and prophylaxis of invasive fungal infection. Therapeutic drug monitoring (TDM) is useful to confirm adequate drug concentrations particularly in patients who do not respond to therapy and to manage drug-drug interactions. Posaconazole exhibits substantial pharmacokinetic variability (Figure). The pharmacokinetics of posaconazole are linear and no further increases in exposure are observed above a total daily dose of 800 mg. Dividing the total posaconazole daily dose (800 mg) as 400 mg twice a day (bd) results in a higher exposure relative to once-a-day administration in patients (Figure). Exposure further increased when posaconazole was given as 200 mg four times daily. Posaconazole exposure for the 400 mg bd regimen is improved by concurrent administration with food. Steady-state concentrations are achieved within 7-10 days of multiple dose administration.
Concentration-effect relationshipAntifungal efficacy and the pharmacodynamics of posaconazole were studied in experimental animal models and preliminary data suggest that the time the plasma posaconazole concentration remains above the MIC over the dosing interval may be associated with antifungal efficacy. Groll A, et al., Mycoses, 49 (Suppl. 1), 7-16 (2006). In a study of salvage therapy of invasive aspergillosis, a successful global response at end of treatment was seen in 42 % of posaconazole-treated patients compared to 26 % of the control group (P=0.006) and higher response rates were observed in patients with higher steady state posaconazole plasma concentrations (Walsh et al. Clin Infect Dis 2007:44:2-12). A therapeutic range for posaconazole has not been developed. Preliminary evidence suggests that trough plasma concentrations (for a sample taken just before the next dose at steady-state) should be targeted to be > 700 ng/mL for best efficacy in patients refractory to conventional therapy. Walsh T et al., Clin Infect Dis 2007; 44:2-12. Concentrations >250 ng/mL are suggested for prophylaxis (preliminary evidence only). In a pharmacokinetic study of patients with refractory fungal infections, an initial loading dose of posaconazole 200mg QID for 3days followed by 400mg bd showed the highest exposures and a response rate of 50% (N=6/12) (Ullmann et al Antimicrob. Agents Chemother. 2006 50: 658-666). In two large
randomized controlled prophylaxis trials, a significant reduction in the incidence of
invasive fungal infections was demonstrated while subjects received posaconazole
prophylaxis. Among
patients for whom the results of pharmacokinetic testing were available, the mean trough
concentration of posaconazole was 1470 ng/ml in the 82 patients with chronic GVHD, 958
ng/ml in the 158 patients with acute GVHD and 583 ng/ml in 215 neutropenic patients with
AML/MDS undergoing induction chemotherapy. Sample Collection & Transport· Wait at least 7 days after commencing/changing therapy to reach steady state before collecting blood for analysis. Blood samples for TDM can be collected earlier if efficacy or toxicity are concerns or a loading dose is used. · Collect a 5 mL EDTA (purple top) tube 12 hours (or 6 hour if qid regimen used) after the dose (i.e. trough collection, just before the next dose). Do not use tubes with gel separator. · Outside laboratories separate plasma and send in an Eskie with an ice brick. If sample transport delayed for 12 h, freeze sample as soon as possible after collection and send frozen. ·
Cost: Covered by Medicare
(Medicare request form must accompany sample) or $30 cross charged for service to other
hospitals if Medicare does not apply. Contact John Ray |
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