Posaconazole DR Tablet Serum Concentrations in the Bone Marrow Transplant Population: Association with Prevention or Treatment of Invasive Fungal Infections

Background: Posaconazole (PCZ) delayed-release (DR) tablets were FDA approved in late 2013 for prophylaxis of invasive fungal infections (IFI).  In 3 clinical studies leading to approval, PCZ DR exhibited significant pharmacokinetic advantages over oral suspension (OS), largely due to improved absorption.  Historically, subtherapeutic PCZ OS levels were linked with breakthrough IFI.  We aim to evaluate PCZ DR serum levels in the bone marrow transplant (BMT) population and link levels to IFI breakthrough prevention and treatment. 

Methods:  After approval by Pharmacy and Therapeutics, PCZ levels were routinely obtained in BMT patients ≥18 years old started on PCZ DR. A retrospective chart review was performed between January 1 and June 30, 2014.  Baseline demographics, PCZ dose and levels, as well as patient specific factors with the potential to affect levels and development of IFIs were collected.

Results:  Steady state (≥ 5 days maintenance PCZ) concentrations (n = 34) were evaluated in 24 BMT patients (median age 62 years (22 – 78), 45% female), with 20 treated prophylactically (maintenance 300 mg daily), and 4 dosed with treatment intent (400 mg daily with 1 patient adjusted to 300 mg after a level of 4.3). An average weight-based dose of 4.13 mg/kg yielded average levels of 1.53 mcg/mL. Ranges of 3 to 5 mg/kg (16/24 patients) led to average levels of 1.37 mcg/mL (0.5 – 2.5).  Higher levels (2.32 mcg/mL (0.8 – 4.3)) were seen in doses >5 mg/kg (6/24 patients). Doses < 3 mg/kg yielded low levels (0.4) (2 patients).  Of 20 patients on prophylaxis, 1 developed a probable IFI with a therapeutic PCZ level. Of 4 patients on treatment, 2 improved and 2 died (both of progressive AML), all with therapeutic/supratherapeutic levels.

Conclusion: Therapeutic drug monitoring has previously been used for PCZ treatment and prophylaxis.  Levels ≥ 0.7 mcg/mL in prior OS studies were associated with successful prophylaxis vs. IFI breakthrough. In this adult BMT population, levels exceeded this threshold, and were consistent with treatment doses or higher. We postulate that weight-based dosing may give adequate prophylactic levels on lower total mg doses while offering benefits of reduced cost and avoided toxicities.  Further associations of PCZ levels with efficacy and adverse events are warranted.