Analysis of posaconazole as oral antifungal prophylaxis in pediatric patients under 12 years of age following allogeneic stem cell transplantation

Abstract

Background: Pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) are at high risk of acquiring fungal infections. Antifungal prophylaxis shortly after transplantation is therefore indicated, but data for pediatric patients under 12 years of age are scarce. To address this issue, we retrospectively assessed the safety, feasibility, and initial efficacy of prophylactic posaconazole in children.

Methods: 60 consecutive pediatric patients with a median age of 6.0 years who underwent allogeneic HSCT between August 2007 and July 2010 received antifungal prophylaxis with posaconazole in the outpatient setting. 28 pediatric patients received an oral suspension at 5 mg/kg body weight b.i.d., and 32 pediatric patients received the suspension at 4 mg/kg body weight t.i.d. The observation period lasted from start of treatment with posaconazole until its termination (maximum of 200 days post-transplant).

Results: Pediatric patients who received posaconazole at 4 mg/kg body weight t.i.d. had a median trough level of 383 μg/L. Patients who received posaconazole at 5 mg/kg body weight b.i.d. had a median trough level of 134 μg/L. Both regimens were well tolerated without severe side effects. In addition, no proven or probable invasive mycosis was observed.

Conclusion: Posaconazole was a well-tolerated, safe, and effective oral antifungal prophylaxis in pediatric patients who underwent high-dose chemotherapy and HSCT. Posaconazole at a dosage of 12 mg/kg body weight divided in three doses produced consistently higher morning trough levels than in patients who received posaconazole 5 mg/kg body weight b.i.d. Larger prospective trials are needed to obtain reliable guidelines for antifungal prophylaxis in children after HSCT.

Figure 1

Blood analyses. Box plot of peripheral blood cell count values the day before posaconazole therapy began (Begin) and at the end of oral antimycotic monoprophylaxis with posaconazole (End). A: Platelet counts. B: CD3⁺ cell counts. C: CD4⁺ cell counts. D: CD16⁺/CD56⁺ cell counts. A timely reconstitution of platelets (***P < 0.001), CD3⁺ cell counts, and CD4⁺ cell counts took place during posaconazole treatment.

Figure 2

Hepatotoxicity. Box plot of liver parameters the day before posaconazole therapy began (Before), their maximums during therapy (Maximum), and values at the end of oral antimycotic monoprophylaxis with posaconazole (End). A: Plasma alanine aminotransferase (ALT) (normal value, ≤ 39 U/L). B: Plasma aspartate aminotransferase (AST) (normal value, ≤ 59 U/L for pediatric patients < 12 years of age). C: Total plasma bilirubin (normal value, ≤ 1.1 mg/dL). D: Direct plasma bilirubin (normal value, ≤ 0.3 mg/dL). Statistical analysis by the Wilcoxon matched-pairs signed-ranks test showed a significant increase (***P < 0.001) in ALT and AST beyond their upper normal limits during treatment post-transplant respective to baseline measurements taken the day before the start of posaconazole prophylaxis (Before).

Figure 3

Posaconazole trough levels. Analysis of posaconazole morning trough levels at 5 mg/kg body weight daily (b.i.d.) (n = 48) and morning trough levels at 4 mg/kg body weight daily (t.i.d.) (n = 41). These morning trough levels were significantly different (P < 0.001) according to the Mann-Whitney U test. The gray area indicates the reported range of posaconazole trough levels in adults.