Pharmakokinetics of Valganciclovir after AlloSCT: A Fixed Oral Dose Can Be Used for Preemptive Therapy in Patients with Normal Body Weight - Even with Intestinal GVHD.

Background: After alloSCT, oral valganciclovir (VALGCV) is a promising alternative to IV GCV against CMV but its pharmacokinetics (PK) have not been studied.

Methods: We investigated the PK of GCV after VALGCV in a randomized, crossover phase II-study of 48 patients (pts) after alloSCT. Pts who had >400 copies/ml of CMV DNA in plasma measured by quantitative PCR were randomized to receive a fixed dose of VALGCV 900 mg BID (adjusted for renal function) for 7 days, followed by IV GCV as 1-h-infusion at 5mg/kg every 12 h for another 7 days, or to receive the inverse sequence of study drug administration. The PK of GCV were assessed on days 4 and 11. Safety monitoring was done until day 84 after alloSCT.

Results: 28 pts were fully assessable for PK analyses. Among the 22 pts without intestinal graft-versus-host disease (GVHD), the mean±SD AUC 0–12 (mg/L*h) was 53.8±18.0 on VALGCV vs 39.5±13.9 on IV GCV (mean difference 14.3 [95% CI 7.6 to 20.9]); Cmax (mg/L) was 8.8±2.4 vs 10.3±2.1; tmax was 2.7±0.8 vs 1.1±0.6; and t1/2 was 4.2±1.1 vs 3.4±0.8. Among the 6 pts with intestinal GVHD, the mean±SD AUC 0–12 (mg/L*h) was 46.6±24.9 on VALGCV vs 35.3±12.8 on IV GCV (mean difference 11.3 [95% CI −13.4 to 35.9]); Cmax (mg/L) was 7.1±3.6 vs 11.1±3.1; tmax (h) was 2.7±0.8 vs 1.2±0.4; and t1/2 (h) was 5.6±2.0 vs 3.3±0.7. The bioavailability of GCV after VALGCV was 53%. Using a VALGCV fixed oral dose (1.800mg) for preemptive therapy in pts with low body weight led to a sharp increase of the VALGCV / IV GCV ratio (i.e. 50kg = 1.9). With a limited number of pts with low body weight included in this study no severe GCV associated toxicity was seen in these pts. Non-fatal CMV pneumonia developed in 2 pts during follow-up after antiviral therapy, and servere neutropenia < 500/μl occurred in 3 pts. Clearance of CMV DNA was equally effective in both arms.

Conclusions: In alloSCT, exposure to GCV after preemptive therapy using VALGCV is higher compared to that with IV GCV in patients with and without intestinal GVHD. In addition to patients with renal dysfunction patients with low body weight < 60kg and normal renal function should be treated very carefully to avoid over-exposure to GCV. Although no severe toxicity was demonstrated in this pk-study a further study to address the safety and efficacy of VALGCV in alloSCT is needed.