A Matched Case-Control Study to Evaluate Predicted Drug Exposures and Neutropenia during Valganciclovir Prophylaxis...

Neutropenia during valganciclovir (VGCV) prophylaxis for cytomegalovirus infection in pediatric solid organ transplant (pSOT) recipients is common, but it is uncertain if this toxicity is exposure-dependent.

To compare ganciclovir (GCV) exposures in children treated with VGCV with and without neutropenia, we performed a retrospective matched case-control study among pSOT prescribed VGCV, dosed based on body surface area. Cases were defined as an absolute neutrophil count (ANC) < 1000/µL. Controls without neutropenia were matched by age (+/-1 year), transplanted organ, and duration of VGCV prophylaxis. We used a published population pharmacokinetic model to inform predictions of GCV concentrations using Pmetrics, accounting for each subject's time-dependent variables (age, weight, creatinine clearance). We then calculated 24-h, 7-day, and cumulative area under the curve (AUC) in each subject and used conditional logistic regression to compare GCV exposures among cases and controls.

Among 164 pSOT recipients prescribed VGCV, we identified 35 case-control matches. There were no statistically significant differences in the 24-h (odds ratio [OR] 0.990, 95% confidence interval [CI] 0.964-1.018), 7-day (OR 1.000, 95% CI 0.996-1.004), or cumulative AUCs (OR 1.00, 95% CI 0.9996-1.00) among all cases and controls. AUC metrics by SOT type also showed no statistically significant differences.

Predicted GCV exposures were similar among pSOT recipients with and without neutropenia, suggesting that differences in dosing and pharmacokinetics covariates did not drive toxicity in our population. Measurement of GCV concentrations may discern whether toxicity relates to exposures/concentrations or intrinsic factors (i.e., genetics) in the pSOT population.