PBPK simulation-based evaluation of ganciclovir crystalluria risk factors: effect of renal impairment, old age and low fluid intake

Dosing guidance is often lacking for chronic kidney disease (CKD) due to exclusion of
such patients from pivotal clinical trials. Physiologically-based pharmacokinetic (PBPK)
modelling supports model-informed dosing when clinical data are lacking, but
application of these approaches to patients with impaired renal function is not yet at full
maturity. In the current study, a ganciclovir PBPK model was developed for patients
with normal renal function and extended to CKD population. CKD-related changes in
tubular secretion were explored in the mechanistic kidney model, implemented either
as proportional or non-proportional decline relative to GFR. Crystalluria risk was
evaluated in different clinical settings (old age, severe CKD and low fluid intake) by
simulating ganciclovir medullary collecting duct (MCD) concentrations.
The ganciclovir PBPK model captured observed changes in systemic pharmacokinetic
endpoints in mild-to-severe CKD; these trends were evident irrespective of assumed
pathophysiological mechanism of altered active tubular secretion in the model. Minimal
difference in simulated ganciclovir MCD concentrations was noted between young
adult and geriatric populations with normal renal function and urine flow (1mL/min),
with lower concentrations predicted for severe CKD patients. High crystalluria risk was
identified at reduced urine flow (0.1mL/min) as simulated ganciclovir MCD
concentrations exceeded its solubility (2.6–6 mg/mL), irrespective of underlying renal
function. The analysis highlighted the importance of appropriate distribution of virtual
subjects’ systems data in CKD populations. The ganciclovir PBPK model illustrates the
ability of this translational tool to explore individual and combined effects of age, urine
flow and renal impairment on local drug renal exposure.