PMID- 34907479
OWN - NLM
STAT- MEDLINE
DCOM- 20220404
LR  - 20220405
IS  - 1550-7416 (Electronic)
IS  - 1550-7416 (Linking)
VI  - 24
IP  - 1
DP  - 2021 Dec 14
TI  - PBPK Simulation-Based Evaluation of Ganciclovir Crystalluria Risk Factors: Effect 
      of Renal Impairment, Old Age, and Low Fluid Intake.
PG  - 13
LID - 10.1208/s12248-021-00654-1 [doi]
LID - 13
AB  - 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 and 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 (1 mL/min), with lower concentrations predicted for severe CKD 
      patients. High crystalluria risk was identified at reduced urine flow 
      (0.1 mL/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.
CI  - (c) 2021. The Author(s).
FAU - Scotcher, Daniel
AU  - Scotcher D
AD  - Centre for Applied Pharmacokinetic Research, School of Health Sciences, 
      University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, 
      UK.
FAU - Galetin, Aleksandra
AU  - Galetin A
AD  - Centre for Applied Pharmacokinetic Research, School of Health Sciences, 
      University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, 
      UK. Aleksandra.Galetin@manchester.ac.uk.
LA  - eng
PT  - Journal Article
DEP - 20211214
PL  - United States
TA  - AAPS J
JT  - The AAPS journal
JID - 101223209
RN  - P9G3CKZ4P5 (Ganciclovir)
SB  - IM
MH  - Aged
MH  - Computer Simulation
MH  - *Ganciclovir
MH  - Humans
MH  - Kidney
MH  - Models, Biological
MH  - *Renal Insufficiency
MH  - Young Adult
PMC - PMC8816528
OTO - NOTNLM
OT  - Chronic kidney disease
OT  - Kidney model
OT  - Physiologically based pharmacokinetic model
COIS- The authors declare no conflict of interests.
EDAT- 2021/12/16 06:00
MHDA- 2022/04/05 06:00
PMCR- 2021/12/14
CRDT- 2021/12/15 07:31
PHST- 2021/05/06 00:00 [received]
PHST- 2021/10/02 00:00 [accepted]
PHST- 2021/12/15 07:31 [entrez]
PHST- 2021/12/16 06:00 [pubmed]
PHST- 2022/04/05 06:00 [medline]
PHST- 2021/12/14 00:00 [pmc-release]
AID - 10.1208/s12248-021-00654-1 [pii]
AID - 654 [pii]
AID - 10.1208/s12248-021-00654-1 [doi]
PST - epublish
SO  - AAPS J. 2021 Dec 14;24(1):13. doi: 10.1208/s12248-021-00654-1.