Standard ganciclovir dosing results in slow decline of cytomegalovirus viral loads.
Journal
The Journal of antimicrobial chemotherapy
ISSN: 1460-2091
Titre abrégé: J Antimicrob Chemother
Pays: England
ID NLM: 7513617
Informations de publication
Date de publication:
02 02 2022
02 02 2022
Historique:
received:
25
05
2021
accepted:
14
10
2021
entrez:
2
2
2022
pubmed:
3
2
2022
medline:
4
3
2022
Statut:
ppublish
Résumé
Cytomegalovirus (CMV) can cause severe disease, including rejection in transplant recipients. Ganciclovir and its oral prodrug valganciclovir have been used as first-line therapy for CMV disease in transplant recipients. The exposure targets of ganciclovir are not exactly known, and toxicity and resistance have interfered with ganciclovir therapy. To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ganciclovir in transplant recipients. We used patient data from a previous observational study on ganciclovir therapeutic drug monitoring (TDM) in prophylaxis and therapy. The ganciclovir concentrations and CMV viral loads were determined during routine clinical care. The PK/PD population modelling and simulations were done with non-parametric methodology using the Pmetrics program. Eighty-five patients were included in the PK modelling. The final PK model was a two-compartment model with first-order absorption and elimination. A subset of 17 patients on CMV therapy were included in the PD modelling. A median of 4 (range 2-8) viral loads were obtained per patient. A simulation of 10 000 patients showed that an approximately 1 log10 reduction of CMV viral load will be observed after 12.5 days at the current recommended dose. The developed linked PK/PD population model and subsequent PD simulations showed slow decline of CMV viral load and it appears that dosing of (val)ganciclovir in this study might have been inadequate to achieve fast reduction of viral load. It is clear that further studies are needed to specify the PD effects of ganciclovir by performing systematic measurements of both ganciclovir concentrations and CMV viral loads.
Sections du résumé
BACKGROUND
Cytomegalovirus (CMV) can cause severe disease, including rejection in transplant recipients. Ganciclovir and its oral prodrug valganciclovir have been used as first-line therapy for CMV disease in transplant recipients. The exposure targets of ganciclovir are not exactly known, and toxicity and resistance have interfered with ganciclovir therapy.
OBJECTIVES
To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ganciclovir in transplant recipients.
METHODS
We used patient data from a previous observational study on ganciclovir therapeutic drug monitoring (TDM) in prophylaxis and therapy. The ganciclovir concentrations and CMV viral loads were determined during routine clinical care. The PK/PD population modelling and simulations were done with non-parametric methodology using the Pmetrics program.
RESULTS
Eighty-five patients were included in the PK modelling. The final PK model was a two-compartment model with first-order absorption and elimination. A subset of 17 patients on CMV therapy were included in the PD modelling. A median of 4 (range 2-8) viral loads were obtained per patient. A simulation of 10 000 patients showed that an approximately 1 log10 reduction of CMV viral load will be observed after 12.5 days at the current recommended dose.
CONCLUSIONS
The developed linked PK/PD population model and subsequent PD simulations showed slow decline of CMV viral load and it appears that dosing of (val)ganciclovir in this study might have been inadequate to achieve fast reduction of viral load. It is clear that further studies are needed to specify the PD effects of ganciclovir by performing systematic measurements of both ganciclovir concentrations and CMV viral loads.
Identifiants
pubmed: 35107143
pii: 6433477
doi: 10.1093/jac/dkab419
pmc: PMC8809194
doi:
Substances chimiques
Antiviral Agents
0
Valganciclovir
GCU97FKN3R
Ganciclovir
P9G3CKZ4P5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
466-473Subventions
Organisme : Marie Curie
Pays : United Kingdom
Investigateurs
Angela E Edwina
(AE)
Johannes G M Burgerhof
(JGM)
Stefan P Berger
(SP)
Anoek de Joode
(A)
Kevin Damman
(K)
Erik A M Verschuuren
(EAM)
Hans Blokzijl
(H)
Martijn Bakker
(M)
Daan J Touw
(DJ)
Anne-Grete Mä Rtson
(AM)
Marieke G G Sturkenboom
(MGG)
Marjolein Knoester
(M)
Tjip S van der Werf
(TS)
Jan-Willem C Alffenaar
(JC)
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.
Références
Clin Pharmacol Ther. 2002 Aug;72(2):142-50
pubmed: 12189361
Ther Drug Monit. 2004 Feb;26(1):68-77
pubmed: 14749553
Transplantation. 2005 Jun 15;79(11):1477-83
pubmed: 15940035
Rev Infect Dis. 1988 Jul-Aug;10 Suppl 3:S507-14
pubmed: 2847287
Open Forum Infect Dis. 2019 Jan 14;6(2):ofz003
pubmed: 30775403
BMC Infect Dis. 2010 Jan 06;10:2
pubmed: 20053269
Lancet Infect Dis. 2019 Aug;19(8):e260-e272
pubmed: 31153807
Expert Opin Drug Metab Toxicol. 2015 Feb;11(2):205-19
pubmed: 25428442
Am J Transplant. 2006 Oct;6(10):2356-64
pubmed: 16889599
Antimicrob Agents Chemother. 2009 Jul;53(7):3017-23
pubmed: 19307355
Drugs. 1990 Apr;39(4):597-638
pubmed: 2161731
J Pediatric Infect Dis Soc. 2016 Mar 8;5(2):231-232
pubmed: 26962197
J Antimicrob Chemother. 2016 Feb;71(2):484-9
pubmed: 26538506
Antimicrob Agents Chemother. 2021 Feb 17;65(3):
pubmed: 33318012
Antimicrob Agents Chemother. 2012 Jul;56(7):3732-8
pubmed: 22526305
Antimicrob Agents Chemother. 2019 Feb 26;63(3):
pubmed: 30602515
BMJ Case Rep. 2015 Dec 15;2015:
pubmed: 26670887
Bone Marrow Transplant. 2008 May;41(10):873-9
pubmed: 18209721
J Popul Ther Clin Pharmacol. 2011;18(2):e257-60
pubmed: 21576729
Am J Transplant. 2009 Nov;9(11):2453-8
pubmed: 19843027
Transpl Int. 2017 Aug;30(8):817-826
pubmed: 28432714
Am J Transplant. 2013 Feb;13 Suppl 3:24-40; quiz 40
pubmed: 23347212
Int J Antimicrob Agents. 2014 Jun;43(6):572-3
pubmed: 24853257
BMC Infect Dis. 2018 Jun 28;18(1):289
pubmed: 29954328
Transplantation. 2013 Aug 27;96(4):333-60
pubmed: 23896556
Ther Drug Monit. 2012 Aug;34(4):467-76
pubmed: 22722776
Clin Pharmacokinet. 2005;44(5):495-507
pubmed: 15871635
Ther Drug Monit. 2019 Apr;41(2):107-110
pubmed: 30883503
Expert Rev Anti Infect Ther. 2021 Jun;19(6):707-718
pubmed: 33201745
Transpl Infect Dis. 2015 Dec;17(6):810-5
pubmed: 26354293
Drugs. 2001;61(8):1153-83
pubmed: 11465876
GE Port J Gastroenterol. 2017 Nov;24(6):262-268
pubmed: 29255766
Antimicrob Agents Chemother. 2009 Nov;53(11):4816-24
pubmed: 19738014
J Infect Dis. 2005 Jan 1;191(1):89-92
pubmed: 15593008
Antibiotics (Basel). 2021 Jan 15;10(1):
pubmed: 33467490
Antimicrob Agents Chemother. 2014 Sep;58(9):5602-5
pubmed: 24982073
Curr Opin Pharmacol. 2008 Oct;8(5):549-56
pubmed: 18625339
Clin Infect Dis. 2002 Apr 15;34(8):1094-7
pubmed: 11914998
Pediatr Transplant. 2014 Feb;18(1):103-11
pubmed: 24152053
Clin Pharmacokinet. 2009;48(6):399-418
pubmed: 19650679
Am J Transplant. 2004 Apr;4(4):611-20
pubmed: 15023154
J Antimicrob Chemother. 2021 Aug 12;76(9):2356-2363
pubmed: 34160036
Antiviral Res. 2019 Mar;163:50-58
pubmed: 30677427
Antimicrob Agents Chemother. 2005 Mar;49(3):873-83
pubmed: 15728878
J Clin Pharmacol. 2021 Mar;61(3):328-338
pubmed: 32926418
Clin Microbiol Infect. 2014 Feb;20(2):160-6
pubmed: 23607363