Abstract
The population pharmacokinetics of ganciclovir was investigated in a group of 27 newborns with symptomatic congenital cytomegalovirus infection by nonlinear mixed-effects modeling analysis. Individual characteristics including approximated creatinine clearance from serum (ASCC) and body weight (WGE) were identified to significantly influence total clearance from plasma (CL) and the apparent total volume of distribution (V) of ganciclovir, respectively. The regression equations used to model these relationships were expressed as CL (in liters per hour) = 0.262 + (0.00271 x ASCC) and V (in liters) = 0.627 + (0.437 x WGE). By using this model, typical values of the pharmacokinetic parameter CL and V were 0.428 +/- 0.079 liters/h and 1.773 +/- 0.320 liters, respectively. Upon validation with a larger number of newborns, this model should allow for the definition of possible relationships between the pharmacokinetic disposition of ganciclovir and pharmacodynamic events in neonates.
Full Text
The Full Text of this article is available as a PDF (204.1 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Buhles W. C., Jr, Mastre B. J., Tinker A. J., Strand V., Koretz S. H. Ganciclovir treatment of life- or sight-threatening cytomegalovirus infection: experience in 314 immunocompromised patients. Rev Infect Dis. 1988 Jul-Aug;10 (Suppl 3):S495–S506. doi: 10.1093/clinids/10.supplement_3.s495. [DOI] [PubMed] [Google Scholar]
- Dieterich D. T., Chachoua A., Lafleur F., Worrell C. Ganciclovir treatment of gastrointestinal infections caused by cytomegalovirus in patients with AIDS. Rev Infect Dis. 1988 Jul-Aug;10 (Suppl 3):S532–S537. doi: 10.1093/clinids/10.supplement_3.s532. [DOI] [PubMed] [Google Scholar]
- Faulds D., Heel R. C. Ganciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections. Drugs. 1990 Apr;39(4):597–638. doi: 10.2165/00003495-199039040-00008. [DOI] [PubMed] [Google Scholar]
- Field A. K., Davies M. E., DeWitt C., Perry H. C., Liou R., Germershausen J., Karkas J. D., Ashton W. T., Johnston D. B., Tolman R. L. 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine: a selective inhibitor of herpes group virus replication. Proc Natl Acad Sci U S A. 1983 Jul;80(13):4139–4143. doi: 10.1073/pnas.80.13.4139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fletcher C., Sawchuk R., Chinnock B., de Miranda P., Balfour H. H., Jr Human pharmacokinetics of the antiviral drug DHPG. Clin Pharmacol Ther. 1986 Sep;40(3):281–286. doi: 10.1038/clpt.1986.177. [DOI] [PubMed] [Google Scholar]
- Fong J., Johnston S., Valentino T., Notterman D. Length/serum creatinine ratio does not predict measured creatinine clearance in critically ill children. Clin Pharmacol Ther. 1995 Aug;58(2):192–197. doi: 10.1016/0009-9236(95)90197-3. [DOI] [PubMed] [Google Scholar]
- Harbison M. A., De Girolami P. C., Jenkins R. L., Hammer S. M. Ganciclovir therapy of severe cytomegalovirus infections in solid-organ transplant recipients. Transplantation. 1988 Jul;46(1):82–88. doi: 10.1097/00007890-198807000-00015. [DOI] [PubMed] [Google Scholar]
- Keay S., Petersen E., Icenogle T., Zeluff B. J., Samo T., Busch D., Newman C. L., Buhles W. C., Jr, Merigan T. C. Ganciclovir treatment of serious cytomegalovirus infection in heart and heart-lung transplant recipients. Rev Infect Dis. 1988 Jul-Aug;10 (Suppl 3):S563–S572. doi: 10.1093/clinids/10.supplement_3.s563. [DOI] [PubMed] [Google Scholar]
- Kwong M. B., Tong T. K., Mickell J. J., Chan J. C. Lack of evidence that formula-derived creatinine clearance approximates glomerular filtration rate in pediatric intensive care population. Clin Nephrol. 1985 Dec;24(6):285–288. [PubMed] [Google Scholar]
- Laskin O. L., Cederberg D. M., Mills J., Eron L. J., Mildvan D., Spector S. A. Ganciclovir for the treatment and suppression of serious infections caused by cytomegalovirus. Am J Med. 1987 Aug;83(2):201–207. doi: 10.1016/0002-9343(87)90685-1. [DOI] [PubMed] [Google Scholar]
- Mar E. C., Cheng Y. C., Huang E. S. Effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on human cytomegalovirus replication in vitro. Antimicrob Agents Chemother. 1983 Oct;24(4):518–521. doi: 10.1128/aac.24.4.518. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martin J. C., Dvorak C. A., Smee D. F., Matthews T. R., Verheyden J. P. 9-[(1,3-Dihydroxy-2-propoxy)methyl]guanine: a new potent and selective antiherpes agent. J Med Chem. 1983 May;26(5):759–761. doi: 10.1021/jm00359a023. [DOI] [PubMed] [Google Scholar]
- Paul S., Dummer S. Topics in clinical pharmacology: ganciclovir. Am J Med Sci. 1992 Oct;304(4):272–277. doi: 10.1097/00000441-199210000-00010. [DOI] [PubMed] [Google Scholar]
- Schwartz G. J., Brion L. P., Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am. 1987 Jun;34(3):571–590. doi: 10.1016/s0031-3955(16)36251-4. [DOI] [PubMed] [Google Scholar]
- Snydman D. R. Ganciclovir therapy for cytomegalovirus disease associated with renal transplants. Rev Infect Dis. 1988 Jul-Aug;10 (Suppl 3):S554–S562. doi: 10.1093/clinids/10.supplement_3.s554. [DOI] [PubMed] [Google Scholar]
- Sommadossi J. P., Bevan R. High-performance liquid chromatographic method for the determination of 9-(1,3-dihydroxy-2-propoxymethyl)guanine in human plasma. J Chromatogr. 1987 Mar 6;414(2):429–433. doi: 10.1016/0378-4347(87)80069-5. [DOI] [PubMed] [Google Scholar]
- Sommadossi J. P., Bevan R., Ling T., Lee F., Mastre B., Chaplin M. D., Nerenberg C., Koretz S., Buhles W. C., Jr Clinical pharmacokinetics of ganciclovir in patients with normal and impaired renal function. Rev Infect Dis. 1988 Jul-Aug;10 (Suppl 3):S507–S514. doi: 10.1093/clinids/10.supplement_3.s507. [DOI] [PubMed] [Google Scholar]
- Swan S. K., Munar M. Y., Wigger M. A., Bennett W. M. Pharmacokinetics of ganciclovir in a patient undergoing hemodialysis. Am J Kidney Dis. 1991 Jan;17(1):69–72. doi: 10.1016/s0272-6386(12)80253-8. [DOI] [PubMed] [Google Scholar]
- Tocci M. J., Livelli T. J., Perry H. C., Crumpacker C. S., Field A. K. Effects of the nucleoside analog 2'-nor-2'-deoxyguanosine on human cytomegalovirus replication. Antimicrob Agents Chemother. 1984 Feb;25(2):247–252. doi: 10.1128/aac.25.2.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Trang J. M., Kidd L., Gruber W., Storch G., Demmler G., Jacobs R., Dankner W., Starr S., Pass R., Stagno S. Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group. Clin Pharmacol Ther. 1993 Jan;53(1):15–21. doi: 10.1038/clpt.1993.4. [DOI] [PubMed] [Google Scholar]
- Yuen G. J., Drusano G. L., Fletcher C., Capparelli E., Connor J. D., Lalezari J. P., Drew L., Follansbee S., Busch D., Jacobson M. Population differences in ganciclovir clearance as determined by nonlinear mixed-effects modelling. Antimicrob Agents Chemother. 1995 Oct;39(10):2350–2352. doi: 10.1128/aac.39.10.2350. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zacchello G., Bondio M., Saia O. S., Largaiolli G., Vedaldi R., Rubaltelli F. F. Simple estimate of creatinine clearance from plasma creatinine in neonates. Arch Dis Child. 1982 Apr;57(4):297–300. doi: 10.1136/adc.57.4.297. [DOI] [PMC free article] [PubMed] [Google Scholar]