PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital

Volume 1 5 Number 10 October 20 09

Gancic lovir and Valganci clovir Use in Children Marcia L. Buck, Pharm.D., FCCP , FPPAG

anciclovir and its prodrug valganciclovir, CMV replication ranges from 0 .1 to 3.48 G are used for the prevention or treatment mcg/mL. Viral resistance to ganciclovir has been of cytomegalovirus (CMV) disease in demonstrated in vitro and in vivo , with treatment immunocompromised or immunosup pres sed failures reported in patients on long -term therapy patients. 1 W hile valganciclovir has been only for CMV retinitis. Af ter prolonged recently approved for use in children by the Food administration, selection of mutations in UL97 or and Drug Administration (FDA) , both of the se in the viral polymerase gene UL54 results in a drugs are a common part of treatment protocols reduc ed form ation of ganciclovir triphosphate. 1-4 following renal , hepatic, lung, cardiac , or bone marrow transplantation in child ren of all ages .2-4 Pharmacokinetics Several recent studies suggest that these agents Ganciclovir is poorly absorbed after oral are very effective in preventing CMV in children administration, with a bioavailability of with transplants and are generally well tolerated. approximately 5%. Administration with food Other recent papers have described successful increased bioavailability slightly to 6 -10%. After treatment of congenital or neonatal CMV oral administration of standard adult doses, infection with these agents. This issue of maximum serum ganciclovir concentra tions Pediatric Pharmacotherapy will review the basic typically are 0.5 to 1.5 mcg/m L. After IV pharmacology of ganciclovir and valganciclovir administration, maximum serum ganciclovir and provide an overview of recent studies of concentrations of 7 to 19 mcg/mL are typically their use in pediatric patients. achieved. Oral bioavailability is significantly improved with valganciclovir, with an average Mechanism of Action value of 59.4 +6.1% reported from premarketing Ganciclovir is a synthetic acyclic nucleoside clinical tri als in adults. The mean maximum analogue of 2’ -deoxyguanosine. Valganciclovir serum ganciclovir concentration achieved after is the L -valyl ester of ganciclovir. After oral valganciclovir administration (with food) was administration, it is rapidly cleaved by esterases 5.61 +1.52 mcg/mL. 2-4 in the intestine wall and liver to form active ganciclovir. Ganciclovir inhi bits replication of At steady -state, the volume of distribution of herpes viruses, including CMV and herpes ganciclovir is approximately 0.74 +0.15 L/kg. simplex virus (HSV). In CMV -infected cells, Ganciclovir is only minimally bound to serum ganciclovir undergo es phosphorylation to a proteins (1 -2%). Ganciclovir is primar ily monophosphate form by a CMV -encoded (UL97 eliminated through renal glomerular filtration and gene) protein kinase . Significantly greater active tubular secretion . Over 90% of a dose is phosphorylation occu rs in CMV -infected cells eliminated as unchanged drug. The average than in non -infected cells. Ganciclovir elimination half -life is approximately 3 to 5 monophosphate is then conver ted to dipho sphate hours in adults. Renal impairment significantly and triphosphate form s by cellular kinases. 1-4 reduces ganciclovir clearance. In patients with severe renal impairment, elimination half life Ganciclovir triphosphate , the active moiety, may exceed 20 to 50 hours. Hemodialysis persists for several days in CMV -infected cells. reduces ganciclovir serum concentrations by It inhibi ts vira l D NA synthesis by competi ng approximately 50%. 2-4 with deoxyguanosine triphosphate as a substrate for viral DNA polymerase. Ganciclovir The pharmacokinetic profile of ganciclovir and triphosphate is also incorpor ated into viral DNA, valganciclovir in infants and children has been resulting in termination of viral DNA elongation evaluated in several studies. In 1993, Trang and and inhibition of viral replication . The in vitro colleagues evaluated the pharmacokinetic median concentration of ganciclovir that inhibits characteristics of IV ganciclovir in 27 neonates (2 to 49 days of age) .5 T he maximum serum received a CMV positive organ. All of the concentration was 5.5 +1.6 mcg/mL after a dose children were receiving steroids and tac rolimus, of 4 mg/kg and 7.0 +1.6 mcg/mL after 6 mg/kg. with 30% also getting mycophenolate. Patients Mean volume of distribution was 669 +70 mL/kg received a valganciclovir dose of 15 to 18 mg/kg for the 4 mg/kg group and 749 +59 mL/kg for the given once daily. All patients tolerated 6 mg/kg group. Volume of distribution incre ased valganciclovir, with no reports of bone marrow with increasing weight (r = 0.689, p = 0.0001). suppression or renal dysfunction. Asymptomatic The mean elimination half -life was 2.4 hours. CMV infection was detected on routine CMV antigenemia in one child at one week of In a 2003 study by Zhang and colleagues treatment, but cleared with a dose increase to 15 conducted in 1 1 children ( mean age 11.0 +3.9 mg/kg twice daily. After three negative tests, the years) , the maximum concentration after an IV dose was reduced to once daily. Based on their dose of 5 mg/kg given e very 12 hours for 15 days initial experience, the authors suggest that was 11 .77 +2.82 mcg/mL, with a n AUC of valganciclovir is an acceptable therapy for CMV 42.29 +17.57 mcg·hr/mL. 6 Administration of an prophylaxis in pediatric transplant patients. oral dose of 50 mg/kg every 12 hours for 3 months produced a maximum concentration of Valganciclovir has also been used successfully in 2.70 +1.07 mcg/mL and an AUC of 18.97 +9.36 the treatment of infants with congenital CMV mcg·hr/mL. The au thors concluded that the infection. In 2007, Galli and colleagues treated 8 doses administered produced adequate serum inf ants with severe CMV disease with IV ganciclovir concentrations for treatment. ganciclovir for 1 week followed by oral valganciclovir for 5 weeks. The first four infants The pharmacokinetics of valganciclovir in were treated with 15 mg/kg once daily, but this children were first described in a case report of a resulted in a suboptimal mean maximum 6 year old girl with CMV. 7 A single 4.4 mg/kg concentration of 0.42 mcg/mL (range 0.40 -0.74 IV g anciclovir dose was compared to 13.2 mg/kg mcg/mL). Dosing for the second group of four and 26.3 mg/kg oral valganciclovir doses. The infants was increased to 15 mg/kg twice daily, two doses of valganciclovir provided area under which produced a maximum concentration of 3.1 the serum concentration -time curve (AUC) mcg/mL (range 2.5 -3.9 mcg/mL). Average urine values of 14.3 and 28.7 mcg·hr/mL , respectively. CMV viral load prior to treatment was 6.9 +1.32 Earlier this year, Zhao and colleagues utilized copies/mL. Viral loa d lowered during treatment nonlinear mixed -effects modeling (NONMEM) to 3.72 +0.71 and 2.66 +0.51 copies/mL in the techniques to evaluate valganciclovir two groups, respectively). pharmacokinetics in 22 renal transplant patients between 3 and 17 years of age. 8 The model The most current research with these agents has provided an estimated systemic clearance value focused on optimizing drug administration. I n a of 10.1 L/hr (or 0.30 L/hr/kg), with a volume of study published last year in Transplantation , distribution of 5.2 L, similar to values reported in Gerna and col leagues conducted a randomized, adults. Based on their model, the authors suggest open -label study of ganciclovir prophylaxis that a valganciclovir dose of approximately 500 versus preemptive therapy along for prevention mg once daily would produce an AUC of of CMV in pediatric liver transplant patients. 43 +10.6 mcg·hr/mL, thus achieving adequate Twenty -one children were randomized to receive concentrations for CMV prophylaxis. either ganciclovir 5 mg/kg twice daily for 30 days (prophylaxis) or preemptive therapy, where Clinical Studies in Children treatment was initiated only after the CMV viral The first report of ganciclovir treatment in an load reached 100,000 DNA copies/mL and infant with CMV was published in 1988. 9 Since stopped when two consecutive tests were below that time, a variety of case reports and clinical the cut -off. At the 24 month interim analysis, studies have been published describ ing the use of similar numbers of patients in each group had ganciclovir in infants and children. In addition, a developed CMV disease, 7 of the 10 children small number of papers have documented the (70%) in the prophylaxis group and 9 of the 11 efficacy of valganciclovir. The efficacy of (81%) in the preemptive group; however, valganciclovir as prophylaxis for CMV in infection occurred significantly later in the pediatric liver transplant patients was evaluated prophylaxis arm (54 versus 24 days, p = 0.05). by Clark and colleagues in 2004. In their The re was no difference in overall response to retrospective study, the authors evaluated 10 infection. As a result, the authors suggest that children (mean age 4.9 +5.6 years). The majority long -term prophylaxis may not be necessary. of the patients (50%) were CMV negative and Drug Interactions considered as potentially teratogenic and may Ganciclovir and valganciclovir should be used adversely affect sperm production. A ll patients with caution in patients receiving other c ytotoxic should be informed of the se risk s and the drugs , such as amphotericin, dapsone, importance of contraceptive use. 1-4 doxorubicin, flucytosine, pentamidine, trimethoprim/sulfamethoxazole, vinblastine, and Rapid administration of IV doses may result in vincristine, Seizures have been reported in elevated plasma concentrations and a greater patients taking imipenem -cilastatin and likelihood for toxicity. Because of the alkaline ganciclovir. The combination of imi penem - nature of the drug (pH 11), dilution to cilastatin and either ganciclovir or valganciclovir concentrations less than 10 mg/mL is necessary should not be used. Nephrotoxic drugs , to minimize the risk for pain and phlebitis. including cyclosporine and amphotericin, a s well Ganciclovir should never be administ ered as probenecid should be used with caution in intramuscularly or subcutaneously. 1-4 patients taking ganciclovir or valganciclovir , as the resulting increase in ganciclovir Adverse Effects concentration s may produce toxicity. 1-4 Among the most commonly reported adverse effects with ganciclovir and valganciclovir are When ganciclovir is administered simultaneously lab test abnormalities, including neutropenia ( in with, or within 2 hours prior to, didanosine, the 3-41% of patients in adult trials), AUC of didanosine may be reduced by 10 -40%. thrombocytopenia ( 1-65%), and an increase in If the drugs are given simultaneously, the AUC serum creatinine ( 4-69 %). Other adverse effects of ganciclovir may be decreased by up to 20%, include fever (30 -48%), nausea and diarrhea (41 - although studies conducted with didanosine 48%), tremor (28%), headache (22%), anorexia administered 2 hours prior to a ganciclovir dose (14 -19%), hypertension (18%), insomnia (16%), produced no significant effect. A similar result vomiting (11 -21 %), diaphoresis (11 -14%), occurs with simultaneous administration of pru ritus (5 -10%), and infections (4 -15%). ganciclovir and zidovudi ne. The steady -state Retinal detachment has been reported in patients AUC of ganciclovir may be decreased by up to with CMV retinitis, but a relationship to 20%, while the AUC of zidovudine may be treatment has not been established. Rare, but increased by 11 -74%. Use of valganciclovir severe adverse reactions include h ypersensitivity with didanosine or zidovudine should be and paresthesias .1-4 expected to produce the same interactions. 1-4 Adve rse effects reported in pediatric clinical Precautions trials have been similar to those reported in Ganciclovir and valganciclovir can produce adults. In a study of 120 immunocompromised significant neutropenia, anemia, and children with CMV infection, the most common thrombocytopenia. They should be used with adverse effects were granulocytopenia (17%) and caution in patients with underlying blood thrombocytopenia (10%). In a nother study of 16 dyscrasias and should not be administered to children , the adverse effects included patients with an absolute neutrophil count les s hypokalemia (25%), decreased renal function, than 500 cells/mcL , a platelet count less than sepsis, or thrombocytopenia (19%), leukopenia, 25,000 cells/mcL , or a hemoglobin less than 8 coagulation disorders, hypertension, pneumonia, g/dL. If neutropenia occurs , it typically resol ves or immune system disorders (13%). 1-4 within a week of discontinuation. 1-4 Dosing Recommendatio ns High concentrations of ganciclovir have Ganciclovir prophylaxis is typically initiated at a produced carcinogenic effects in animal models. dose of 5 mg/kg IV over 1 hr every 12 hours for As a result, ganciclovir is considered a potential 7 to 14 days post -transplant, followed by 5 carcinogen in humans. The drug should be mg/kg given once daily . Maintenance handled with appropriate personal protective prophylaxis with oral ganciclovir in adults and equipment, according to institutional policies. children 13 years and o lder is 1,000 mg given Families preparing valganciclovir suspension three times daily with food. The dose of shou ld understand the potential risk of direct valganciclovir for CMV prophylaxis in adults is contact with the drug and should be aware of 900 mg (two 450 mg tablets) given once daily steps to minimize exposure. After direct contact with food ; p ediatric patients should receive a with the suspension, broken or crushed tablets, dose of 15 to 18 mg/kg once daily. Duration patients or caregivers should wash thoroughly varies among transplantation protocols. Children with soap and water. Ga nciclovir should also be with CMV infection, including i nfants with congenital CMV , should be treated with IV 4. Valcyte ® information. Roche Laboratories Inc., January ganciclovir 5 -6 mg/kg given every 12 to 24 hou rs 2006. Available at www.valcyte.com (accessed 10 /1 3/09). 5. Trang JM, Kidd L, Gruber W, et al. Linear single -dose or valganciclovir 15 to 18 mg/kg given orally pharmacokinetics of ganciclovir in newborns with congenital 1-12 twice daily . The manufacture r recommends cytomegalovirus infections. Clin Pharmacol Ther that doses be calculated based on body surface 1993;53:15 -21. area and creatinine clearance. The formula is 6. Zhang D, Lapeyraque A, Popon M, et al. Pharmacokinetics of ganciclovir in pediatric renal transplant provided in the prescribing information and on recipients. Pediatr Nephrol 2003;18:943 -8. the product website at www.valcyte.com . 7. Burri M, Wiltshire H, Kahlert C, et al. Oral valganciclovir in children: single dose pharmacokinetics in a six -year -old Patients with renal i mpairment require lower girl. Pediatr Infect Dis J 2004;23:263 -6. 8. Zhao W, Baudouin V, Zhang D, et al . Population ganciclovir or valganciclovir doses. In patients pharmacokinetics o f ganciclovir following administration of receiving IV ganciclovir who have mild renal valganciclovir in pediatric renal transplant patients. Clin dysfunction, the dose should be reduced by 50% Pharmacokinet 2009;48:321 -8. to a daily dose of 2.5 mg/kg. Patients with 9. Lim W, Kahn E, Gupta A, et al. Treatment of cytomegalovirus enterocolitis with ganciclovir in an infant moderate renal dysfunction should receive 25 % with acquired immunodeficiency syndrome. Pediatr Infect of the regular dose (1.25 mg/kg) daily , and Dis J 1988;7 :354 -7. pat ien ts with severe renal impairment should 10. Clark BS, Chang I, Karpen SJ, et al. Valganclovir for the receive 0.625 mg/kg three times per week after prophylaxis of cytomegalovirus disease in pediatric liver hemodialysis, or on a schedule determined by transplant recipients [letter]. Transplantation 2004;77:1480. 11 . Galli L, Novelli A, Chiappini E, et al. Valganciclovir for their ability to eliminate the drug. For patients congenital CMV infection: a pilot study on plasma with mild renal dysfun ction who are being concentration in newborns and infants. Pediatr Infect Dis J treated with valganciclovir , the dosing interval 2007;26:451 -3. should be reduced to once daily. For moderate 12. Gerna G, Lilleri D, Callegaro A, et al. Prophylax is followed by preemptive therapy versus preemptive therapy impairment, the dose should also be reduced by for prevention of human cytomegalovirus disease in pediatric 50% . For severe renal dysfunction (estimate d patients undergoing liver transplantation. Transplantation creatinine clearance < 25 mL/min), the dose 2008;86:163 -6. sho uld be reduced by 50% and be administered 13. Drug Topics. Red Book: Montvale, NJ: Thompson Healthcare (accessed on -line via McKesson 8/10/09). twice weekly. Valganciclovir is not 14. Harkin CC, Griener JC, Tan Eick AP. Stability of 1-4 recommended in patients requiring dialysis. valganciclovir in extemporaneously compounded liquid formulations. Am J Health -Syst Pharm 2003;60:687 -90. Availability and Cost Ganciclovir (Cytovene ® and generics) is Formulary Update available as 250 and 500 mg capsules, as well as The following actions were taken by th e an injection (500 mg/10 mL vial). The average Pharmacy and Therapeutics Committee at their wholesale price (AWP) for ganciclovir is $ 4.72 meeting on 9/ 25 /09 : per capsule or $ 73.43 for a 10 mL vial. 1. Two additional pancrelipase products ® ® Valganciclovir (Valcyte ®) is available as 450 mg (Viokase 8 and Creon ) were added to the tablets and a 50 mg/mL oral suspension (100 mL Inpatient and Outpatient Formularies. ® bottle) . The AWP is $ 46.61 per tablet , AWP 2. Basiliximab (Simulect ) was added for pricing for the suspension is not yet available .13 prophylaxis of acute organ r ejection after kidney transplantation. TM Summary 3. Prasug rel (Effient ) was added with Ganciclovir and valganciclovir have become restriction to Cardiology. ® standard components in most bone marrow or 4. Methylnaltrexone (Relistor ) was added with solid organ transplantation protocols for the restriction to Palliative Care and Oncology. prevention of CMV disease. Several recent studies describe the ir utility in the pediatric Contributing Editor:Marcia L. Buck, Pharm.D. transplant population as well as in congenital and Editorial Bo ard: Kristi N. Hofer, Pharm.D. neonatal CMV infection. Michelle W. McCarthy, Pharm.D. Susan B. Cogut, Pharm.D. References Website: Terry Bennett 1. McGavin JK, Goa KL. Ganciclovir: an update of its use in If you have comments or suggestions for future the prevention of cytomegalovirus infection and disease in issues, please contact us at Box 800674, UVA transplant recipie nts. Drugs 2001;61:1153 -83. Health System , Charlottesville, VA 22908 or 2. Ganciclovir and valganciclovir. Drug Facts and by e -mail to [email protected] . This Comparisons 4.0 . Efacts [online]. 2009. Available from Wolters Kluwer Health, Inc. (accessed 7/14/0 9). newsletter is also available a t 3. Cytoven -IV ® information. Roche Laboratories Inc., http://www.hea lthsystem.virginia.edu/internet/p August 2008. Availabl e at www.cytovene.com (accessed ediatrics/education/pharmnews.cfm 7/14/09).