antivirals for cytomegalovirus infection in neonates and
TRANSCRIPT
REVIEW ARTICLEPo"''''' Drugs 'XD>; II (5); :309-321117',51378/ry,~/$49,951O
@ 2009 Ad:s Dcr.c lnfotmOfoo BV, AI noNS fesetved.
..•. ...,. .-
Antivirals for Cytomegalovirus Infectionin Neonates and InfantsFocus on Pharmacokinetics, Formulations, Dosing, and Adverse Events
Beth C. Marshall and William C. Koch
Division of Infectious Diseases, Department of Pediatrics, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA
Contents
Abstract ....................•..•.........................•................................................•...... , 3091. Ganciclovir .............•...••.................................................................................. 311
1.1 Mechanism of Action ...................•.....................................•........•..................... 311
1.2 Spectrum of Activity ......•............... " ................................................................• 3111.3 Mechanism of Resistance 3111.4 Formulations..............................................................•..............•.................. 3121.5 Pharmacokinetics of Intravenous Ganciclovir In Infants ; 3121.6 Pharmacokinetics of Oral Ganclclovir in Infants ...........................................•...................... 313
1.7 Toxicityand Adverse Events.................................................•............................... '.. 3132. Vaiganciclovir ....•............................................................................................. 314
2.1 Mechanism of Action ............................................•....•.....•................................ 3142.2 Formulations..............................•...........................................................•..... 3142.3 Pharmacokinetics In Infants ......................................................•.•.......................... 314
2.4 Toxicity and Adverse Events............•...•..•............................................................... 3163. Foscarnet 316
3.1 MechanIsm of Action ...•..•......•.............•...•.•.....•................................................ 316
3.2 Spectrum of Activity ........•.... , ..........•.............. " ...................•.•.......................... 3173.3 Mechanism of Resistance ...•....•.•.•.............................•.•...........••........•................. 3173.4 Formulationsand Administration ...•.•.•........................•.....•........................................ 3173.5 Pharmacokinetics ............................................................................•......•....... 317
./ 3.6 Toxicityand Adverse Events , .•..•............•...............•....•................................... 3174. Cldofovir ....•.....•••.••............•.......•.................................................................. 318
4.1 Mechanism of Action ...................................................................•....••............•. 318
4.2 Spectrum of Activity .........................................................•...............•................ 3184.3 Mechanism of Resistance 3184.4 Formulationsand Administration ...........................................•.........•..••..................... 3184.5 Pharmacokinetics 318
4.6 Toxicity and Adverse Events '" ...................•............. ,3185. Dose Recommendations .....................•....•.............................................................. 319
6. Conclusion ..............•..................•... .' .. : •.•......................................................... 320
Abstract Cytomegalovirus (CMV) infection is very common throughout the world, and has become more of apediatric clinical concern given the high incidence of congenital CMV infections as well as the increasingnumbers of immunocompromised patients. Because of this, the need for antiviral therapies in infants andneonates is growing.
310 Mnrshnll & Koch
Currently, there are four antivirals available that are active against CMV: ganciclovir, valganciclovir,foscarnct, and cidofovir. At this time, none have approved indications for use in chiJdren. Although there arelimited data regarding the dose, pharmacokinetics (PK), safety, and adverse events for some of theseantivirals, ganciclovir, and its oral prodrug valganciclovir, have been the best studied in the infant and
neonate populations. In general, pharma~eutical PK studies in young children are limitcd by the constraintsof sampling difficulties and blood volume requirements; fewcr sampling times and studies may be avaiJablefor drug evaluation. Given this caveat, ganciclovir and valganciclovir PK in chiJdren thus far appcars tofollow a monocompartmental model, contrary to what has been described in adults. However, when normalized for weight, thc volume of distribution, clearance, and half·life of ganciclovir are similar to thosefound in adults. Given the findings that ganciclovir (and thus valganciclovir) clearance is directly proportionate to renal function, care must be taken when administering the drug to patients with impaired renalfunction. Recent studies evaluating valganciclovir PK in infants (at a dose of 16mglkg every 12hours) haveshown similar areas under the plasma concentration-time curve (AVCs) to intravenous ganciclovir (at adose of6 mglkg every 12hours), and that these AVCs remain quite stable over a number of weeks. As seen inadults, oral gancic10vir has a low bioavailability (4.8% in a pediatric analysis) and is therefore a pooralternative for treating serious CMV infections.
Neutropenia is the most frequent toxicity associated with ganciclovir and valganciclovir therapy, whereassignificant (and possibly irreversible) renal toxicity can be seen with cidofovir. Foscamet administrationcan also result in rcnal toxicity as well as significant electrolyte imbalances. Several of these drugs havepotential toxicities that arc of concern, including carcinogenesis, teratogenesis, and azospermia (ganciclovir,valganciclovir, and cidofovir) and deposition into bone or dentition (foscamet) that may have significant implications when treating an infant. Given these potential ill effects, careful consideration of the in·dications for the clinical use of these antivirals is necessary before using them for CMV infection in neonatesand infants.
Cytomegalovirus (CMV) is a ubiquitous virus first isolatedin the late 1950s from infants experiencing congenital infection,then termed cytomegalic inclusion disease,!1-3]It is a member of
the family of eight human herpesviruses and thus shares many
similar characteristics with these viruses, including its physicalstructure as well as features such as latency and the potential forreactivation.
CMV itself is most often of minor clinical importance, as most
.infections in healthy children and adults go unnoticed, or manifest as a self-limited mononucleosis-type syndrome. The virus iscommon in all areas of the world, and in fact in the US by the ageof 80 years, >90% of healthy adults have become infected with
CMV,!4] It is in situations where the immune system is compromised that CMV becomes much more of a clinically significantinfection. Such scenarios may include those seen with primaryimmunodeficiencies or with secondary immunodeficiencies, such
as with HIV infection, or with iatrogenic immune suppression,such as following bone marrow or solid organ transplant.
One particular instance of natural immune suppression isduring fetal life. During this time ill IItero, if a mother sustainseither a primary infection with CMV or a secondary infectionwith a different CMV strain, often neither she nor the fetus has
an immune response sufficient to prevent transmission to and
C>2009 Adi. Data In/ormation BV. All right. re.erved.
infection in the developing infant. The result is the syndrome ofcongenital CMV infection.
Congenital CMV infection is the most common congenitallyacquired viral infection in newborns in the developed world,and is estimated to occur in I% of all live births in the US
(approximately 40000 infants per year).!S] Symptomatic neo
natal infections often have significant sequelae with life-longimpact, as affected children frequently have severe cognitivedisability and developmental delays. Congenital CMV infection is also the leading infectious cause of sensorineural hearingloss; this frequently occurs in those infants symptomatic atbirth, but may also occur in up to 15% of infants withoutclinical evidence of congenital infection.l6]
Even though the syndrome and potentially devastatingoutcomes of congenital CMV infections have been understoodfor decades, it is only since the early 1980s that there has beeneven a potential pharmaceutical therapeutic option that is ac·
tive against CMV.[7] Furthermore, since this time, technologicadvances in the treatment of numerous conditions (such asmalignancies, autoimmune disorders, and solid-organ andbone marrow transplantation) have bcen·made, many of whichrequire significant immunosuppression for success. Likewise,the emergence of the HIV/AIDS epidemic has introduced
Pediatr Drug. 2OJ9; 11 (5)
Antivirals for CMV Infection in Neonates and Infants
another large group of chronically immunosuppressed patients.Because of all of this, CMV, either as a primary infection or as adisease of viral reactivation, has become much more of a clin
ical concern. Over time and with this changing medical climate,
these groups of immunocompromised patients have come toinclude neonates and infants who, alongside those infants with
congenital disease, may require therapy against CMV.Given these clinical scenarios, the need for antiviral therapy
active against CMV in neonates and infants has intensified;however, thus far there have been few therapeutic drug options
that have been studied in this group. This review presents a
systematic look at the potential pharmacologic options that areavailable to treat CMV in infants, and the data that are avail
able regarding the formulations, dose, pharmacokinetics (PK),and potential adverse events of each of these drugs.
A literature search was conducted using MEDLINEIPubMed and all available and pertinent literature was utilized
for the preparation of this review. Search terms included thenames of the individ!lal antivira]s used to treat CMV; these wereused in combination with 'pediatric', 'child', 'infant', and'neonate'. Searches for individual antivirals were also con
ducted using the Pubmed infant and pediatric age range limits.Focus was placed on studies reporting neonatal and infant
pharmacokinetics; however, when data were limited, studiesincluding older children were also used. Many additional references were identified from the reference lists of the published
articles identified by the electronic searches.
1. Ganciclovir
1.1 Mechanism of Action
The first agent found to have significant anti-CMV activity
. and to be approved for its treatment was ganciclovir. Previouslytermed DHPG on the basis of its chemical structure (9-[1,3
dihydroxy-2-propoxy-methyl]guanine), ganciclovir is similar toacic10vir in that it acts as a nucleoside analog of guanosine, and
structurally differs only by an additional hydroxyl group. Bothdrugs must undergo triphosphorylation once inside infcctedcells to become active; however, unlike in herpes simplex virus
(HSV)-infected cells, CMV-infected cells have no thymidinekinase for the initial phosphorylation step. It is the enzymeproduct of the CMV viral open reading frame (ort) UL97,
phosphotransferase, that first converts ganciclovir to5'-monophosphate gancic1ovir. Subsequent to this, cellularkinases d,iphosphorylate this monophosphate intermediate toganci~lovir triphosphate. In this triphosphorylated forn1, the
drug is able to inhibit viral DNA synthesis by two mec~anisms.
<C>'2OCFI Adis Dolo Information BV. All rights reserved.
311
First, the drug competitively inhibits the incorporation ofdeoxyguanine triphosphate by DNA polymerase, and hashigher affinity for the viral polymerase over the host cell enzyme, thus reducing (but not eliminating) inhibition of host cell
DNA production. Second, the drug becomes directly incorporated into the viral DNA chain, and, given the instabilityafforded by the acylic sugar side chain, it serves to inhibit the
addition of other nucleotides for chain elongation. Althoughaciclovir triphosphate is highly active against CMV DNApolymerase in cells, ganciclovir triphosphate is able to reachconcentrations JO-fold higher and thus has much greater inhibition of CMV replicationJ7J
1.2 Spectrum of Activity
In ill vitro studies, gancic10vir has been shown to have significant activity against CMV, inhibiting laboratory strains and
clinical isolates from growth in concentrations from 0.1 to1.6 JlglmL. It has also been shown to be active in tissue culture
against other herpesviruses, including HSV-l and -2; EpsteinBarr virus, human herpesvirus-6, and varicella-zoster virus(VZV)pJ
1.3 Mechanism of Resistance
The primary mechanism of viral resistance to ganciclovir isthrough mutations in the UL97 gene. As this gene encodes theviral kinase, mutations in two major regions of UL97 render the
enzyme less able or unable to phosphorylate gancicJovir; thus,the drug cannot be activated. As ganciclovir is the only one ofthe currently available antivirals against CMV requiring aninitial phosphorylation step, this mechanism of resistance isfairly specific to ganciclovir, and UL97 mutations alone do notpredict resistance to other agents active against CMV, such asfoscarnet or cidofovir. UL97 mutations account for 95% of
ganciclovir-resistant viral strains.[Sj
Another site for mutations that may confer viral resistanceto ganciclovir is that in the viral DNA polymerase. UL54 is theCMV gene that encodes the viral DNA polymerase, so unlikethe case with mutations in UL97, mutations in this area may
. confer cross-resistance to the other antivirals, most commonly
cidofovir. However, these mutations represent only 5% of thegancicJovir-resistant isolates)S!
It is generally believed that UL97 mutations arise first, andproduce moderate-level gancic1ovir-resistance at dose levelsthat are infectious to 50% of those exposed (IDso) of
8-30 ~lmollL(the normal IDso for CMV is 0.5-3 JlmoIlL). Highlevel resistance via UL54 and other mutations in the DNA
Pediatr Drugs 2009; 11 (5)
iiiiiilf
312 Marshall & Kodl
Table I. Pharmacokinetic data for intravenous gancfcfovir administered every 12hours to neonates in published studies and compared with adults·
Study (y) Dose (mg'kg) Vd (ml./kg)
Trang et alp21 (1993) 4 669±70 (396-1341)
Trang etalP2] (1993) 6 749±59 (524-1280)
ZhouetaLl13] (1996) 4-£ 694±69d
Anderson et aLl141(1995) [adultsj 5 750±10d .•
a Values are means±standard error of the mean (range) except where otherwise stated.
b Values are means (range).
c Values are means±standard error of the mean.
d Values are means ± standard deviation.
e Values are for V••.
Converted from mUminlkg.
9 Values are means.
CL = clearance: Cmu= maximum plasma concentration: ND= data not available: t",=half·life: Vd =volume of distribution; V•• = Vd at steady state.
CL (mUhlkg)
189±28 (63-479)
189±28 (63-479)
172±45d
231±35d.I
t~ (h)
2.4 (1.&;-7.2)b
2.4 (2.1-£.9)b
ND
2.99
C""" (l1gtmL)
5.5±1.6c
7.0±1.6c
ND
8.39
polymerase is reported at >30 Ilmol/L.[9.11]Clinical tcsting usingrestriction enzyme analysis to detect m.utations in the UL97 and
viral DNA polymerase genes to predict drug resistance iscommercially available and often used when expected clinicalresponse is not achieved.
1.4 Formulations
Intravenous (IV) gancicIovir is available as a powder forreconstitution in 100mL of 5% dextrose in water, normal sa
line, or lactated ringers that must be infused over I hour. Theoral formulation of gancicIovir is available as a 250 mg capsule.(available as a generic formulation only). Currently, there is no
commercially prepared suspension of ganciclovir available.
1.5 Pharmacokinetics of Intravenous Ganciclovir in Infants
Although the PK of gancicIovir in adults has been well stu
died, such data for the pediatric population are minimal. Furthermore, PK information for infants and neonates is
particularly sparse as pediatric drug PK studies are subject tothe significant limitations of small blood volumes and few
. sampling times allowed in clinical studies in children. Most ofthe information known about gancicIovir PK in infants derives
from three studies originating from the National Institute ofAllergy and Infectious Diseases Collaborative Antiviral StudyGroup (NIAID CASG).
The first study of gancicIovir PK in neonates was reported byTrang et al.[12]in 1993. In this open-label, phase I-II trial, thePK of IV ganciclovir were studied in 27 neonates, aged 2-49days, with symptomatic congenital CMV infection. All hadevidence of CNS involvement with or without concurrent dis-
iO 2009 Adjs Dolo Information BV. AJItighls reserved.
case in other organ systems. These neonates were randomizedto gancicIovir therapy at either 4 or 6 mglkg per dose every12 hours for 6 weeks. Serial blood sampling provided PK data,and analyses were based on a single-compartment open modelassuming zero-order input and first-order elimination.
Specific PK data for each of the doses studied are presentedin table 1.(12)The mean values obtained for the apparent volumeof distribution (Vd), clearance (CL), and half-life (ty,) did not
differ significantly between the dose groups, and when normalized for bodyweight, were found overall to be similar tothose reported in adults. There was wide variation in the valuesofVd and Vss (Vd at steady state) found for individual infants,reflecting the variation in infant bodyweight; these parametersincreased with an increase in bodywcight. Likewise, CL in
creased with patient age, reflecting the well known changingrenal function in newborns; however, this change was not significant enough for the authors to recommend dose alterationswith age, even for premature infants.
As seen with Vd and CL, mean residence time and area under
the plasma concentration-time curve normalized for dose given
(AUC/dose) were also similar between both dose groups,l12]Plasma concentrations of gancicIovir decreased mono
exponentially in each neonate, and the mean maximum plasmaconcentration (Cmax) peaks in groups receiving 4 mglkg and6 mglkg were 5.5 IlglmL and 7.0 IlglmL. rcspectively;[12]this was
somewhat lower than in adults, who demonstrated a mean peakrange of 8-11 ~tglmL after a dose of 5mglkg,l15] The mean tv,for both dose groups was 2.4 hours, consistent with the
reported ty, in adults (2.9 hours[14]).Urinary excretion of gancicIovir over a 24-hour time period
was measured in 12 of the infants, with recovery of unchangedgancicIovir found at 117.1% of the total administered dose of
Pediatr Drugs 2009; 11 (5)
;;.,......... .1,
Antivirals for CMV Infection in Neonates and Infants
8 mglkglday (n=7) and 95.4% of the total administered dose of
12mglkglday (n = 5).[12]Further evaluation of urinary excretionat days ],2, 'and 10 after completion of therapy found no residual ganciclovir present in the urine. This confirmed that, asin adults, ganciclovir is entirely excreted, unchanged, by thekidneys.
Overall, the conclusions from this study, although poten
tially limited by the small number of sampling times, includedthe finding that a one-compartment model with linear PK satisfactorily described ganciclovir disposition in these neonateswith congenital CMV infection.l12) This conclusion was different from that of adult PK studies that demonstrated that dis
position and CL in this population are multicompartmentaJ.ll6]In another study published 3 years later, Zhou et a]'p3) re
analyzed the same 27 infants examined by Trang et aJ.[12]to
perform a population-based PK analysis (using non-linearmixed-effects modeling analysis). This modeling analysis
attempted to identify individual characteristics of infantsthat may account for individual variations in drug PK. In all,13 co-variates were analyzed that potentially impacted PK
parameters. Of the characteristics studied, the authors foundthat the approximate serum creatinine CL (ASCC) for eachinfant' affected ganciclovir CL, and bodyweight altered drugYd. Regression equations were subsequently formulated tomodel these relationships, and the final CL and Vd were quite
similar to those obtained by Trang et al.[12](see table I).These authors concluded, as did Trang et al.,[12]that ganci
clovir CL increases linearly with increased ASCC and that Vd is
a linear function of the weight of the infant.I13]However, giventhe similarities in the findings, no basis for dose alterations
could be made. Again, however, the significant impact of renalfunction on drug disposition was found, suggesting that keenattention must be paid to alterations in dose in those with renal
impairment.In the largest PK study of ganciclovir in infants to date,
Whitley et a1.(17)evaluated 42 infants with symptomatic'congenital CMV infection who received IV ganciclovir at one oftwo doses for 6 weeks in a phase II trial. These infants included
those reported on by Trang et al.[12]and Zhou et aJ.l13]Fourteeninfants received a dose of 4mglkg every ]2 hours while 18 received 6mglkg every ]2 hours. All infants were <I month of age,70% were White, and over one-third were premature. Blood
samples for PK analysis were obtained at times 0, 0.5, 2, 3, 4, 6,8,24, and 48 hours of administration; weekly peaks and troughswere obtained thereafter. Again, based on the previous CASGstudies, a one-compartment model, with zero-order input andfirst-order elimination was used. The ganciclovir dose was
changed (reduced by 50%) if the absolute neutrophil count
~ 2009 Ad .•s Data 1nIocmotion BV. All rights reserved.
313-(ANC) fell below 500 cells/~IL or platelets below 50000/~1L.Although this was largely a safety and tolerability study forinfants with congenital CMV infection, as with previous studies, this study found that plasma drug CL was proportionateto renal function in these infants, and Vd was proportionateto bodyweight.
Data regarding ganciclovir tissue penetration data are in
complete, particu]arly for the pediatric population. Despite this,it does appear that ganciclovir crosses the blood-brain barrier togain CNS penetration. One study showed that at a serum concentration of 2.2 ~g1mL (3.5 hours after an IV dose of 2.5 mglkg
in adults), a cerebrospinal fluid concentration of 0.7 IlglmL wasobtainedP61 The fraction of the administered dose of ganciclovirthat is able to penetrate the CNS is unknown.
1.6 Pharmacokinetics of Oro 1 Ganclclovir In Infants
In the only large pediatric study evaluating the PK oforal ganciclovir, children with HIV and CMV disease (aged2 \veeks-20 years) were administered varying doses of oral
ganciclovir in either tablet form or a compounded suspension;
ganciclovir powder used for the IV formulation was dissolvedin sterile water and mixed with cherry syrup for administration to children unable to swallow pills,ll8] This study ex
amined ganciclovir doses ranging from 10mglkg to 50 mglkgevery 8 hours and measured Cmax, which was found to occur2-2.5 hours after the oral dose for all dose levels in all children.
The mean bioavailability of the suspension (4.8%) was similarlypoor to that reported in adults (6-9%).17)
Only two of the children in this study were aged <2 years.[I8]Both of these children received ganciclovir 30 mglkg andhad the lowest AUCs of the children studied at 1.0 and
2.9 Ilg. h/mL. The third-youngest child (25 months of age) hadan AUC of7.0~g.h/mL at a dose of 50mglkg. Overall, themedian AUC for the children studied (largely represented by
older children) was 4.9 Jlg • h/mL at a dose of30 mglkg, which iscomparable to the AUC of 4.29 J.1g. h/mUI8) found in adultsadministered - 15mglkg (1000 mg dose). However, the extent ofabsorption was generally limited.
1.7 Toxicity and Adverse Events
In adult studies, the most frequently encountered and
serious drug toxicity associated with ganciclovir is bonemarrow suppression, particularly neutropenia, occurring inabout 40% ofpatients'p9] Thrombocytopenia may also oceur inabout 20% of ganciclovir-treated adults, and anemia in about2% of these patients. However, all of these blood-count
Pedia!r Drugs 2009; 11 (5)
•I
314
abnonnalities may also occur as a result ofCMV infection and
if one of these is present prior to starting ganciclovir, it mayactually improve with therapy.
In the phase II study by Whitley et a1.,(17)neutropenia (defined as >50% decrease in ANC from baseline or ANC
<1000 cells/j.tL) was also the most significant adverse eventseen in infants. Sixty-three percent of infants treated with a
total daily dose of 8 mg/kg and 19% of infants treated with atotal daily dose of 12mg/kg demonstrated neutropenia, givingrise to an overall rate of neutropenia of 34% in all infantstreated with ganciclovir. Three of the children in the 8 mg/kg
dose group had to discontinue the drug because of persistent. neutropenia despite dose reduction. In this group of infants,
neutropenia was not dependent on dose; however, in adultstudies, this toxicity has appeared to be dose dependent. Inadult studies, ·the neutropenia may be dose-limiting in 15% ofcourses;[19]however, as is also scen in pediatric data, this toxi
city is reversible on discontinuation of the drug.Neutropenia associated with gancicJovir was a)so noted in
an efficacy study published in 2003 involving congenitally infected infants.(20) Overall, 63% of infants who received ganci
clovir experienced grade 3 or 4 neutropenia compared with 21%of infants who were not treated. Fourteen of the 29 infants
treated with gancielovir who developed neutropenia requireddose reduction and four ultimately had to discontinue gandclovir to resolve the neutropenia.
In the study of oral ganciclovir in children,[IB] 22% had
neutropenia (defined as an ANC <400cells/j.tL),. but anadditional 13.9% had an ANC of 400-1 200 celis/ILL. This is
similar to the less-frequent occurrence of this toxicity seen in
adults. Again, this adverse event was not found to be doserelated but revcrsible on discontinuation of GCV.
As in adults, another adverse event seen in infants treated with
IV ganciclovirll7)was thrombocytopenia; overall, 38% of children
in this study developed platelet counts <50000 celiS/ilL. Adultstudies have reported about a 15% incidence of thrombocytopenia.[7]Only 2% of children in this study[l7] developed anemia.
Another concern in adult studies is that of other laboratory
abnormalitics, including elevations in creatinine and liverfunction test results. In the study by Whitley et al.,!17]68% ofthe infants studied had no changes in serum creatinine levels.
Of those that had changes in serum creatinine levels, no childhad more than a 0.5 mg/dL increase from baseline, and nonedeveloped a creatinine level >2.0mg/dL. A total of 36% hadincreases in hepatic enzymes (AST >250IU/dL and AL T> 150 IU/dL) and 66% had elevations in direct bilirubin.
There are a host of other adverse events of gancicJovir reported
primarily in adult patients, including CNS disturbances (includ-
It> 2009 Adis Dolo Information BV. An rights reserved.
~ ...
Marshall & Koch
ing headache and psychosis) as well as fever and rash.[I5]Data on ,the occurrence of these adverse events in children are lacking.
One concerning toxicity found with gancicJovir administration in animal studies is that of azospennia and the potential·
for pennanent reproductive toxicity that may occur in males ;(and possibly females).£2I) Preclinical studies have also de
monstrated teratogenicity and mutagenicity in animalsp2]Thus, long-tenn concerns for impairment of fertility as well ascarcinogenesis must be considered when treating children withgancic1ovir, notwithstanding the fact that data regarding thesetoxicities in humans are incomplete.
2. Valganciclovir
2. t Mechanism of Action
Valgancic10vir is an L-valine ester prodrug of gancic10virdeveloped to increase the bioavailability of orally administered
gancic1ovir[23]and to avoid the inconvenicnce and risks associated with IV administration and catheter-related complica
tions. Oral gancic10vir has a bioavailability of only 6%,[22]whereas valgancic10vir has been shown to have a 10-fold increased bioavailability over this (-60%) in adult studiesP3]
After ingestion, valgancic10vir is transported from the intestine to the bloodstream by a peptide transporter, and sub
sequently liver and intestinal esterases rapidly convertvalgancic10vir to gancic1ovir. The mechanism thereafter is assumed to be as described for gancic1ovir.
2.2 Formulations
Currently, valgancic10vir is commercially available only as ahydrochloride in a 450 mg tablet fonn. Although there is asuspension fonnulation in development, it is not available atthis time, and there are no current US FDA-approved indications for the use ofvalgancic1ovir in children. Extemporaneouspreparations have been proposed and found to be stable for
up to a month when refrigerated;(24) however, use of thesecompounded solutions is controversial and not generallyrecommended given the potential lack of consistency in theformulation and the potential variability in their preparation.
Although not yet commercially available, a pharmaceutical grade suspension of valgancic10vir is currently beingevaluatedp5.26]
2.3 Pharmacokinetics in Infants
As with most newly introduced medications, the majority ofavailable PK data for valgancic10vir thus far are derived from
Pediot, Drugs 2009; 11 (5)
-~ .~
Antivirals for CMV Infection in Neonates and Infants
studies in adults. In these studies, concentrations of valgancidovir have been found to be transient: the mean tv, is <I hourafter dose administration, and gancicIovir Cmax usually occurs2-3 hours after administration. Studies in adults have shown
that although the drug is well absorbed, a high-fat meal increases the AVe by 24-56%; therefore, it is recommended thatvalgancic10vir be administered with food. These PK data in
adults have shown tha! valgancic10vir 900 mg/day achieves similar AVC to the standard ganciclovir 5 mglkg/day maintenance dose,127)
There are several individual case reports of infants treatedwith valgancicIovir compounded as a suspension for the
treatment of congenital CMV or CMV disease in the perinatalperiod;128-31]however, few PK studies exist in the pediatricpopulation in general. Most reports of the use ofvalganciclovirin children have been either in patients with HIV infection or inthose immunocompromised after transplantation.
In the first study examining valganciclovir plasma concentrations specifically in infants, eight neonates between the
ages of 4 and 90 days with symptoms of CNS involvement ofcongenital CMV infection were studied.[32] After an initialfirst week ofIV ganciclovir treatment (5 mglkg every 12 hours),
the parents of these infants refused to consent to centralcatheter placement for the additional 5 weeks of therapy; thus,oral valganciclovir (as a compounded suspension) was initiated. Based on reports of 40-60% bioavailability of ganciclovir from valganciclovir,[31,33] the first four infants enrolledreceived valganciclovir 15mglkg once daily. This dose resulted
in low plasma concentrations of ganciclovir and the nextfour infants accordingly received valganciclovir 15mglkg
twice daily.Trough (immediately before dosing) and peak (I hour after IV
ganciclovir and 1.5 hours after valgancicIovir) plasma con'centrations were obtained once drug concentrations were at a
steady state (after 3 days for IV ganciclovir and after 7 days fororal valganciclovir)'p2) Only the infants treated with valganci
clovir 15mglkg twice daily had drug concentrations that werestatistically not different from those for IV ganciclovir: a peakconcentration of 3.111g/mL was measured in the valganciclovirtreated infants and a peak concentration of 1.9511g/mL wasmeasured in the IV ganciclovir-treated infants. In addition,
this study demonstrated that the significant decrease in CMVviruria seen with IV gancicIovir therapy was similar to that seenwith both dose levels ofvalganciclovir; however, the higher total
dosage of 15mgikg twice a day resulted in less quantitative viral
shedding compar~d with the lower dose of 15mg/kg once a day.In the largest study of valgancicIovir in pediatric patients
reported thus far, investigators from the NIAID CASG
II:) 2009 Adis Data Information BV. All rights reserved.
315
performed a phase I-II study ofpopulation'PK in 24 neonatesusing the commercial oral suspension of valgancicIovir that isnot yet available for clinical usePS] This study was conducted
in anticipation of the use of the oral preparation in studiesdesigned to determine the optimal duration of therapy toachieve the best outcome in infants with eNS involvement with
symptomatic congenital CMV infection.In this study,[2S) infants received some combination of IV
ganciclovir and oral valgancicIovir for 6 weeks. The first five
patients (version I) received 6 mglkg of IV ganciclovir every12 hours with interruptions on days 5-6 and days 35-36, atwhich time oral valganciclovir (14 mglkg twice daily) was givenwith PK data collccted on days 4,'6, 34, 35, and 36. Accrual inthis initial version of the study was difficult, resulting in onlyfive patients over a 22-month period. Accordingly, a secondversion of the study was commenced to enrol greater numbers.Over the next II months, 19 more infants were enrolled in
the more pennissive (version 2) protocol: infants received a
single dose ofvalganciclovir followed by serial blood samplingto assess PK data, and were then started on IV ganciclovirfor 2 weeks. PK data on IV ganciclovir (again administeredat 6mglkg every 12 hours) were obtained afler the seconddose was given. After the infants had received 2 weeks of IV
therapy and their PK data on the initial oral valganciclovir
had been analyzed, the infants began 4 weeks of oral t~erapyat home.
During the oral valganciclovir phase, samples were obtainedI week and 2 weeks after starting this therapy; dosing started at14mglkg but could be changed based on the PK determinations
for each infantPS] The goal of therapy for this version was anAVC from time 0 to 12h (AUC12) of27mg. h/L, based on thepilot study by Trang et al.[12]Data from both versions wereanalyzed together.
In version 2, nine patients received 14mglkg/dose, six
received 16mglkg/dose, and four received 20 mglkg/dose,all twice dailyPS] All PK data were consistent with a one-compartment model, and bodyweight was the most significant factor(postnatal age, sex, and body surface area did not provide different information once weight was taken into account). Overall,
the findings of this study were very comparableto previous studies of IV ganeiclovir PK. Previous studies ofinf.1nts receiving 6mglkg of IV ganciclovir reported an AVe(AVe to time infinity by the trapezoidal rule) of 27 mg. hfL(12)and, in adults, 5 mglkg of IV ganciclovir provided an Aueof25.4 mg. hfL.[21)In the study by Acosta et al.pS] 6 mglkg of IVvalganciclovir provided an AVC of 21 mg. hfL and 16mglkg ofvalganciclovir suspension provided an AVe of 27 mg. h/L.Thus, a 16mglkg dose of the phannaceutical grade valganciclovir
Pedial, Drugs 2009; 11 (5)
Supplied by The British Library - "The world's knowledae"
./
316
suspension twice daUy appears to adequately establish gancicIovirconcentrations similar to those achieved with the 6 mg/kg twicedaily IV gancicIovir formulation.
Another important finding of this study was that in this
population of neonates, valgancicIovir demonstrated an overall54% bioavaiiabilityJ25] In another evaluation ofvalgancicIovirtablets, a bioavailability of 43% was found in a 6-year-oldchUdP~] Adult data have demonstrated a bioavailability of
60%,[35Jand it is therefore important to recognize that drugavailability might not be equivalent in this younger population,at least until further data are obtained.
In a recent publication by Kimberlin et al.,[26]additional PKdata from the same infants evaluated in the previous report[25]showed that in the five infants treated with IV gancicIovir theAUC12 for gancicIovir was reduced by almost one-half (41%reduction), whereas the CL of IV gancicIovir nearly doubled(73% increase) in the first 6 weeks of life. By contrast, only asmall decrease in AUC12 was seen with oral valgancicIovir (15%decrease) over the same time period. The investigators attributed this relative stability in AUC12 to the increase in drugbioavailability (32% increase) that occurred during this timewhen a concurrent increase in CL was also taking place.
Given the significant impact of CM;V disease on transplant
patients, many pediatric transplant centers are using valganciclovir both prophylactically and therapeutically in theirpatients because of the need for long-term therapy andthe advantage of oral formulations. The majority of the published studies in these groups of patients are in older childrenand therefore outside the neonatal/infant age group pertinentto this review. However, given the differences in some of
the data that have been reported, it is important to note thatthe PK of both ganciclovir and valganciclovir in this specialpopulation may differ somewhat from the studies reviewed .
here and this may also impact infant dosing in this clinicalsituation.
In a review of 20 children post-solid organ transplant
(mostly renal transplants, mean age 8.6±5.5 years), 15 ofwhom were treated with oral valganciclovir,[36] a similar bioavailability compared to that mentioned previously[25.3~] forvalgancicIovir of 42% was found. Despite the similarity topreviously reported data, this study, together with another that
preceded it[37] (also in pediatric renal transplant patients),found significant interpatient variability in gancicIovir concentrations, as high as 83%, with valgancicIovir. Even whencomparing the findings of these two studies with one another,trough concentrations of IV gancicIovir administered at thesame dose varied by over 70% between the populations.The major difference in these studies was the mean age of the
<c>2009 Adis Data Information BV. All rights reserved.
Marshall & Kodl
patients; the study reporting the lower measured troughs[36]evaluated children with a mean age of 4.5±3.1 years whereasthe study reporting the higher troughs[37]studied children witha mean age of 11.0± 3.9 years. In addition to the age of thepatient acting as a major factor in drug concentration and PKvariability, the authors of these studies also suggested thatvariable function of the transplanted kidney (sometimes froman adult donor) plus significant potential drug-drug interactions in these post-transplant patients may significantly alterdisposition of valganciclovir (as well as gancicIovir and otherantivirals) from what is expected.
Although not yet available, resulls from studies of thepharmaceutical grade oral suspension of valganciclovir in
general appear to be promisingP6,38] While such studies havealso been conducted primarily in the pediatric transplantpopulation, recent reports suggest that the safety and overallPK of the suspension are bioequivalent to those of the tabletformulationp9]
2.4 Toxicity and Adverse Events
The toxicity and adverse events of valganciclovir seen inadults are essentially the same as those for ganciclovir, given
that valganciclovir is a prodrug of the latter. In individual casereports of the use of valganciclovir in neonates and infants,
toxicities have varied from none[28.30,31]to neutropenia (after5 weeks of therapy on 15mglkg three times daily in a 7-monthoJd[29]).In a retrospective review of pediatric liver transplantrecipients (mean age 4.9±5.6 years) who received valganciclovir 15-18 mglkglday for 100 days post-operatively for CMVprophylaxis, no CMV disease was encountered and novalganciclovir-related toxicities were reported.[40]
In the recently published valganciclovir PK study by Kimberlin
et al.,[26]of the 24 infants enrolled, 38% (n=9) developed grade
3 or 4 neutropenia on therapy (seven developed grade 3; twodeveloped grade 4). Of these nine infants, one required
dose adjustment and one required discontinuation of the drug.Other toxicities seen included grade 3 anemia in 13%; grade3 hyperbilirubinemia in I%; and grade 3 increased ALTin 1%.
3. Foscornet
3.1 Mechanism of ActIon
Foscamct (trisodium phosphonoformate) is an inorganicpyrophosphate analog that binds reversibly to viral DNA polymerase and blocks cleavage of the pyrophosphate from deoxynucleotide triphosphates, thus halting DNA chain elongation.[41)
Pedia!, Drugs 2009; II (5)
Antivirals for CMV Infection in Neonates and Infants
Since foscamet has a higher affinity for viral polymerase, inhibition of host DNA polymerase requires lOa-fold greater concentmtions of the drug.£42]Unlike gancic1ovir, foscamet requiresno modifications once in the host to become active.
3.2 Spectrum of Activity
Foscamet has been shown to be active ill vitro against many
members of the herpesvirus family, including HSV-l and -2,CMV and VZV. It also has activity against hepatitis B, and
given that it may also inhibit reverse transcriptase, it is alsoactive against HIV, although it is rarely used clinically to treatthese viruses.[42]
3.3 Mechanism of Resistance
Unlike gancic10vir (and valganciclovir), foscamet does not
require activation (phosphorylation) by the viral kinase; therefore, resistance to these agents via UL97 mutations does not resultin cross-resistance to foscamet. Since all current antivirals active
against CMV ultimately act on the viral DNA polymerase as an
end-target, mutations in the region encoding this enzyme couldpotentially confer resistance to any ofthese antivirals, and certainpatterns of resistance have been seen. Although less commonthan the well recognized cross-resistance that can be seen between
gancic10vir and cidofovir, cross-resistance between foscamet andcidofovir has also recently been described.£43]
3.4 Formulations and Administration
Given its poor bioavailability, foscamet can be administered
only as an IV formulation; it is available as a solution in a concentration of 24 mg/mL. Careful administration is required, at arate not exceeding 1mglkglminute, and dilution is required for
peripheral administration. Given the renal complications thatmay occur (see section 3.6), prehydration with normal saline or5% dextrose in water is recommended. Careful attention must
also be made to solutions being administered concurrently:foscamet is incompatible with lactated ringers, total parenteralnutrition (TPN), vancomycin, or any solutions containingcalcium or magnesium. Currently, there are no FDA-approvedindications for the use of foscarnet in pediatric patients.
3.5 Pharmacokinetics
PK data on foscamet derive almost exclusively from adultstudies as no such studies in infants or children have been re
ported to date. There are numerous small case series or reports
(: 2009 Adis Data Information BV. All rights reserved.
317
of children who have been treated with foscarnet, usually in the
case of presumed or proven infection with CMV, VZV, or HSV,and most have had fairly favorable outcomes. However, mostof these children have been older, and most have been im
munocompromised by chemotherapy or stem-cell transplantation; therefore, evaluation offoscarnet toxicities is difficult in
light of concurrent disease and therapies. The only report offoscamet use in a neonate with congenital CMV disease andextensive liver pathology resulted in a favorable outcome.[44]
Data from adult studies have shown that 80% of the ad
ministered foscarnet dose is renally excreted metabolicallyunchanged,£451indicating that dose adjustments for any degreeof renal impairment must be made. Roughly 20% of theadministered drug is taken up into bone and cartilage[42] andthis may have serious implications, particularly for pediatricpatients. The ty, of foscamet has been estimated at 48 hours,and although data regarding tissue distribution are lacking,cerebrospinal fluid levels are about two-thirds of serumconcentrations.!461
3.6 Toxicity and Adverse Events
The most significant and worrisome toxicities associatedwith foscamet arc renal insufficiency and electrolyte disturbances. In adult studies, 27% of AIDS patients receiving
foscarnet experienced a decrease in renal function, most likelyas a result of renal tubular damage.!42] This adverse findingmost often occurs 6-15 days after starting on the medication
and is reversible in patients with normal underlying renalfunction; thus, frequent monitoring of renal function tests
(creatinine, blood-urea nitrogen) is prudent. Occasionally thistubular dysfunction may manifest as nephrogenic diabetes insipidus without evidence of rising creatinine levels; therefore,monitoring for clinical symptoms, such as polyuria and polydipsia, is also recommended. Careful attention to hydrationstatus appears to limit renal toxicities significantly.
Electrolyte abnormalities also occur quite frequently in patients taking foscarnet, and these also must be carefully andcontinually monitored.!42] Hypocalcemia occurs often and ismost likely due to complex formation between free calcium andthe drug (thus, foscarnet may not be co-administered with TPNor other calcium-containing solutions such as vancomycin).Additionally, hypomagnesemia may occur (contributing to thehypocalcemia and also to hypokalemia) in addition to hypo- orhypcrphosphatemia.
About 10% of adult AIDS patients treated with foscarnetwere reported to have developed seizures; however, many ofthese were due to electrolyte abnormalities, impaired renal
Pediatr Drugs 2009; 11 (5)
.•...... '-
318
function, or a baseline seizure disorder.[42] This adverse event,
like many others noted for foscarnet as well as cidofovir, isdifficult to evaluate because most patients treated with these
agents have significant underlying disease states and arc takingconcurrent medications that may have played a role in toxicity.
As a significant portion of the administered dose offoscarnet
deposits in bone and cartilage, the potential for bone and dentaltoxicity is a significant concern, particularly for the pediatric
population.[47]
4. Cidofovir
4.1 Mechanism of Action
Cidofovir (HPMPC, or 1-[(S)-3-hydroxy-2-(phosphono
methoxy)-propyIJcytosine dihydrate) is a monophosphate nucleotide analog of cytosine. Once inside the host cell, cidofovir
must undergo diphosphorylation via cellular enzymes. Becausethe drug is itself a phosphonate, cidofovir is not dependent onviral kinases as is ganciclovir. Once diphosphorylated to itsactive state, cidofovir acts to competitively inhibit incorpora
tion of host deoxycytidine into the viral DNA by viral DNA
polymerase.[48] Once incorporated into the DNA chain, cidofovir significantly impairs further chain elongation, and in
corporation of two consecutive diphosphorylated cidofovirmolecules halts DNA synthesis.f49]
4.2 Spectrum of Activity
Cidofovir has ill I'itro antiviral activity against a very broad
spectrum of DNA viruses. It has demonstrated activity againstall of the human herpesviruses as well as numerous animal
herpesviruses, and its activity against guinea pig CMV has facilitated studies of its use in the potential prevention of con
genital disease because this animal model is used in the study ofmaternal-fetal transmission of cMV.fSO,51]
Additionally, cidofovir has been shown to have activity
against poxviruses, polyomaviruses, papovaviruses, and 'adenoviruses.[52] As a systemic agent, it has historically been usedmost often to treat CMV, particularly CMV retinitis in AIDS
patients or in refractory or resistant infections. More recently, ithas increasingly been used to treat some other viral infections,
particularly when they are tife threatening.
4.3 Mechanism of Resistance
As with f~scarnet and less frequently with ganciclovir, mutations in viral DNA polymerase may confer resistance to
<:> 2009 Adis Dota Information BV. All righls reserved,
...- ...
Marshall & Koch
cidofovir. Resistance via this mechanism may often occur
concurrently with ganciclovir resistance.[S3] Since cidofovirdoes not require phosphorylation by the CMV phosphotransferase, viral resistance to ganciclovir via these mutations
does not imply cross-resistance to cidofovir.
4.4 Formulations and Administration
Cidofovir is available only as an IV solution at a con
centration of 75 mg/mL. Similar to foscarnet, patients must be
well hydrated prior to cidofovir administration to minimizerenal complications. In adults, prehydration with I L of normalsaline is generally recommended, and, if the patient is able totolerate it, again 2-3 hours after the infusion. Because there areno FDA-approved indications for use of cidofovir in children,these recommendations must be adjusted by each practitioner
according to the size of the patient.
4.5 Pharmacokinetics
As with foscarnet, PK data for cidofovir in children are ex
tremely limited, and information regarding the disposition ofthe drug derives from adult literature, mostly on immuno
compromised patients.Most (over 80%) of the drug is renally excreted unchanged
within 24 hours after administration. There is an active meta
bolite, cidofovir diphosphate, which is eliminated more slowlyin a diphasic manner, with a first phase intracellular tv. of24 hours and a second phase intracellular t y, of 65 hours. Because of the slow elimination of this metabolite, cidofovir is
able to be administered every 2 weeks,fs4]One report of a single
pediatric cancer patient (age not given) found significantlygreater CL of cidofovir (with a resultant markedly reduced ty,and CmaJ, which suggests that pediatric patients may requirehigherdoses.[5S] However, further investigation is required.
4.6 Toxicity and Adverse Events
As with foscarnet, the most commonly encountered toxicityfound with cidofovir administration is renal impainnent, which
is seen in approximately 50% of adults in clinical trials.fs6]Thiseffect may initially manifest as proteinuria, increased serumcreatinine, or a Fanconi-type syndrome (proteinuria, glycos
uria, bicarbonate wasting), and may result in pennanent renal
impairment or failure. Thus, great care must be taken whenadministering cidofovir to individuals with proteinuria and/orelevated creatinine levels at baseline, or to patients takingconcurrent nephrotoxic medications.
Pediatr Drugs 2009; 11 (5)
Antivirals for CMV Infection in Neonates and Infants
In one case series of pediatric stem-cell transplant patients(median age [range] 10 [2-14] years), ten patients received thedose recommended for adult patients.[S71 Only one patient demonstrated renal toxicity, and he had concurrent, significantlyelevated tacrolimus concentrations that may have served as a
predisposing impairment.Two interventions have been recommended in attempts to
prevent this renal toxicity: hydration and probenecid administration. Hydration, preferably with normal saline, before andafter cidofovir administration is recommended and has been
shown to significantly reduce renal toxicity.rs8)Probenecid, whichblocks active renal tubular secretion, prevents drug uptakeinto the proximal tubular epithelial cells and hence drug-induceddamage. In this way, probenecid also acts to slow renal excretionof the drug and maintain drug concentrationsJs9] Probenecidshould be given prior to as well as after cidofovir administration
and may itself cause nausea/vomiting and/or rash.As with foscarnet, careful monitoring of renal function, in
cluding proteinuria, glycosuria, and serum creatinine levels,
should be performed prior to each subsequent dose of cidofovir. Renal dysfunction is usually reversible with discontinua-
319
tion of the drug; however, permanent renal impairment hasbeen seen in several HIV-infected patientsJs61
Other toxicities seen with cidofovir include neutropenia,
metabolic acidosis, and ocular hypotony.[60] The frequency ofneutropenia seen with cidcifovir (approximately 20% of patients) has been difficult to assess as direct drug toxicity sinceCMV disease itself often produces low white blood cell counts.
Also similar to gancicIovir, animal data have shown that
cidofovir has carcinogenic and teratogenic potential.[611 Additionally, cidofovir also has been found to cause hypospermiain these preclinical studies. Although there is no evidence of
these effects in humans at this time, these findings indicate thatcare should be taken when administering the drug to children.
5. Dose Recommendations
Formulating dose recommendations for children for the anti
virals discussed in this review is difficult because of the paucity ofavailable data. Table II represents the best current recom
mendations for neonates and infants, with doses for gancic\ovir
Table II. Dosage and administration recommendations for antivirals against cytomegalovirus (CMV) In neonatesJinfants
Same as for ganciclovir
Prehydrate with normal saline
Monitor renal function carefully during
therapy; monitor electrolytes including
potassium, phosphate, calcium
Requires dose adjustment for renal
impairment (creatinine clearance
~1.4ml.J1<g'min)
Monitor renal function carefully during
therapy
Requires dose adjustment for renal
impairment (serum creatinine >1.5mg/dL,creatinine clearance $55mUmin, urine
protein ~100 mg/dL [~+ protein))
Probenecid should be administered prior todose
a Although not approved, many experts consider symptomatic congenital CMV infection with CNS involvement an indication for IV ganciclovir therapy.
b Recommendations are for the pharmaceutical grade suspension only.
IV=lntravenous; PO = orally.
Drug
Ganciclovir (IV)
Valganciclovir
Foscarnet
Cidofovir
Dosage and administration
6 mglkg IV every 12 h
16mgikg PO every 12hb
60 mgikg IV every 8 h or
90 mgikg every 12 h for 14-21 d
(induction) then 9G-120mgikg
every 24 h (maintenance)
5 mgikg IV daily for 2 wk
(induction) then 5 mgikg every
other wk (maintenance)
Notes
Monitor complete blood count weekly
(neutropenia, thrombocytopenia, rarely
anemia); monitor liver enzymes
Requires dose adjustment for renal
Impairment
Approved Indications
Ufe- or sight
threatening Infections in
immunocompromised
patients; prophylaxis In
immunocompromised
patients8
None
None
CMV retinitis
References
17
25,26
No established
guidelines for pediatric
dosage andadministration
No established
guidelines for pediatric
dosage andadministration
~ 2009 Ad~ Doto Information BV. No rights reserved. Pediatr Drugs 2009; 11 (5)
320
and valgancic10vir (phannaceutical grade suspension) being bestsupported by data in this subgroup of pediatric patients in thesetting of congenital CMV infection. Dose infonnation for foscamet and cidofovir, which are clearly second-line agents for antiCMV therapy, is based on recommendations for the treatment ofadults with HIV infection.
6. Conclusion
Although antiviral options for children with CMV diseasehave progressed significantly over the past several decades, data
regarding the disposition and, thus, optimal dosing for thispopulation, particularly with respect to second-line drug options, are sti11lacking. It is fortunate that advances have beenmade with these data for the first-line therapy of IV ganciclovirin children, and more recently for the more desirable oral for
mulation valgancic1ovir. However, the potential need for al
tern~tive therapies such as cidofovir and foscarnet stilI existsbecause of the ever-advancing field of transplantation, thegrowing number of children living with HIV infection, and thefaet that both of these groups are expanding to include infants.
Acknowledgments
No sources of funding were used to assist in the preparation of this
review. The authors have no confiicts of interest that are directly relevantto the content of this review.
References1. Smith MG. Propagation in tissue cultures of a cytopathogenic \irus from
human salivary gland virus (SGY) disease. Proc Soc Exp BioI Med 1956 Jun;92 (2): 424-30
2. Rowe WP. Hanley JW. Waterman S. et al. Cytopathogenic agent resemblinghuman salivary gland \'irus recovered from tissue cultures of human adenoids.Proc Soc Exp BioI Med 1956 Jun; 92 (2): 418-24
3. Weller TII, Macauley JC, Craig JM, et a!. Isolation of intranuclear inclusionproducing agents from infants \\ith illnesses resembling cytomegalic inclusion
disease. Proc Soc Exp Bioi Mcd 1957 Jan; 94 (I): 4-124. Staras SA, Dollard SC. Radford KW. et al. Seropre\'alence of cytomegalo\irus
infection in the United States, 1988-1994. Clin Infect Dis 2006 Nov; 43 (9):1]43-51
5. Demmler GJ, Infectious Diseases Society of America and Centers for DiseaseControl. Summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis 1991 1I-far-Apr; 13 (2): 315-29
6. Fowler KB, Dahle AJ, Boppana SR, et al. Newborn hearing screening: w;1Ichildren with hearing loss caused by congenital cytomegalo\irus infection bemissed? J Pediatr 1999 Jul; 135 (I): 60-4
7. Crumpacker CS. Ganciclovir. N Engl J Med 1996 Sep; 335 (10): 721-9
8. Erice A. Resistance of human cytomegalO\irus to antiviral drugs. ClinMicrobiol Rev 1999 Apr; 12 (2): 286-97
C 2009AdisDolo InformationBV.Anrightsreserved.
Marshl/II & Koch
9. Erice A, Gil-Roda C, Perez JL, et al. Anti\iral susceptibilities and nnalysis ofUL97 and DNA polymerase sequences of clinical c)10megalo\irus isolatesfrom immunocompromised patients. J Infect Dis 1997 May; 175(5): 1087-92
10. Cytomegalo\irus (CMY) culture results, drug resistance, and clinical outcomein patients with AIDS and CMV retinitis treated \~ith foscarnet or ganciclovir.Studies of Ocular Complications of AIDS (SOCA) in collaboration with theAIDS Clinical Trial Group. J Infect Dis 1997Jul; 176 (I): 50-8
II. Smith IL. Cherrington JM. Jiles RE, et al. High-level resistance of cytomegalo\irus to ganciclovir is associated \\ith alterations in both the UL97 and DNA
pol)merase genes. J Infect Dis 1997 Jul; 176 (I): 6?-77
12. Trang JM, Kidd L, Gruber W, et al. Linear single-dose pharmacokinetics ofganciclO\ir in newborns with congenital cytomegalovirus infections. NIAIDCollaborative Antiviral Study Group. Clin Pharmacol Ther 1993Jan; 53 (\):15·21
13. Zhou XJ, Gruber W. Demmler G, et al. Population pharmacokinetics ofganciclovir in newborns with congenital cytomegalo\irus infection. NIAIDCollaborative Antiviral Study Group. Antimicrob Agents Chemother 1996Sep; 40 (9): 2202-5
14. Anderson RD, Griffy KG. Jung D, et al. Gancic\o\ir absolute bioa\'ailabilityand steady-state pharmacokinetics after oral administration of two 3000mgld dosing regimens in human immunodeficiency \irus- and cytomegalo\irus-seropositive patients. Clin Ther 1995 May-Jun; 17 (3): 425-32
15. Markham A, Faulds D. Ganciclo\ir. an update ofits therapeutic use in cytomegalo\irus infection. Drugs 1994 Sep; 48 (3): 455-84
16. Fletcher C, Sawchuk R. Chinnock B, et al. Human pharmacokinetics of theantiviral drug DHPG. Clin Pharmacol Ther 1986 Sep; 40 (3): 281-6
17. Whitley RJ. Cloud G, Gruber W, et al. Ganciclo~;r treatment ofs)mptomaticcongenital cytomegalo\irus infection: results of a phase II study. NIAIDCollaborative Antiviral Study Group. J Infect Dis 1997 May; 175 (5): 1080-6
18. Frenkel LM. Capparelli EV, Dankner WM. et al. Oral ganciclovir in children:pharmacokinetics, safety, tolerance, and antiviral effects. The Pediatric AIDSClinical Trial Group. J Infect Dis 2000 Dec; 182 (6): 1616-24
19. Kimberlin DW. Antiviral therapy for cytomegalovirus infections in pediatricpatients. Semin Pediatr Infect Dis 2002 Jan; 13 (1): 22-30
20. Kimberlin DW. Lin CY. Sanchcz PJ, et al. Effect of ganciclo\ir therapy onhearing in symptomatic congenital cytomegalovirus disease invohing thecentral nervous system: a randomized, controlled trial. J Pediatr 2003 Jul;143 (I): 16-25
21. Faulds D, Ileel RC. Ganciclo\·ir. a re\iew of its antiviral acthit)'. pharmacokinetic properties and therapeutic efficacy in cytomegalovirus infections.Drugs 1990 Apr; 39 (4): 597-638
22. Cytovene (ganciclo\ir) [package insert]. Nutley (NJ): Roche Lnboratories.2006 Jan
23. Cocohoba JM, McNicholllR. Valgancic\ovir: an advance in cytomegalovirustherapeutics. Ann Pharmacother 2002 Jun; 36 (6): 1075-9
24. lIenkin CC, Griener JC, Tcn Eiek AP. Stability of valganciclovir in extemporaneously compounded liquid formulations. Am J Health Syst Pharm2003 Apr I; 60 (7): 687·90
25. Acosta EP, Brundage RC, King JR, et al. NIAID ganciclovir populationpharmacokinetics in neonates follO\\ing intra\'enous administration ofganciclo~ir and oral administnltion of a liquid valganciclovir formulation.Clin Pharnlacol Ther 2007 Jun; 81 (6): 867-72
26. Kimberlin DW. Acostn EP. Sinchez PJ, et al. on behalf of the NIAID Collaborath'e Anthiral Study Group. Pharmacokinctic and pharmacodynamicassessment of oral valganciclovir in the treatment of s)mptomatic congenitalcytomegalo\irus disease. J Infcct Dis 2008 Mar 15; 197 (6): 836-45
27. Valcyte (valganciclovir) (package insert]. Nutley (NJ): Roche Laboratories,2006 Jan
28. Meine Jansen CF, Toet MC, Rademaker CM. et n\. Treatment ofs)mptomaticcongenitalC)'tomegalovirus infection with valganciclO\ir. J Perinat Med 2005;33 (4): 364-6
Pediotr Drugs ~; 11 (5)
Antivirals for CMV Infection in Neonates and Infants
29. Buonuomo PS, Maurizi p. Valentini P, et al. Successful treatment with oralvalgancicJovir in immunocompetent infant with gastrointestinal manifestations ofcytomegalo\irus infection. 1 Perinatol2oo6 Oct; 26 (10): 648-9
30. Muller A, Eis-Hubinger AM. Brandhorst G, et a!. Oral valgancicJo\ir for
symptomatic congenital cytomegalovirus infection in an extremely low birthweight infant. 1 Perinatol2oo81an; 28 (t): 74-6
31. Sehulzkc S, Bilhrer C. ValgancicJo\ir for treatment of congenital c)'tomegalo·virus infection. Eur 1 Pediatr 2006 Aug; 165 (8): 575-6
32. Galli L, Novelli A, Chiappini E. et al. ValgancicJovir for congenital CMVinfection: a pilot study on plasma concentration in newborns and infants.Pediatr Infect Dis 12007 May; 26 (5): 451-3
33. Martin DF. Sierra-Madero 1, Walmsley S, et al., on behalf of the Va!ganci·cJo\ir Study Group. A controlled trial ofvalgancicJo\ir as induction therapyfor c)'tomcgalovirus retinitis. N Engll Med 2002 Apr II; 346 (IS): 1119-26
34. Burri M, Wiltshire H, Kahlert C, et al. Oral valgancicJo\ir in children: singledose pharmacokinetics in a six-year-old girl. Pediatr Infect Dis 1 2004 Mar;23 (3): 263-6
35. Czock D, Scholle C, Rasche FM, et a!. Pharmacokinetics of valganciclovirand gancicJovir in renal impairment. Clin Pharmacol Ther 2002 Aug; 72 (2):142-50
36. Vethamuthu 1, Feber 1, Chretien A, et al. Unexpectedly high inter- and intra·patient variability of ganciclovir levels in children. Pediatr Transplant 2007May; 11 (3): 301-5
37. Zhang D, Lapeyraque AL, Popon M, et al. Pharmacokinetics of ganciclovirin pediatric renal transplant recipients. Pediatr Nephrol 2003 Sep; 18 (9):943-8
38. Vaudry W, Ettenger R, lara p, et al. Valganciclovir dosing according tobody surface area and renal function in pediatric solid organ transplantrecipients. Valeyte WV16726 Study Group. Am 1 Transplant 2009 Mar; 9 (3):636-43
39. Peseo\itz MD, lain A, Robson R, et al. Establishing pharmacokinetic bioequivalence of valganciclo\'ir oral solution versus the tablct formulation.Transplant Proc 2007 Dec; 39 (10): 3111·6
40. Clark BS, Chang IF, Karpen Sl, et al. ValgancicJovir for the prophylaxis ofcytomegalovirus disease in pediatric Ih'er transplant recipients. Transplan·tation 2004 May 15; 77 (9): 1480
41. Schleiss MR. Anthiral therapy of congenital cytomegalovirus infection. SeminPediatr Infect Dis 2oo51an; 16 (I): 50-1
42. Wagstaff AJ. Bryson HM. Foscamet: a rcappraisal of its anth'iral activity,pharmacokinetic properties and therapcutic use in immunocompromisedpatients \\ith viral infections. Drugs 1994 Aug; 48 (2): 199·226
43. Chou S, Marousek GI, Van Wechel LC, et al. Gro\\1h and drug resistancephenotypes resulting from cytomegalovirus DNA polymerase region IIImutations observed in clinical specimens. Antimicrob Agents Chemother2007 Nov; 51 (11): 4160·2
44. Nigro G, Sali E, Anceschi MM, et al. Foscamet therapy for congenital cytomegalovirus liver fibrosis follo\\ing prenatal ascites. J Matern Fetal NeonatalMed 2004 May; 15 (5): 325-9
102009 Adi> Data Information BV. AJ1 rights reserved.
...-.. .....
q;!
321
45. Eksborg S. The pharmacokinetics of antiviral therapy in paediatric patients.Herpes 2003 Dec; 10 (3): 66·7\
46. Hengge UR, Brockmeyer NH, Malessa R, et al. Foscarnet penetrates theblood-brain barrier: rationale for therapy of cytomegalovirus encephalitis.Antimicrob Agents Chemother 1993 May; 37 (5): 1010-14
47. Luck S, Sharland M, Griffiths P. et al. Advances in the antiviral therapy ofherpes virus infection in children. Expert Rev Anti Infect Ther 2006 Dec; 4 (6):1005·20
48. Safrin S, Cherrington J, Jaffe HS. Clinical uses of cidofovir. Rev Med Virol1997 Sep; 7 (3) 145·56
49. Xiong X, Smith JL. Chen MS. Effect of incorporation of cidofovir intoDNA by human C)'1omegalovirus DNA polymerase on DNA elongation.Antimicrob Agents Chemother 1997 Mar; 41 (3): 594-9
50. Schleiss MR,Anderson JL. McGregor A. Cyclic cidofovir (cHPMPC) preventscongenital cytomegalovirus infection in a guinea pig model. Virol J 2006 MarI; 3: 9
51. White DR, Choo 01, Stroup G, et al. The effect of cidofovir on cytomegalo.,irus·induced hearing loss in a Guinea pig model. Arch Otolaryngol !leadNeck Surg 2006 Jun; \32 (6): 608·15
52. De Clercq E. The acyclic nucleoside phosphonates from inception to cliclcaluse: historical pcrspecth'e. Antiviral Res 2007 Jul; 75 (I): 1·\3
53. Chou SW. Cytomegalovirus drug resistance and clinical implications. TransplInfect Dis 200I; 3 Suppl. 2: 20-4
54. Lea AP. Bryson HM. Cidofovir. Drugs 1996 Aug; 52 (2): 225·30
55. Breddemann A. Hsien L, Tot E, et al. Quantification of cidofovir in humanserum by LC-MS/MS for children. 1 Chromatogr DAnalyt Technol DiomedLife Sci 2008 Jan I; 861 (1); 1-9
56. Vistide (cidofovir) [package insert]. Foster City (CA): Gilead Sciences, 2000
57. Cesaro S, Zhou X. Manzardo C, et al. Cidofovir for cytomegalo\irusreactivation in pediatric patients after hematopoietic stem cell transplantation. J Clin Virol 2005 Oct; 34 (2): 129-32
58. Dosi A, Bartolozzi B, Vannucchi AM, et al. Polymerase chain reaction-based"pre-emptive" therapy \\ith cidofo\ir for cytomegalovirus reactivation inallogeneic hematopoietic stem cell transplantation recipients: a prospectivestudy. Haematologica 2002 Apr; 87 (4): 446-7
59. Cundy KC. Clinical pharmacokinetics of the antiviral nucleotide analoguescidofovir and adefo\ir. Clin Pharmacokinet 1999 Feb; 36 (2): 127-43
60. Kimberlin DW. Anthiral therapies in children: has their time arrived? PediatrClin North Am 2005 Jun; 52 (3): 837·67
61. Biron KK. Antiviral drugs for cytomegalovirus diseases. Anthiral Res 2006Sep; 71 (2-3): 154-63
Correspondence: Dr Belh C. MarsJllIlI, Sanger Hall, Room 12-051, 1101 E.Marshall Street, Richmond, VA 23298-0163, USA.E-mail: [email protected]
Pediatr Drugs 2009; 11 (5) ,
DOCUMENT SUPPLYBoston Spa, WetherbyWest Yorkshire LS23 7BQwww.bLuk
Please note the following:
This is the best copy available
~.,<
oo
o
o
This article has a very tight binding
Some pages within the original article areadvertisements and have therefore notbeen sent
Adv~rtisement pages: .
Some pages within the original are blankand have therefore not been sent
Blank pages: .
The article you require is on different pagesto those that you quoted
Supplied by The British Library - "The world's knowledge"~----- AEB-11 I OS/07