penetration intravitréenne de la VALACYCLOVIR orale

7/27/2019 penetration intravitrenne de la VALACYCLOVIR orale

1/5

Vitreous Penetration of Orally AdministeredValacyclovir

TONY H. HUYNH, MARK W. JOHNSON, GRANT M. COMER, AND DOUGLAS N. FISH

PURPOSE: To investigate the vitreous penetration of

acyclovir, the active metabolite of valacyclovir, after oraladministration of valacyclovir. DESIGN: Prospective, interventional case series. METHODS: Ten patients scheduled for elective pars

plana vitrectomy at a single academic institution were

given three oral doses of valacyclovir 1000 mg eight

hours apart the day before surgery, with a fourth dose on

the morning of surgery. Blood and undiluted vitreous

samples were obtained during surgery and subsequently

were analyzed with high-performance liquid chromatog-raphy to determine the concentrations of acyclovir

present. RESULTS: Ten eyes of 10 subjects ranging in age from

46 to 83 years were included. All patients had normal

renal and hepatic function as confirmed by metabolic

panels obtained before surgery. Mean serum acyclovir

concentration standard deviation was 4.41 0.88

g/ml (range, 3.18 to 5.92 g/ml), mean vitreous acy-

clovir concentration was 1.03 0.23g/ml (range, 0.67

to 1.33 g/ml), and mean vitreous-to-serum concentra-

tion ratio of acyclovir was 0.24 0.06 (range, 0.16 to

0.34). CONCLUSIONS: Orally administered valacyclovir re-

sults in substantial vitreous penetration of acyclovir. The

vitreous concentrations achieved in noninflamed eyes arewithin the reported inhibitory ranges for most strains of

herpes simplex 1, herpes simplex 2, and varicella zoster

virus. This suggests that orally administered valacyclovir

may be an alternative to intravenous acyclovir in the

treatment of acute retinal necrosis. (Am J Ophthalmol

2008;145:682 686. 2008 by Elsevier Inc. All rights

reserved.)

ACUTE RETINAL NECROSIS (ARN) WAS FIRST DE-scribed in six patients by Urayama and associates

in 1971.1 The cause of this condition was not well

understood until more than a decade later, when Culbert-

son and associates first provided histologic evidence for

herpes virus particles in the retina of an affected eye.2

Today, ARN is recognized as an infectious retinitis char-

acterized by one or more foci of retinal necrosis withdiscrete borders in the fundus periphery, rapid circumfer-

ential progression of disease, evidence of occlusive retinal

arteritis, and a prominent inflammatory reaction in the

vitreous and anterior chamber.3 The usual etiologic agents

are believed to be varicella zoster virus (VZV), herpes

simplex virus 1 (HSV-1), and herpes simplex virus 2

(HSV-2). Evidence of causative roles for cytomegalovirus

and Epstein-Barr virus in this condition is limited.4,5

Current standard treatment of ARN consists of intrave-nous acyclovir (10 mg/kg every eighth hour or 1500 mg/m2

daily) for five to 10 days followed by oral acyclovir 800 mg

five times daily for six weeks, prophylactic laser demarca-

tion, and possible adjunctive therapy with aspirin and

corticosteroids.6 However, the inconvenience and costs

associated with administration of intravenous acyclovir

have spawned interest in the use of newer oral antiviral

agents, such as valacyclovir and famciclovir, as primary

treatment for ARN. Aslanides and associates reported

successful treatment in three cases of ARN with oral

valacyclovir in 2002.7 More recently, Aizman and associ-

ates and Emerson and associates reported their results intreating ARN with oral antiviral therapy without intrave-

nous acyclovir.8,9 Although these reports have demon-

strated successful clinical outcomes with oral antiviraltherapy in patients with ARN, little is known about the

ocular penetration of these antiviral agents in human eyes.

To our knowledge, no published studies have reported the

direct measurement of vitreous acyclovir concentrations

after oral valacyclovir. We examined the vitreous penetra-

tion of orally administered valacyclovir to understand

further the role of this drug in the primary treatment of

ARN.

METHODS

TEN PATIENTS SCHEDULED FOR ELECTIVE PARS PLANA VIT-

rectomy were enrolled in the study. Exclusion criteria

included hypersensitivity to valacyclovir or acyclovir, cur-

rent pregnancy or breast feeding, renal or hepatic disease

(as confirmed by history and metabolic panels), infection

with human immunodeficiency virus, history of bone

marrow or renal transplantation, history of any antiviral

therapy within one month of surgery, history of probenecid

or cimetidine use within one month of surgery, previous

Accepted for publication Nov 16, 2007.From the W. K. Kellogg Eye Center, Department of Ophthalmology

and Visual Sciences, University of Michigan, Ann Arbor, Michigan(T.H.H., M.W.J., G.M.C.); and the Department of Clinical Pharmacy,University of Colorado Health Sciences Center, Denver, Colorado(D.N.F.).

Inquiries to Mark W. Johnson, W. K. Kellogg Eye Center, 1000 WallStreet, Ann Arbor, MI 48105; e-mail:[email protected]

2008 BY ELSEVIER INC. ALL RIGHTS RESERVED.682 0002-9394/08/$34.00doi:10.1016/j.ajo.2007.11.016
mailto:[email protected]:[email protected]:[email protected]


2/5

vitrectomy, vitreous hemorrhage within one month ofscheduled surgery, active uveitis or vasculitis, endoph-

thalmitis, and rhegmatogenous retinal detachment.

All patients were instructed to take three 1000-mg doses

of valacyclovir eight hours apart the day before surgery

with an additional dose on the morning of surgery. Logsheets were given to the participants to record the time at

which they took each dose. Just before surgery, before

infusion of any intravenous solutions, two 5-ml samples of

venous blood were collected (two samples were collected

from each patient to confirm the precision of the high-

performance liquid chromatography [HPLC] assay). At the

beginning of the vitrectomy procedure, 1 ml undiluted

vitreous was obtained with the vitreous cutter, taking care

to avoid sampling any vitreous contaminated by blood

from sclerotomy sites. Collection times of all samples were

recorded. After the blood samples were allowed to clot,

they were centrifuged and the serum was collected. Serum

and vitreous samples then were frozen and stored at 70 Cuntil analysis.

Serum and vitreous samples were analyzed for valacy-

clovir and acyclovir concentrations using validated HPLC

assays. Valacyclovir and acyclovir samples were prepared

for HPLC analysis by extraction in methanol through aC18 solid phase extraction column, evaporation to dryness

under nitrogen gas, reconstitution in 5.0 mM aqueous

sodium acetate mobile phase solution, and centrifugation.

Aliquots of prepared samples then were injected into the

HPLC system for drug assay. Chromatographic conditions

included ultraviolet detection at a wavelength of 254 nm,

ambient room temperature, and mobile phase flow rates of

3.0 ml/minute. The mobile phase consisted of 5.0 mM

aqueous sodium acetate and acetonitrile (99:1) adjusted to

a pH of 3.0 for determination of valacyclovir concentra-

tions; the mobile phase for the acyclovir assay was similar

except for the omission of acetonitrile. Assay of both drugs

TABLE 1. Subject Characteristics, Indications for Surgery, and Specimen Collection Times from the Last Dose of Valacyclovir

Subject No. Age (yrs) Gender Eye Indications for Surgery

Time to Blood Sample

Collection (hrs)

Time to Vitreous Sample

Collection (hrs)

1 77 M Left Macular hole 3.25 3.87

2 73 F Left Macular hole 2.42 3.13

3 68 M Right Epiretinal membrane 2.10 2.504 83 M Left Epiretinal membrane 4.17 4.72

5 46 F Left Macular schisis 2.25 2.75

6 52 F Right Vitreous opacities 1.50 2.75

7 57 F Right Macular hole 2.67 3.25



10 78 M Left Macular hole 2.00 2.93

MeanSD 2.42 0.80 3.11 0.71

F female; M male; SD standard deviation.

TABLE 2. Serum and Vitreous Acyclovir Concentrations after the Administration of Oral Valacyclovir

Subject No. Serum 1 ( g/ml) Serum 2 ( g/ml) Mean Serum ( g/ml) Vitreous ( g /ml ) Vi treo us -t o-S er um R at io

1 4.45 4.38 4.42 1.14 0.26

2 3.98 4.02 4.00 0.84 0.21

3 4.76 4.80 4.78 1.33 0.28

4 5.22 5.19 5.21 0.90 0.17

5 4.27 4.22 4.25 1.16 0.27

6 3.61 3.70 3.66 1.24 0.34

7 5.92 5.86 5.89 1.30 0.22

8 3.21 3.18 3.20 0.88 0.28

9 3.43 3.41 3.42 0.67 0.2010 5.28 5.27 5.28 0.87 0.16

MeanSD 4.41 0.89 4.40 0.87 4.41 0.88 1.03 0.23 0.24 0.06

SD standard deviation.

VITREOUS PENETRATION OF VALACYCLOVIRVOL. 145, NO. 4 683


3/5

used guanosine as the internal standard. Validation of

assay methods was performed before assay of study samples.

Five-point standard curves were constructed for both drugs

on each validation and study day. Standard curves were

linear over the range of 0.0 to 100 g/ml of valacyclovir

and acyclovir (mean, r2 0.997 for valacyclovir and 0.998

for acyclovir). The within-day and between-day coeffi-

cients of variation for valacyclovir and acyclovir assayswere 1.6% and 2.3%, respectively.

RESULTS

TEN EYES OF THE 10 ENROLLED SUBJECTS WERE INCLUDED IN

the study. Mean patient age was 66.1 years (range, 46 to 83years; Table 1). Six eyes underwent pars plana vitrectomy

for macular hole, two for epiretinal membrane, one for

vitreous opacities, and one for myopic macular schisis. The

mean time standard deviation (SD) from the last

valacyclovir dose to collection of the serum samples was2.42 0.80 hours (range, 1.50 to 4.17 hours), whereas the

mean time SD from last valacyclovir dose to collection

of the vitreous sample was 3.11 0.71 hours (range, 2.32

to 4.72 hours; Table 1). No detectable valacyclovir levels

were found in any serum or vitreous specimens. The mean

SD serum acyclovir concentration was 4.41 0.89 g/ml

(range, 3.21 to 5.92 g/ml) for the first set of serum

samples and 4.40 0.87 g/ml (range, 3.18 to 5.86 g/ml)

for the second set (Table 2). The overall mean SD

serum acyclovir level was 4.41 0.88 g/ml (range, 3.18

to 5.92 g/ml). The mean SD vitreous acyclovir

concentration was 1.03 0.23 g/ml (range, 0.67 to 1.33g/ml), and the mean SD vitreous-to-serum acyclovir

concentration ratio was 0.24 0.06 (range, 0.16 to 0.34).

Analysis showed no statistically significant relationship

between the serum sample collection times and the serum

acyclovir levels (Pearson correlation coefficient, 0.51; P

.14) or between the vitreous sample collection times and

the vitreous acyclovir levels (Pearson correlation coeffi-cient, 0.11; P .75). No serious adverse events were

associated with the administration of oral valacyclovir.

The drug was tolerated well by all participants with no

reported side effects.

DISCUSSION

VALACYCLOVIR (VALTREX; GLAXOSMITHKLINE, RESEARCH

Triangle Park, North Carolina, USA) was approved by the

Food and Drug Administration in 1995 for the treatment

of herpes virus infections. Its current indications include

herpes zoster (shingles), genital herpes simplex, and herpes

labialis. The drug is the l-valyl ester of acyclovir and is

converted rapidly to acyclovir after oral administration.

Orally administered valacyclovir offers a distinct advan-

tage over orally administered acyclovir because of its

greater bioavailability. In healthy individuals, the bioavail-

ability of valacyclovir has been reported to be 54%, more

than three times that of comparable doses of acyclovir.10

This increased bioavailability is believed to result from

greater absorption of valacyclovir across the intestinal wall

as compared with acyclovir. After being absorbed, valacy-

clovir is converted rapidly into acyclovir by valacyclovir

hydrolase during first-pass metabolism.11

The high bioavailability of valacyclovir leads to plasma

acyclovir levels comparable with those obtained with

intravenous administration of acyclovir. Weller and asso-

ciates found that 1000 mg valacyclovir given four times

daily resulted in acyclovir area under the concentration-

time curve values comparable with that of intravenous

administration of acyclovir at doses of 5 mg/kg every eighthours.12 This was later confirmed by Hoglund and associ-

ates.13 Furthermore, plasma acyclovir levels comparable

with intravenous doses of 10 mg/kg every eight hours can

be achieved with higher valacyclovir doses of 2000 mg

given four times daily.12 Hoglund and associates postulatedthat the lower peak plasma concentrations associated with

oral therapy may reduce the risk of renal adverse events

compared with intravenous acyclovir administration.13

Virus sensitivity testing has not been standardized, and the

quantitative relationshipbetween the in vitro susceptibility of

herpes viruses to antiviral agents and the clinical response to

treatment has not been established in humans.14 Published

50% inhibitory concentration (IC50) values of acyclovir for

HSV-1, HSV-2, and VZV vary over a wide range, probably

attributable to differences in the assays and laboratories used

to derive them. Reported IC50 values for HSV-1 range from

0.02 to 13.5 g/ml, those for HSV-2 range from 0.01 to 9.9g/ml, and those for VZV range from 0.12 to 10.8g/ml.14,15

Given these values, valacyclovir has been shown to achieve

serum levels within the inhibitory ranges for most strains of

HSV-1, HSV-2, and VZV. Inhibitory acyclovir levels for

most strains also are achieved in the cerebrospinal fluid (CSF)

after repeated doses of valacyclovir.16 The high end of the

reported IC50 ranges likely represents relatively resistant virusstrains that are encountered less commonly in the clinical

setting.

Although acyclovir levels in serum and CSF after

administration of oral valacyclovir have been well de-

scribed, little is known about the intraocular levels ofacyclovir achieved with either intravenous acyclovir or

orally administered valacyclovir. In 2002, Dias and associ-

ates reported a study of ocular penetration of intravenous

acyclovir and intravenous valacyclovir in New Zealand

albino rabbits.17 Although they were able detect acyclovir

in the aqueous humor, they failed to detect measurable

levels of the drug in the vitreous.

To our knowledge, our study is the first to measure vitreous

acyclovir concentrations after either oral valacyclovir or

intravenous acyclovir dosing. We found that the oral admin-

istration of valacyclovir quickly leads to substantial vitreous

acyclovir concentrations in noninflamed human eyes. The

AMERICAN JOURNAL OF OPHTHALMOLOGY684 APRIL 2008


4/5

vitreous levels achieved were consistent among study sub-

jects. As with serum concentrations, the mean vitreous levels

were within but not above the reported IC50 ranges for

HSV-1, HSV-2, and VZV, suggesting that certain strains may

be resistant. On average, the vitreous acyclovir levels were

approximately 25% of the serum levels. The serum acyclovir

levels in our study were consistent with those previously

reported for oral valacyclovir,12,13 and the fact that serumconcentrations measured in the two sets of serum samples

were nearly identical indicates a high level of precision of our

HPLC assay.

Our study is limited by the fact that vitreous levels were

measured at a single time point. Our methodology there-

fore precludes any conclusions regarding steady-state vit-

reous levels of acyclovir during oral valacyclovir therapy.In addition, the treatment time required to achieve ther-

apeutic levels and the duration of these levels cannot be

determined from our data.

The time to maximum serum concentration of acyclovir

after an oral dose of valacyclovir has been reported to beapproximately two hours.12 Our mean collection time for

serum samples was somewhat greater than two hours,

which may explain the slightly lower serum acyclovir

concentrations in our study compared with previously

reported maximum serum concentrations. The time to

maximum vitreous acyclovir concentration has not been

reported. It therefore is not known whether the vitreous

acyclovir concentrations obtained in this study represent

maximum vitreous concentrations after oral valacyclovir at

standard doses. The values obtained in this study may

underestimate the maximum vitreous concentration of

acyclovir because vitreous sampling may have occurred

before or after the time to maximum vitreous concentra-

tion. No statistically significant relationship between the

serum and vitreous sample collection times and the serum

and vitreous acyclovir levels was detected in our study,

possibly because of the small patient sample size.Of note is the fact that our study was conducted in

noninflamed eyes, unlike those affected by ARN. One may

postulate that vitreous acyclovir concentrations higher

than those reported in our study may be achieved in eyes

with ARN, because the blood-retina barrier is severely

compromised in these eyes.

The findings of our study demonstrate that the oraladministration of valacyclovir rapidly can result in poten-

tially therapeutic concentrations of acyclovir in the vitre-

ous for nonresistant strains of HSV-1, HSV-2, and VZV.

These results, in conjunction with several recent clinical

case series demonstrating the successful use of valacyclovirin the primary treatment of ARN, suggest that oral

valacyclovir may be a reasonable alternative to intrave-

nous acyclovir in the management of ARN. In selected

cases, initial adjunctive therapy with intravitreal antiviral

agents, higher doses of oral antiviral drugs, or both may be

considered to achieve high vitreous drug concentrations

rapidly. Further studies are needed to clarify the role and to

determine the ideal dosing regimen for valacyclovir in the

treatment of ARN.

THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN DESIGN ANDconduct of study (T.H.H., M.W.J., G.M.C.); collection of data (T.H.H., M.W.J., G.M.C., D.N.F.); management of data (T.H.H., M.W.J., D.N.F.);analysis of the data (T.H.H., M.W.J., D.N.F.); interpretation of the data (T.H.H., M.W.J., G.M.C., D.N.F.); preparation of the manuscript (T.H.H.,M.W.J., G.M.C., D.N.F.); review of the manuscript (T.H.H., M.W.J., G.M.C., D.N.F.); and approval of the manuscript (T.H.H., M.W.J., G.M.C.,D.N.F.). Informed consent was obtained from all participants and the study was approved by the University of Michigan Institutional Review Board.

The authors thank David C. Musch, PhD, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan forproviding statistical consultation.

REFERENCES

1. Urayama A, Yamada N, Sasaki T, et al. Unilateral acute

uveitis with periarteritis and detachment. Rinsho Ganka

1971;25:607619.

2. Culbertson WW, Blumenkranz MS, Pepose JS, Stewart JA,Curtin VT. Varicella zoster virus is a cause of the acute

retinal necrosis syndrome. Ophthalmology 1986;93:559

569.

3. Holland GN, Executive Committee of the American

Uveitis Society. Standard diagnostic criteria for the acute

retinal necrosis syndrome. Am J Ophthalmol 1994;117:

663667.

4. Silverstein BE, Conrad D, Margolis TP, Wong IG. Cytomeg-

alovirus-associated acute retinal necrosis syndrome. Am J

Ophthalmol 1997;123:257258.

5. Kramer S, Brummer C, Zierhut M. Epstein-Barr virus

associated acute retinal necrosis. Br J Ophthalmol 2001;

85:114.

6. Pepose JS, Van Gelder RN. Acute retinal necrosis syndrome.

In: Ryan SJ, Hinton DR, Schachat AJ, Wilkinson P, editors.

Retina, 4th ed. Vol. 2. Medical retina. Philadelphia, Penn-

sylvania: Mosby, 2006: 16731681.

7. Aslanides IM, De Souza S, Wong DT, et al. Oral valacyclovir

in the treatment of acute retinal necrosis syndrome. Retina2002;22:352354.

8. Aizman A, Johnson MW, Elner SG. Treatment of acute

retinal necrosis syndrome with oral antiviral medications.

Ophthalmology 2007;114:307312.

9. Emerson GG, Smith JR, Wilson DJ, Rosenbaum JT, Flaxel

CJ. Primary treatment of acute retinal necrosis with

oral antiviral therapy. Ophthalmology 2006;113:2259

2261.

10. Soul-Lawton J, Seaber E, On N, Wootton R, Rolan P, Posner

J. Absolute bioavailability and metabolic disposition of

valacyclovir, the L-valyl ester of acyclovir, following oral

administration to humans. Antimicrob Agents Chemother

1995;39:27592764.

VITREOUS PENETRATION OF VALACYCLOVIRVOL. 145, NO. 4 685


5/5

11. Granero GE, Amidon GL. Stability of valacyclovir: implications

for its oral bioavailability. Int J Pharmacol 2006;317:1418.

12. Weller S, Blum MR, Doucette M, et al. Pharmacokinetics

of the acyclovir prodrug, valacyclovir after escalating

single- and multiple-dose administration to normal volun-

teers. Clin Pharmacol Ther 1993;54:595605.

13. Hoglund M, Ljungman P, Weller S. Comparable acyclovir

exposures produced by oral valacyclovir and intravenous

acyclovir in immunocompromised cancer patients. J Antimi-

crob Chemother 2001;47:855861.

14. Physician Desk Reference. 60th ed. Montvale, New Jersey:

Thompson PDR, 2006:1573.

15. OBrien JJ, Campoli-Richards DM. Acyclovir: an updated

review of its antiviral activity, pharmacokinetic properties

and therapeutic efficacy. Drugs 1989;37:233309.

16. Lycke J, Malmestrom C, Stahle L. Acyclovir levels in

serum and cerebrospinal fluid after oral administration of

valacyclovir. Antimicrob Agents Chemother 2003;47:

24382441.

17. Dias C, Nashed Y, Atluri H, Mitra A. Ocular penetration of

acyclovir and its peptide prodrugs valacyclovir and val-

valacyclovir following systemic administration in rabbits: an

evaluation using ocular microdialysis and LC-MS. Curr Eye

Res 2002;25:243252.

AMERICAN JOURNAL OF OPHTHALMOLOGY686 APRIL 2008

Documents

penetration intravitréenne de la VALACYCLOVIR orale