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Ocular Iontophoretic Supplementation of Intravenous Foscarnet Therapy
Ocular lontophoretic Supplementation of Intravenous Foscarnet Therapy MARC O. YOSHIZUMI, MD., JOSE A. ROCA, M.D., DAVID A. LEE, MD., GRACE LEE, AND IRENE GOMEZ • PURPOSE: Reactivation of cytomegalovirus retinopathy during intravenous antiviral therapy is usually treated with higher doses of drug. We sought to determine whether ocular iontophoresis increases the intravitreal foscarnet concentration attained by intravenous injection. • METHODS: We injected foscarnet (120 mg/kg or 180 mg/kg) intravenously into 24 rabbits and determined the time of maximal concentrations in serum and vitreous humor. We injected the same doses into 24 additional rabbits and administered ocular foscarnet iontophoresis one hour later. Vitreous humor concentrations were assayed at one, four, eight, 24, 60, and 120 hours after iontophoresis and compared with those from injec tion alone. • RESULTS: Maximum serum and vitreous humor concentrations were achieved one hour after each intravenous dose. Maximum vitreous humor con centrations were achieved four hours after 120mg/kg intravenous doses plus iontophoresis and eight hours after 180-mg/kg intravenous doses plus iontophoresis. Vitreous humor levels were significantly higher in eyes receiving intravenous foscarnet (120 mg/kg, P < .0001; 180 mg/kg, P < .0001) plus ocular foscarnet iontophoresis than in those receiving intravenous foscarnet alone. Vitre ous humor foscarnet levels in eyes receiving 120 mg/kg intravenously did not differ significantly Accepted for publication Feb. 6, 1996. From the Retina Division (Drs. Yoshizumi and Roca, Ms. Lee, and Ms. Gomez) and the Glaucoma Division (Dr. Lee), Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, School of Medicine, Los Angeles, California. This study was supported in part by Research to Prevent Blindness, Inc., New York, New York (Dr. Roca). Reprint requests to Marc O. Yoshizumi, M.D., Jules Stein Eye Insti tute, 100 Stein Plaza, University or California, Los Angeles, CA 90095-7000.
86
from those in the group receiving 180 mg/kg intravenously (P < .1). The intravenous dose did not significantly affect vitreous humor levels after iontophoresis (P < .1). Vitreous concentrations fell below therapeutic levels (25 μΜ) in all eyes 60 hours after intravenous foscarnet and ocular foscarnet iontophoresis. • CONCLUSIONS: Ocular iontophoresis signifi cantly increased intravitreous foscarnet concen trations above those attained by intravenous injec tion alone and may be an effective alternative to increasing the intravenous drug dose in patients with reactivated cytomegalovirus retinopathy.
C
YTOMEGALOVIRUS RETINOPATHY IS THE MOST
common retinal infection in patients with acquired immunodeficiency syndrome (AIDS), affecting up to 40% of patients.1'6 Intrave nous administration of foscarnet, a well-established treatment for cytomegalovirus retinopathy, involves an induction dose of 180 mg/kg of body mass per day for two weeks followed by a lower maintenance dose of 90 to 120 mg/kg per day.7'13 Despite continued maintenance therapy, however, lesions eventually reactivate and enlarge in nearly all patients, usually necessitating periodic administration of higher doses of intravenous drug (reinduction). Intravenous foscarnet may result in systemic toxicity (nephropathy, hypocalcemia, hypophosphatemia, and hypomagnesemia).1011 Local ocular therapies, including injections of ganciclovir or foscarnet or the implanta tion of intravitreous, sustained-release devices, have been used in patients intolerant of or unresponsive to intravenous treatment, but these therapies can occa sionally result in serious intraocular complications (retinal toxicity, retinal detachment, endophthalmitis, or vitreous hemorrhage).14'20
© AMERICAN JOURNAL OF OPHTHALMOLOGY 1996;122:86-90
JULY 1996
Sarraf and associates21 demonstrated that thera peutic concentrations of foscarnet can be achieved in the vitreous body by ocular iontophoresis. In this study, we used an animal model to determine wheth er added administration of foscarnet by ocular ionto phoresis raises intravitreous foscarnet levels above those achieved by intravenous infusion of foscarnet alone.
METHODS WE USED 48 HEALTHY, PIGMENTED RABBITS WEIGHING
approximately 3 kg each and conducted the study under the provisions of the Animal Research Com mittee at the University of California, Los Angeles. All procedures, including intravenous administration of drugs, were performed five to ten minutes after anesthetizing animals with an intramuscular injec tion of xylazine (12 mg/kg) and ketamine (60 mg/kg). In our first study, peak intravitreous and serum levels of foscarnet were determined after a single intravenous injection of drug at doses of 120 mg/kg (12 rabbits) or 180 mg/kg (12 rabbits). At six time intervals (one, four, eight, 24, 60, and 120 hours) after intravenous injection of foscarnet, two rabbits were killed from each dosage group. We obtained 48 vitreous humor samples (one per eye from each of the 24 rabbits) and 24 intracardiac blood samples (one from each rabbit). In our second study, one hour after administering intravenous foscarnet (the time of peak vitreous humor foscarnet concentration), as described for the first study, we performed ocular iontophoresis on 24 rabbits at doses of 120 mg/kg (12 rabbits) or 180 mg/kg (12 rabbits). Vitreous humor samples were obtained one, four, eight, 24, 60, and 120 hours after iontophoresis. Iontophoresis was performed on the right eye of each rabbit after instillation of one drop of 0.5% proparacaine, placement of a Barraquer-Colibri speculum, and proptosis of the globe. A tuberculin syringe with 0.5 ml of foscarnet (24 mg/ml) was attached to an iontophoretic probe fitted with an Ag-AgCl electrode in a sidearm lumen.21 The probe tip, with a surface area of 0.19 mm2, was connected to the cathode of the iontophoretic apparatus. The anode was attached to the rabbit's contralateral ear. The probe tip was placed over the conjunctiva 2 mm VOL.122,
No. I
posterior to the corneoscleral limbus and 2 mm from the temporal edge of the superior rectus muscle. Iontophoresis was performed using a current of 1.0 mA for 10 minutes. Before vitreous humor sampling, the rabbits were killed with intravenous pentobarbital (50 mg/kg). Aspiration of vitreous humor was performed with an 18-gauge needle on a tuberculin syringe passed through an entry site 2 mm posterior to the corneo scleral limbus and placed in the midvitreous humor under direct visualization through the dilated pupil. Intracardiac blood samples were obtained using an 18-gauge needle on a 5-ml syringe. Vitreous humor samples were collected in plastic centrifuge tubes and centrifuged at 4,000 rpm for 20 minutes to obtain an ultrafiltrate. Blood samples were collected in heparinized tubes and centrifuged at 4,000 rpm for 20 minutes to obtain an ultrafiltrate of plasma. The samples were masked and sent on dry ice (—70 C) to Astra Arcus (Södertälje, Sweden) for quantification of foscarnet by high-performance liquid chromatography according to a method described by Pettersson, Nordgren, and Westerland." Two known concentra tions of foscarnet served as positive controls; two blank vitreous humor samples served as negative controls.
RESULTS IN THE FIRST STUDY, PEAK MEAN FOSCARNET PLASMA
concentrations of 325.5 μ Μ and 340.0 μΜ were achieved one hour after intravenous foscarnet admin istration in the 120-mg/kg and 180-mg/kg groups, respectively. Plasma foscarnet concentrations de clined thereafter, falling to 5 μΜ (minimal measure ment sensitivity) after 24 hours. Peak mean vitreous humor foscarnet concentrations were achieved one hour after 120-mg/kg intravenous foscarnet adminis tration (11.25 μΜ) and eight hours after 180-mg/kg intravenous foscarnet administration (9.25 μΜ). Both declined to less than 9 μΜ after 24 hours in both groups (Table). In the second study, a peak mean vitreous humor concentration of 203 μ Μ was reached four hours after ocular foscarnet iontophoresis in the group that received 120 mg/kg of intravenous foscarnet (Fig. 1). A peak mean vitreous humor concentration of 191
IONTOPHORETIC INTRAVENOUS FOSCARNET THERAPY
87
TABLE PLASMA AND VITREOUS HUMOR CONCENTRATIONS (μΜ FOSCARNET ± S.D.) AFTER A SINGLE INFUSION WITH AND WITHOUT OCULAR IONTOPHORETIC SUPPLEMENTATION FOSCARNET 120 MO/KG INTRAVENOUS DOSE PLASMA (HR)
VITREOUS
WITHOUT IONTOPHORESIS
1 4 8 24 60 120
325.50 35.00 10.00 5.00 5.00 5.00
± ± ± ± ± ±
99.70 26.87 0 0 0 0
11.25 10.75 7.50 5.25 5.00 6.00
± ± ± ± ± ±
12.50 8.02 3.32 0.50 0 2.00
FOSCARNET 180 MG/KG INTRAVENOUS DOSE PLASMA
VITREOUS WITH IONTOPHORESIS
147.67 203.00 194.67 93.50 17.00 5.50
INTRAVENOUS
± ± ± ± ± ±
VITREOUS
WITHOUT IONTOPHORESIS
21.50 12.73 45.21 24.75 0 0.71
340.00 44.50 21.50 5.00 5.00 5.00
± ± ± ± ± ±
98.99 27.58 6.36 0 0 0
7.5 8.75 9.25 8.67 5.00 5.75
± ± ± ± ± ±
IONTOPHORESIS
5.0 5.56 5.19 2.89 0 0.96
141.00 155.5 191.00 101.00 13.33 81.50
± ± ± ± ± ±
1.41 86.97 0 33.94 1.53 4.95
•Time after intravenous infusion and after iontophoresis with foscarnet.
Intravenous injection alone
350 T
-■•-PLASMA 300
\
\
250
i
150
Peak concentration 203 uM
\
Intravenous injection plus ocular iontophoresis
\
200
- - * · - VITREOUS
*
\
VITREOUS AFTER ■
IC - "^
\
100
IONTOPHORESIS
^
50 *
"*^*^~
1 hour 4 hours 8 hours 24 hours 60 hours 120 hours Fig. 1 (Yoshizumi and associates). Foscarnet concentration in plasma and in vitreous humor after 120-mg/kg intravenous foscarnet injection and in vitreous humor after 120-mg/kg intravenous foscarnet injection plus ocular foscarnet iontophoresis.
μΜ was reached eight hours after iontophoresis in the group that received 180 mg/kg of intravenous foscarnet (Fig. 2). Vitreous humor concentrations declined to less than 20 μΜ 60 hours after iontopho resis (Table). We did not find a significant difference between the mean vitreous humor foscarnet concentration in the group receiving 120 mg/kg and that in the group receiving 180 mg/kg (7.63 μΜ and 7.43 μΜ, respec tively; I = .1). Ocular iontophoresis significantly increased the vitreous humor concentrations of 88
foscarnet beyond those achieved by intravenous ad ministration alone in both the group receiving 120 mg/kg (126.77 μΜ vs 7.63 μΜ; Ρ < .00001) and the group receiving 180 mg/kg (86.92 μΜ vs 7.43 μΜ; Ρ < .00001). There was no significant difference be tween the mean vitreous humor foscarnet concentra tion in eyes receiving 120 mg/kg of intravenous foscarnet plus ocular foscarnet iontophoresis (126.77 μΜ) and that in eyes receiving 180 mg/kg of intrave nous foscarnet plus ocular foscarnet iontophoresis (86.92 μΜ; Ρ = .1).
AMERICAN JOURNAL OF OPHTHALMOLOGY
JULY
1996
350
\ 300 250 200
Intravenous injection alone
\\
- · · - PLASMA
\
\
Peak concentration 191 uM
\
\
\
Intravenous injection plus ocular iontophoresis
S
\
· · * - -VITREOUS
VITREOUS AFTER — ■ — IONTOPHORESIS
150
"
100
\
^
50
^
f
··;.·.::-·■—-t — : · · ■ " " · *
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M
U
U
K
U
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:
u
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1 hour 4 hours 8 hours 24 hours 60 hours 120 hours Fig. 2 (Yoshizumi and associates). Foscarnet concentration in plasma and in vitreous humor after 180-mg/kg intravenous foscarnet injection and in vitreous humor after 180-mg/kg intravenous foscarnet injection plus ocular foscarnet iontophoresis.
DISCUSSION KUPPERMANN AND ASSOCIATES2'' STATED THAT REACTI-
vation of cytomegalovirus retinopathy, despite thera peutic blood levels of antiviral drug, may be attributa ble to poor penetration of drugs into the eye, as reflected by low vitreous humor concentrations, and furthermore that vitreous humor drug levels have relevance for retinal tissue drug levels because the broad vitreoretinal interfaces allow the vitreous body to serve as a drug reservoir. Our study confirmed that much higher concentrations of foscarnet can be achieved in the vitreous humor by supplementary ocular iontophoresis than by intravenous infusions with doses of either 120 mg/kg or 180 mg/kg alone. Sarraf and associates21 showed that ocular iontopho resis of foscarnet alone in rabbit eyes resulted in a peak mean vitreous humor foscarnet concentration of 200 μΜ, comparable to the levels obtained in this study. Our study suggests that intravenous foscarnet administration adds little to vitreous humor concen trations in uninfected rabbits treated with ocular iontophoresis. With retinal infection, vitreous humor foscarnet levels would probably be higher because of the breakdown of the blood-brain barrier. It is well established that cytomegalovirus retinopa thy reflects disseminated infection; autopsy studies have shown that all patients with cytomegalovirus VOL.122, N o . 1
retinopathy have nonocular tissue-invasive sites of infection, as well.' Systemic antiviral therapy is im portant for preventing or controlling nonocular cyto megalovirus disease and for preventing development of cytomegalovirus retinopathy in the second eye of patients with unilateral disease. Most patients with cytomegalovirus retinopathy will have reactivation and enlargement of their retinal lesions despite con tinued intravenous maintenance therapy. Because reactivation can occur without clinical signs of non ocular cytomegalovirus disease, interest has grown in local ocular treatment to supplement systemic antivi ral drug therapy. Our study does not address intraocular drug levels achieved with repeated intravenous infusions of drug, nor does it address drug levels that can be achieved with breakdown of the blood-retinal barrier, which is assumed to occur with cytomegalovirus retinopathy. This study does suggest that ocular iontophoresis may be an important, noninvasive technique of local therapy for patients receiving systemic antiviral drugs who need intermittent ocular drug supplementation and who cannot tolerate higher systemic doses during reactivation. Ocular iontophoresis, like other local treatments, will be inadequate for patients requiring systemic therapy for the development or reactivation of nonocular disease. Additional study will be required to determine
lONTOPHORETIC INTRAVENOUS FOSCARNET THERAPY
89
both the appropriate regimen of ocular iontophoresis for supplementing intravenous foscarnet therapy and the risks and benefits of ocular iontophoresis com pared with those of standard intravenous reinduction therapy to control reactivation of cytomegalovirus retinopathy. ACKNOWLEDGMENTS
Ann-Catherine Hedengren and John-Olof Lernestedt, D.D.S., of Astra Arcus, Södertälje, Sweden, performed the high-performance liquid chromatography analysis of the foscarnet in the blood and vitreous samples.
REFERENCES 1. Holland GN, Pepose JS, Pettit TH, Gottlieb MS, Yee RD, Foos RY. Acquired immune deficiency syndrome: ocular manifestations. Ophthalmology 1983;90:859-73. 2. Freeman WR, Lerner CW, Mines JA, Lash RS, Nadel AJ, Starr MB, et al. A prospective study of the ophthalmologic findings in the acquired immune deficiency syndrome. Am J Ophthalmol 1984;97:133-42. 3. Pepose JS, Holland GN, Nestor MS, Cochran AJ, Foos RY. Acquired immune deficiency syndrome: pathogenic mecha nisms of ocular disease. Ophthalmology 1985;92:472-84. 4. Jabs DA, Green WR, Fox R, Polk BF, Bartlett JG. Ocular manifestations of acquired immune deficiency syndrome. Ophthalmology 1989;96:1092-9. 5. Pertel P, Hirschtick R, Phair J, Chmiel J, Poggensee L, Murphy R. Risk of developing cytomegalovirus retinitis in persons infected with the human immunodeficiency virus. J Acquir Immune Defic Syndr 1992;5:1069-74. 6. Hoover DR, Saah AJ, Bacellar H, Phair J, Detels R, Anderson R, et al, for the Multicenter AIDS Cohort Study. Clinical manifestations of AIDS in the era of Pneumocystis prophylaxis. N Engl J Med 1993;329:1922-6. 7. Jacobson MA, O'Donnell JJ. Approaches to the treatment of cytomegalovirus retinitis: ganciclovir and foscarnet. J Acquir Immune Defic Syndr 1991;4(Suppl 1):S11—5. 8. Jabs DA, Newman C, de Bustros S, Polk BF. Treatment of cytomegalovirus retinitis with ganciclovir. Ophthalmology 1987;94:824-30. 9. LeHoang P, Girard B, Robinet M, Marcel P, Zazoun L, Matheron S, et al. Foscarnet in the treatment of cytomegalo virus retinitis in acquired immune deficiency syndrome. Ophthalmology 1989;96:865-74.
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10. Palestine AG, Polis MA, De Smet MD, Baird BF, Falloon J, Kovacs JA, et al. A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med 1991;115:665-73. 11. Studies of Ocular Complications of AIDS (SOCA) Research Group in collaboration with the AIDS Clinical Trials Group (ACTG). Studies of ocular complications of AIDS foscarnet-ganciclovir cytomegalovirus retinitis trial: 1. Rationale, design, and methods. Control Clin Trials 1992;13:22-39. 12. Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group. Mortality in patients with the acquired immunodeficiency syndrome treated with either foscarnet or ganciclovir for cytomegalovi rus retinitis. N Engl J Med 1992;326:213-20. 13. Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group. Foscarnet-ganciclovir cytomegalovirus retinitis trial: 4. Visual out comes. Ophthalmology 1994;101:1250-61. 14. Heinemann MH. Long-term intravitreal ganciclovir thera py for cytomegalovirus retinopathy. Arch Ophthalmol 1989;107:1767-72. 15. Diaz-Llopis M, Chipont E, Sanchez S, Espana E, Navea A, Menezo JL. Intravitreal foscarnet for cytomegalovirus retinitis in a patient with acquired immunodeficiency syndrome. Am J Ophthalmol 1992;114:742-7. 16. Sanborn GE, Anand R, Torti RE, Nightingale SD, Cai SX, Yates B, et al. Sustained-release ganciclovir therapy for treatment of cytomegalovirus retinitis: use of an intravitreal device. Arch Ophthalmol 1992;110:188-95. 17. Yoshizumi MO, Lee D, Vinci V, Fajardo S. Ocular toxicity of multiple intravitreal DHPG injections. Graefes Arch Clin Exp Ophthalmol 1990;228:350-5. 18. Kreiger AE, Foos RY, Yoshizumi MO. Intravitreous granula tion tissue and retinal detachment following pars plana injection for cytomegalovirus retinopathy. Graefes Arch Clin Exp Ophthalmol 1992;230:197-8. 19. Anand R, Nightingale SD, Fish RH, Smith TJ, Ashton P. Control of cytomegalovirus retinitis using sustained release of intraocular ganciclovir. Arch Ophthalmol 1993;111:223-7. 20. Smith TJ, Pearson PA, Blandford DL, Brown JD, Coins KA, Hollins JL, et al. Intravitreal sustained-release ganciclovir. Arch Ophthalmol 1992;110:255-8. 21. Sarraf D, Equi RA, Holland GN, Yoshizumi MO, Lee DA. Transscleral iontophoresis of foscarnet. Am J Ophthalmol 1993;115:748-54. 22. Pettersson KJ, Nordgren T, Westerlund D. Determination of phosphonoformate (foscarnet) in biological fluids by ion-pair reversed-phase liquid chromatography. J Chromatogr 1989;488:447-55. 23. Kuppermann BD, Quiceno JI, Flores- Aguilar M, Connor JD, Capparelli EV, Sherwood CH, et al. Intravitreal ganciclovir concentration after intravenous administration in AIDS patients with cytomegalovirus retinitis: implications for thera py. J Infect Dis 1993;168:1506-9.
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from those in the group receiving 180 mg/kg intravenously (P < .1). The intravenous dose did not significantly affect vitreous humor levels after iontophoresis (P < .1). Vitreous concentrations fell below therapeutic levels (25 μΜ) in all eyes 60 hours after intravenous foscarnet and ocular foscarnet iontophoresis. • CONCLUSIONS: Ocular iontophoresis signifi cantly increased intravitreous foscarnet concen trations above those attained by intravenous injec tion alone and may be an effective alternative to increasing the intravenous drug dose in patients with reactivated cytomegalovirus retinopathy.
C
YTOMEGALOVIRUS RETINOPATHY IS THE MOST
common retinal infection in patients with acquired immunodeficiency syndrome (AIDS), affecting up to 40% of patients.1'6 Intrave nous administration of foscarnet, a well-established treatment for cytomegalovirus retinopathy, involves an induction dose of 180 mg/kg of body mass per day for two weeks followed by a lower maintenance dose of 90 to 120 mg/kg per day.7'13 Despite continued maintenance therapy, however, lesions eventually reactivate and enlarge in nearly all patients, usually necessitating periodic administration of higher doses of intravenous drug (reinduction). Intravenous foscarnet may result in systemic toxicity (nephropathy, hypocalcemia, hypophosphatemia, and hypomagnesemia).1011 Local ocular therapies, including injections of ganciclovir or foscarnet or the implanta tion of intravitreous, sustained-release devices, have been used in patients intolerant of or unresponsive to intravenous treatment, but these therapies can occa sionally result in serious intraocular complications (retinal toxicity, retinal detachment, endophthalmitis, or vitreous hemorrhage).14'20
© AMERICAN JOURNAL OF OPHTHALMOLOGY 1996;122:86-90
JULY 1996
Sarraf and associates21 demonstrated that thera peutic concentrations of foscarnet can be achieved in the vitreous body by ocular iontophoresis. In this study, we used an animal model to determine wheth er added administration of foscarnet by ocular ionto phoresis raises intravitreous foscarnet levels above those achieved by intravenous infusion of foscarnet alone.
METHODS WE USED 48 HEALTHY, PIGMENTED RABBITS WEIGHING
approximately 3 kg each and conducted the study under the provisions of the Animal Research Com mittee at the University of California, Los Angeles. All procedures, including intravenous administration of drugs, were performed five to ten minutes after anesthetizing animals with an intramuscular injec tion of xylazine (12 mg/kg) and ketamine (60 mg/kg). In our first study, peak intravitreous and serum levels of foscarnet were determined after a single intravenous injection of drug at doses of 120 mg/kg (12 rabbits) or 180 mg/kg (12 rabbits). At six time intervals (one, four, eight, 24, 60, and 120 hours) after intravenous injection of foscarnet, two rabbits were killed from each dosage group. We obtained 48 vitreous humor samples (one per eye from each of the 24 rabbits) and 24 intracardiac blood samples (one from each rabbit). In our second study, one hour after administering intravenous foscarnet (the time of peak vitreous humor foscarnet concentration), as described for the first study, we performed ocular iontophoresis on 24 rabbits at doses of 120 mg/kg (12 rabbits) or 180 mg/kg (12 rabbits). Vitreous humor samples were obtained one, four, eight, 24, 60, and 120 hours after iontophoresis. Iontophoresis was performed on the right eye of each rabbit after instillation of one drop of 0.5% proparacaine, placement of a Barraquer-Colibri speculum, and proptosis of the globe. A tuberculin syringe with 0.5 ml of foscarnet (24 mg/ml) was attached to an iontophoretic probe fitted with an Ag-AgCl electrode in a sidearm lumen.21 The probe tip, with a surface area of 0.19 mm2, was connected to the cathode of the iontophoretic apparatus. The anode was attached to the rabbit's contralateral ear. The probe tip was placed over the conjunctiva 2 mm VOL.122,
No. I
posterior to the corneoscleral limbus and 2 mm from the temporal edge of the superior rectus muscle. Iontophoresis was performed using a current of 1.0 mA for 10 minutes. Before vitreous humor sampling, the rabbits were killed with intravenous pentobarbital (50 mg/kg). Aspiration of vitreous humor was performed with an 18-gauge needle on a tuberculin syringe passed through an entry site 2 mm posterior to the corneo scleral limbus and placed in the midvitreous humor under direct visualization through the dilated pupil. Intracardiac blood samples were obtained using an 18-gauge needle on a 5-ml syringe. Vitreous humor samples were collected in plastic centrifuge tubes and centrifuged at 4,000 rpm for 20 minutes to obtain an ultrafiltrate. Blood samples were collected in heparinized tubes and centrifuged at 4,000 rpm for 20 minutes to obtain an ultrafiltrate of plasma. The samples were masked and sent on dry ice (—70 C) to Astra Arcus (Södertälje, Sweden) for quantification of foscarnet by high-performance liquid chromatography according to a method described by Pettersson, Nordgren, and Westerland." Two known concentra tions of foscarnet served as positive controls; two blank vitreous humor samples served as negative controls.
RESULTS IN THE FIRST STUDY, PEAK MEAN FOSCARNET PLASMA
concentrations of 325.5 μ Μ and 340.0 μΜ were achieved one hour after intravenous foscarnet admin istration in the 120-mg/kg and 180-mg/kg groups, respectively. Plasma foscarnet concentrations de clined thereafter, falling to 5 μΜ (minimal measure ment sensitivity) after 24 hours. Peak mean vitreous humor foscarnet concentrations were achieved one hour after 120-mg/kg intravenous foscarnet adminis tration (11.25 μΜ) and eight hours after 180-mg/kg intravenous foscarnet administration (9.25 μΜ). Both declined to less than 9 μΜ after 24 hours in both groups (Table). In the second study, a peak mean vitreous humor concentration of 203 μ Μ was reached four hours after ocular foscarnet iontophoresis in the group that received 120 mg/kg of intravenous foscarnet (Fig. 1). A peak mean vitreous humor concentration of 191
IONTOPHORETIC INTRAVENOUS FOSCARNET THERAPY
87
TABLE PLASMA AND VITREOUS HUMOR CONCENTRATIONS (μΜ FOSCARNET ± S.D.) AFTER A SINGLE INFUSION WITH AND WITHOUT OCULAR IONTOPHORETIC SUPPLEMENTATION FOSCARNET 120 MO/KG INTRAVENOUS DOSE PLASMA (HR)
VITREOUS
WITHOUT IONTOPHORESIS
1 4 8 24 60 120
325.50 35.00 10.00 5.00 5.00 5.00
± ± ± ± ± ±
99.70 26.87 0 0 0 0
11.25 10.75 7.50 5.25 5.00 6.00
± ± ± ± ± ±
12.50 8.02 3.32 0.50 0 2.00
FOSCARNET 180 MG/KG INTRAVENOUS DOSE PLASMA
VITREOUS WITH IONTOPHORESIS
147.67 203.00 194.67 93.50 17.00 5.50
INTRAVENOUS
± ± ± ± ± ±
VITREOUS
WITHOUT IONTOPHORESIS
21.50 12.73 45.21 24.75 0 0.71
340.00 44.50 21.50 5.00 5.00 5.00
± ± ± ± ± ±
98.99 27.58 6.36 0 0 0
7.5 8.75 9.25 8.67 5.00 5.75
± ± ± ± ± ±
IONTOPHORESIS
5.0 5.56 5.19 2.89 0 0.96
141.00 155.5 191.00 101.00 13.33 81.50
± ± ± ± ± ±
1.41 86.97 0 33.94 1.53 4.95
•Time after intravenous infusion and after iontophoresis with foscarnet.
Intravenous injection alone
350 T
-■•-PLASMA 300
\
\
250
i
150
Peak concentration 203 uM
\
Intravenous injection plus ocular iontophoresis
\
200
- - * · - VITREOUS
*
\
VITREOUS AFTER ■
IC - "^
\
100
IONTOPHORESIS
^
50 *
"*^*^~
1 hour 4 hours 8 hours 24 hours 60 hours 120 hours Fig. 1 (Yoshizumi and associates). Foscarnet concentration in plasma and in vitreous humor after 120-mg/kg intravenous foscarnet injection and in vitreous humor after 120-mg/kg intravenous foscarnet injection plus ocular foscarnet iontophoresis.
μΜ was reached eight hours after iontophoresis in the group that received 180 mg/kg of intravenous foscarnet (Fig. 2). Vitreous humor concentrations declined to less than 20 μΜ 60 hours after iontopho resis (Table). We did not find a significant difference between the mean vitreous humor foscarnet concentration in the group receiving 120 mg/kg and that in the group receiving 180 mg/kg (7.63 μΜ and 7.43 μΜ, respec tively; I = .1). Ocular iontophoresis significantly increased the vitreous humor concentrations of 88
foscarnet beyond those achieved by intravenous ad ministration alone in both the group receiving 120 mg/kg (126.77 μΜ vs 7.63 μΜ; Ρ < .00001) and the group receiving 180 mg/kg (86.92 μΜ vs 7.43 μΜ; Ρ < .00001). There was no significant difference be tween the mean vitreous humor foscarnet concentra tion in eyes receiving 120 mg/kg of intravenous foscarnet plus ocular foscarnet iontophoresis (126.77 μΜ) and that in eyes receiving 180 mg/kg of intrave nous foscarnet plus ocular foscarnet iontophoresis (86.92 μΜ; Ρ = .1).
AMERICAN JOURNAL OF OPHTHALMOLOGY
JULY
1996
350
\ 300 250 200
Intravenous injection alone
\\
- · · - PLASMA
\
\
Peak concentration 191 uM
\
\
\
Intravenous injection plus ocular iontophoresis
S
\
· · * - -VITREOUS
VITREOUS AFTER — ■ — IONTOPHORESIS
150
"
100
\
^
50
^
f
··;.·.::-·■—-t — : · · ■ " " · *
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M
U
U
K
U
>
»
_
I
Î
:
u
^
1 hour 4 hours 8 hours 24 hours 60 hours 120 hours Fig. 2 (Yoshizumi and associates). Foscarnet concentration in plasma and in vitreous humor after 180-mg/kg intravenous foscarnet injection and in vitreous humor after 180-mg/kg intravenous foscarnet injection plus ocular foscarnet iontophoresis.
DISCUSSION KUPPERMANN AND ASSOCIATES2'' STATED THAT REACTI-
vation of cytomegalovirus retinopathy, despite thera peutic blood levels of antiviral drug, may be attributa ble to poor penetration of drugs into the eye, as reflected by low vitreous humor concentrations, and furthermore that vitreous humor drug levels have relevance for retinal tissue drug levels because the broad vitreoretinal interfaces allow the vitreous body to serve as a drug reservoir. Our study confirmed that much higher concentrations of foscarnet can be achieved in the vitreous humor by supplementary ocular iontophoresis than by intravenous infusions with doses of either 120 mg/kg or 180 mg/kg alone. Sarraf and associates21 showed that ocular iontopho resis of foscarnet alone in rabbit eyes resulted in a peak mean vitreous humor foscarnet concentration of 200 μΜ, comparable to the levels obtained in this study. Our study suggests that intravenous foscarnet administration adds little to vitreous humor concen trations in uninfected rabbits treated with ocular iontophoresis. With retinal infection, vitreous humor foscarnet levels would probably be higher because of the breakdown of the blood-brain barrier. It is well established that cytomegalovirus retinopa thy reflects disseminated infection; autopsy studies have shown that all patients with cytomegalovirus VOL.122, N o . 1
retinopathy have nonocular tissue-invasive sites of infection, as well.' Systemic antiviral therapy is im portant for preventing or controlling nonocular cyto megalovirus disease and for preventing development of cytomegalovirus retinopathy in the second eye of patients with unilateral disease. Most patients with cytomegalovirus retinopathy will have reactivation and enlargement of their retinal lesions despite con tinued intravenous maintenance therapy. Because reactivation can occur without clinical signs of non ocular cytomegalovirus disease, interest has grown in local ocular treatment to supplement systemic antivi ral drug therapy. Our study does not address intraocular drug levels achieved with repeated intravenous infusions of drug, nor does it address drug levels that can be achieved with breakdown of the blood-retinal barrier, which is assumed to occur with cytomegalovirus retinopathy. This study does suggest that ocular iontophoresis may be an important, noninvasive technique of local therapy for patients receiving systemic antiviral drugs who need intermittent ocular drug supplementation and who cannot tolerate higher systemic doses during reactivation. Ocular iontophoresis, like other local treatments, will be inadequate for patients requiring systemic therapy for the development or reactivation of nonocular disease. Additional study will be required to determine
lONTOPHORETIC INTRAVENOUS FOSCARNET THERAPY
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both the appropriate regimen of ocular iontophoresis for supplementing intravenous foscarnet therapy and the risks and benefits of ocular iontophoresis com pared with those of standard intravenous reinduction therapy to control reactivation of cytomegalovirus retinopathy. ACKNOWLEDGMENTS
Ann-Catherine Hedengren and John-Olof Lernestedt, D.D.S., of Astra Arcus, Södertälje, Sweden, performed the high-performance liquid chromatography analysis of the foscarnet in the blood and vitreous samples.
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AMERICAN JOURNAL OF OPHTHALMOLOGY
JULY 1996