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Use of Intravitreal Ganciclovir (Dihydroxy Propoxymethyl Guanine) for Cytomegalovirus Retinitis in a Patient with AIDS: Reply
842
June, 1987
AMERICAN JOURNAL OF OPHTHALMOLOGY
Correspondence Correspondence concerning recent articles or other material published in THE JOURNAL should be submitted within six weeks of publication. Correspondence must be typed double-spaced, on 8% x 11-inch bond paper with lV4-inch margins on all four sides and should be no more than two typewritten pages in length. Every effort will be made to resolve controversies between the correspondents and the authors of the article before formal publication.
Use of Intravitreal Ganciclovir (Dihydroxy Propoxymethyl Guanine) for Cytomegalovirus Retinitis in a Patient With AIDS EDITOR: As the injection of drugs directly into the vitreous body becomes common practice, treatment schedules should be established that allow a therapeutic level to be maintained in the eye with the greatest interval of time between repeated injections. The article, "Use of intravitreal ganciclovir (dihydroxy propoxymethyl guanine) for cytomegalovirus retinitis in a patient with AIDS," by Keith Henry, Herbert Cantrill, Courtney Fletcher, Barbara J. Chinnock, and Henry H. Balfour (Am. J. Ophthalmol. 103:17, January 1987) illustrates the difficulty in obtaining this information. In order to spare the patient, vitreous taps were taken on two occasions only, after repeat injections of ganciclovir. The authors attempted a statistical analysis of the data even though one of these samples yielded a drug level that was not meaningfully above the lower limit of detection. Tapping the vitreous was probably not necessary for gaining the required information and a treatment guide could be obtained from measurements of the behavior of the drug in rabbits, if a simple comparative experiment on a human eye were carried out. The kinetics of intravitreally injected drugs in the rabbit are fairly well understood, 1 and they should behave similarly in the human eye, with allowances for the obvious differences in the geometry of the globes and perhaps in the active transport mechanism across the retinas. If this assumption is correct, the drug should leave the eye according to a single exponential curve, the half-life of which
could be established by aqueous taps alone at two different times after the injection. I recommend collecting an early aqueous sample soon after the diffusional steady state should have been set up, say at 12 hours, and again, after 24 or 36 hours, to allow the concentration to drop appreciably but not so far as to make its determination difficult. The concentration in the vitreous should decrease, after a brief delay, according to the same exponential curve, and its initial level can be estimated with sufficient accuracy from the quantity of drug injected and the volume of the human vitreous humor. To avoid trauma the volume injected should be limited to 20 u,l or less, which can be adequately defined by a tuberculin syringe, though better by a suitable microliter syringe. 1 The transfer of rabbit data to humans would be improved if the correction factor for the different geometries of the eyes could be established. This requires that a surgeon who has access to a Fluorotron Master fluorometer and has occasion to inject a drug intravitreally should add a small quantity of a low molecular weight FITC dextran to the solution at the time of the final injection and record the vitreous and aqueous concentration levels two or three times during the succeeding weeks. A comparison with corresponding data from the rabbit 2 would allow the behavior of many drugs in the human eye to be immediately predicted from animal experiments. DAVID M. MAURICE, Ph.D. Stanford, California
References 1. Maurice, D. M.: Injection of drugs into the vitreous body. In Leopold, I. H., and Burns, R. P. (eds.): Symposium on Ocular Therapy, vol. 9. New York, Wiley and Sons, 1976, pp. 59-72. 2. Johnson, F., and Maurice, D. A.: simple method of measuring aqueous humor flow with intravitreal fluoresceinated dextrans. Exp. Eye Res. 39:791, 1984.
Reply EDITOR: We agree with many of the points made by Dr. Maurice. In general, we believe that animal experiments involving kinetics of intravitreal drugs are easier to do and can be far
Vol. 103, No. 6
more elegant than what is feasible in human studies. The 0.41 p,M concentration of ganciclovir that we detected at 97.3 hours after the fourth injection was significantly different than zero. A distinction has to be made between the absolute lower limit of detection of the assay and the practical lower limit of detection. We know that we can detect concentrations lower than 0.40 u.M and, on the day that assay was run, the lowest standard detected was 0.24 |xM. For our pharmacokinetic estimates, we did assume uniform distribution of the drug within the vitreous but the validity of that assumption is not known. To characterize the biexponential decay of concentration would require by our standard protocol a minimum of five determinations after one dose. We did not think that would be practical or justifiable under the circumstances. With reference to the half-life and estimated volume of distribution that we used (in the article we did mention that the values were estimated), we did not have all of the data we would have liked to establish a 95% confidence limit for these estimates. However, the values we obtained were clinically useful and at 51.4 hours after dose, the concentration was above our standard ID50 for cytomegalovirus and at 97.3 hours after dose it was not. Therefore, if the ID50 has any clinical meaning (this point can be debated), then we would need a dosing interval of greater than 51.4 hours but less than 97.3 hours for effective therapy. The point raised about the aqueous/vitreous ratio of 0.56 is a good one and does indicate that ganciclovir may be removed from the vitreous by routes other than the one we discussed. Regarding the effect of the vitreous humor on our assay technique, we believe there is no effect on our assay since all samples were filtered to remove protein and ganciclovir is not appreciably protein-bound. Our assay was developed with Burroughs Wellcome and has been validated at the University of Minnesota and elsewhere. We did use a weighted least squares analysis for our pharmacokinetic studies but came up with the same results (a half-life between 12 and 14 hours) whether we used that method or other methods of linear regression analysis. For our calculations, the molecular weight of ganciclovir was 255.23 daltons. Questions regarding the accuracy of our technique and the value of our estimates are
Correspondence
843
legitimate and reflect somewhat the difficulty in obtaining multiple vitreal samples for analysis. We have continued to use this technique in additional patients and have observed similar gratifying responses. We are aware that other centers are now involved with this work and at least several dozen patients have had intravitreal ganciclovir. Another new indication for its use has been in patients with AIDS who are receiving zidovudine for their human immunodeficiency virus infection. Patients receiving zidovudine cannot be receiving other investigational systemic antiviral drugs but intravitreal ganciclovir may be useful in this patient population and warrants further study. We are anxious to see reports from other centers on the safety and efficacy of intravitreal ganciclovir. KEITH HENRY, M.D. HERBERT CANTRILL, M.D. COURTNEY FLETCHER, Pharm. D. BARBARA J. CHINNOCK HENRY H. BALFOUR, Jr., M.D.
Minneapolis, Minnesota
Pseudophakic Malignant Glaucoma—Is It Really Pseudo-Malignant? EDITOR:
I found the editorial, "Pseudophakic malignant glaucoma—is it really pseudomalignant," by D. L. Epstein (Am. J. Ophthalmol. 103:231, February 1987), to be interesting even though somewhat confusing. I believe some of the confusion could be eliminated by considering malignant glaucoma (an unsatisfactory but time-honored term) as a specific entity, namely that condition in phakic eyes occurring when the anterior chamber has been surgically emptied and the lens has come forward to be wedged in the scleral ring. The intraocular pressure is always high and may be lowered by the use of cycloplegic mydriasis as described by Chandler and Grant, 1 although permanent control may require extraction of the crystalline lens. If the term malignant glaucoma is reserved for this syndrome, the term cannot be applied to the glaucoma that occurs with pseudophakia. The glaucoma that occurs after the implantation of an anterior chamber lens may result from the anatomic distortion of the chamber
June, 1987
AMERICAN JOURNAL OF OPHTHALMOLOGY
Correspondence Correspondence concerning recent articles or other material published in THE JOURNAL should be submitted within six weeks of publication. Correspondence must be typed double-spaced, on 8% x 11-inch bond paper with lV4-inch margins on all four sides and should be no more than two typewritten pages in length. Every effort will be made to resolve controversies between the correspondents and the authors of the article before formal publication.
Use of Intravitreal Ganciclovir (Dihydroxy Propoxymethyl Guanine) for Cytomegalovirus Retinitis in a Patient With AIDS EDITOR: As the injection of drugs directly into the vitreous body becomes common practice, treatment schedules should be established that allow a therapeutic level to be maintained in the eye with the greatest interval of time between repeated injections. The article, "Use of intravitreal ganciclovir (dihydroxy propoxymethyl guanine) for cytomegalovirus retinitis in a patient with AIDS," by Keith Henry, Herbert Cantrill, Courtney Fletcher, Barbara J. Chinnock, and Henry H. Balfour (Am. J. Ophthalmol. 103:17, January 1987) illustrates the difficulty in obtaining this information. In order to spare the patient, vitreous taps were taken on two occasions only, after repeat injections of ganciclovir. The authors attempted a statistical analysis of the data even though one of these samples yielded a drug level that was not meaningfully above the lower limit of detection. Tapping the vitreous was probably not necessary for gaining the required information and a treatment guide could be obtained from measurements of the behavior of the drug in rabbits, if a simple comparative experiment on a human eye were carried out. The kinetics of intravitreally injected drugs in the rabbit are fairly well understood, 1 and they should behave similarly in the human eye, with allowances for the obvious differences in the geometry of the globes and perhaps in the active transport mechanism across the retinas. If this assumption is correct, the drug should leave the eye according to a single exponential curve, the half-life of which
could be established by aqueous taps alone at two different times after the injection. I recommend collecting an early aqueous sample soon after the diffusional steady state should have been set up, say at 12 hours, and again, after 24 or 36 hours, to allow the concentration to drop appreciably but not so far as to make its determination difficult. The concentration in the vitreous should decrease, after a brief delay, according to the same exponential curve, and its initial level can be estimated with sufficient accuracy from the quantity of drug injected and the volume of the human vitreous humor. To avoid trauma the volume injected should be limited to 20 u,l or less, which can be adequately defined by a tuberculin syringe, though better by a suitable microliter syringe. 1 The transfer of rabbit data to humans would be improved if the correction factor for the different geometries of the eyes could be established. This requires that a surgeon who has access to a Fluorotron Master fluorometer and has occasion to inject a drug intravitreally should add a small quantity of a low molecular weight FITC dextran to the solution at the time of the final injection and record the vitreous and aqueous concentration levels two or three times during the succeeding weeks. A comparison with corresponding data from the rabbit 2 would allow the behavior of many drugs in the human eye to be immediately predicted from animal experiments. DAVID M. MAURICE, Ph.D. Stanford, California
References 1. Maurice, D. M.: Injection of drugs into the vitreous body. In Leopold, I. H., and Burns, R. P. (eds.): Symposium on Ocular Therapy, vol. 9. New York, Wiley and Sons, 1976, pp. 59-72. 2. Johnson, F., and Maurice, D. A.: simple method of measuring aqueous humor flow with intravitreal fluoresceinated dextrans. Exp. Eye Res. 39:791, 1984.
Reply EDITOR: We agree with many of the points made by Dr. Maurice. In general, we believe that animal experiments involving kinetics of intravitreal drugs are easier to do and can be far
Vol. 103, No. 6
more elegant than what is feasible in human studies. The 0.41 p,M concentration of ganciclovir that we detected at 97.3 hours after the fourth injection was significantly different than zero. A distinction has to be made between the absolute lower limit of detection of the assay and the practical lower limit of detection. We know that we can detect concentrations lower than 0.40 u.M and, on the day that assay was run, the lowest standard detected was 0.24 |xM. For our pharmacokinetic estimates, we did assume uniform distribution of the drug within the vitreous but the validity of that assumption is not known. To characterize the biexponential decay of concentration would require by our standard protocol a minimum of five determinations after one dose. We did not think that would be practical or justifiable under the circumstances. With reference to the half-life and estimated volume of distribution that we used (in the article we did mention that the values were estimated), we did not have all of the data we would have liked to establish a 95% confidence limit for these estimates. However, the values we obtained were clinically useful and at 51.4 hours after dose, the concentration was above our standard ID50 for cytomegalovirus and at 97.3 hours after dose it was not. Therefore, if the ID50 has any clinical meaning (this point can be debated), then we would need a dosing interval of greater than 51.4 hours but less than 97.3 hours for effective therapy. The point raised about the aqueous/vitreous ratio of 0.56 is a good one and does indicate that ganciclovir may be removed from the vitreous by routes other than the one we discussed. Regarding the effect of the vitreous humor on our assay technique, we believe there is no effect on our assay since all samples were filtered to remove protein and ganciclovir is not appreciably protein-bound. Our assay was developed with Burroughs Wellcome and has been validated at the University of Minnesota and elsewhere. We did use a weighted least squares analysis for our pharmacokinetic studies but came up with the same results (a half-life between 12 and 14 hours) whether we used that method or other methods of linear regression analysis. For our calculations, the molecular weight of ganciclovir was 255.23 daltons. Questions regarding the accuracy of our technique and the value of our estimates are
Correspondence
843
legitimate and reflect somewhat the difficulty in obtaining multiple vitreal samples for analysis. We have continued to use this technique in additional patients and have observed similar gratifying responses. We are aware that other centers are now involved with this work and at least several dozen patients have had intravitreal ganciclovir. Another new indication for its use has been in patients with AIDS who are receiving zidovudine for their human immunodeficiency virus infection. Patients receiving zidovudine cannot be receiving other investigational systemic antiviral drugs but intravitreal ganciclovir may be useful in this patient population and warrants further study. We are anxious to see reports from other centers on the safety and efficacy of intravitreal ganciclovir. KEITH HENRY, M.D. HERBERT CANTRILL, M.D. COURTNEY FLETCHER, Pharm. D. BARBARA J. CHINNOCK HENRY H. BALFOUR, Jr., M.D.
Minneapolis, Minnesota
Pseudophakic Malignant Glaucoma—Is It Really Pseudo-Malignant? EDITOR:
I found the editorial, "Pseudophakic malignant glaucoma—is it really pseudomalignant," by D. L. Epstein (Am. J. Ophthalmol. 103:231, February 1987), to be interesting even though somewhat confusing. I believe some of the confusion could be eliminated by considering malignant glaucoma (an unsatisfactory but time-honored term) as a specific entity, namely that condition in phakic eyes occurring when the anterior chamber has been surgically emptied and the lens has come forward to be wedged in the scleral ring. The intraocular pressure is always high and may be lowered by the use of cycloplegic mydriasis as described by Chandler and Grant, 1 although permanent control may require extraction of the crystalline lens. If the term malignant glaucoma is reserved for this syndrome, the term cannot be applied to the glaucoma that occurs with pseudophakia. The glaucoma that occurs after the implantation of an anterior chamber lens may result from the anatomic distortion of the chamber