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Intravitreal Foscarnet for Cytomegalovirus Retinitis in a Patient With Acquired Immunodeficiency Syndrome
686
AMERICAN JOURNAL OF OPHTHALMOLOGY
2. Souza-Dias. C: Additional consequences of muscle co-contraction in Duane's syndrome. In Souza-?ias, C (ed.): Smith-Kettlewell Symposium on Basic Sciences in Strabismus (Anex to the V Congress of the CL.A.D.E.). Sao Paulo, Edicoes Loyola, 1976, pp. 93-101. 3. Huber, A.: Duane's retraction syndrome. Considerations on pathogenesis and etiology of the different forms of Duane's retraction syndrome. In Huber, A. (ed.): Strabismus, London, H. Kimpton, 1970, pp. 36-43.
_ _ _ _ _ _ _ Reply
_
EDITOR:
I appreciate the comments of Dr. SouzaDias. His and Dr. Scott's excellent and innovative explanations of the up- and downshoot in Duane's syndrome and their suggestions for treatment were cited and referenced in my article and in an earlier report on this subject. I Dr. Souza-Dias disagrees with my statement that posterior fixation and recession of both horizontal recti muscles work similarly. Yet, he writes that "the principle of both techniques, with regard to the vertical anomalous movements, is the same." I see no disagreement here because the remainder of the sentence in my article, of which Dr. Souza-Dias cites only the beginning, expresses essentially the same view. It is theoretically correct that retraction of the globe should respond more favorably to recession than to posterior fixation of the horizontal recti muscles because the retraction effect of co-contraction is not lessened by posterior fixations. However, the postoperative photographs of the patient described in my article still show retraction on attempted adduction, despite a 6-mm recession of the medial rectus muscle and an 8-mm recession of the lateral rectus muscle. Perhaps, even larger recessions are necessary to decrease retraction significantly.
G. K. VON NOORDEN, M.D.
Houston, Texas
Reference 1. von Noorden. G. K., and Murray, E. M.: Up- and downshoot in Duane's retraction syndrome. J. Pediatr. Ophthalmol. Strabismus 23:212, 1986.
May, 1993
Intravitreal Foscarnet for Cytomegalovirus Retinitis in a Patient With Acquired Immunodeficiency Syndrome EDITOR:
We read with interest the article, "Intravitreal foscarnet for cytomegalovirus retinitis in a patient with acquired immunodeficiency syndrome," by M. Diaz-Llopis, E. Chipont, S. Sanchez, E. Espana, A. Navea, and J. L. Menezo (Am. J. Ophthalmol. 114:742, December 1992), and we commend the authors for their investigation of an alternate method of delivering foscarnet to the eye in the treatment of cytomegalovirus retinitis. We have been investigating alternate delivery techniques for a variety of compounds. Part of this work has centered around the clearance of drugs after intravitreal injection. We were surprised by their conclusion that the half-life of foscarnet is 54 hours. The authors have based their calculation of distribution volume and half-life on a model proposed by Sawchuck and associates in 1977. 1 In this work, Sawchuck and associates described the calculation of the distribution volu.me and elimination rate constant of gentamiCIn after an intravenous infusion. It would appear that Diaz-Llopis and associates have misinterpreted this work and have applied a formula which, although appropriate for Sawchuck and associates' study, does not adequately describe their own experimental conditions. Diaz-Llopis and associates have apparently used the data point 23.25 hours after the first intravitreal injection and the data point 49.5 hours after the sixth injection to calculate the half-life and distribution volume by using a simple nonlinear regression. To use regression analysis in this situation the essential assumption is that all of the drug was cleared from the eye during the interval between injections. Complete clearance will only occur if the dosing interval is much longer than the half-life. Based on the half-life that the authors themselves report, it is apparent that this is not true and that significant and measurable amounts of foscarnet remain in the eye 72 hours after application (the dosing interval). Pharmacokinetic parameters after multiple dosing can be readily calculated by using the approach described by Gibaldi and Perrier.? For a single compartment model, the concen-
687
Correspondence
Vol. 115, No.5
tration of drug at any time during a dosing interval can be determined by using the equation:
centration would fall below the mean 50% inhibition level for cytomegalovirus approximately 41 hours after a single dose. P. ANDREW PEARSON, M.D. GLENN J. JAFFE, M.D.
(1)
where C, is the drug concentration at time T (elapsed time since dose, N), Co is the maximum concentration after dose administration, N is the number of the dose, k is the elimination rate constant, and t is the dosing interval. Using the data provided in the article (409 umol /I 23.25 hours after the first dose and 292 umol Zl 49.5 hours after the sixth dose), equation 1 simplifies to: 409 urnolyl = Co e-23.25k (2) and: 292 umoly] = Co ([1 - e- 432kJ/ [l - e-72kj)e-49.5k (3)
Equation 2 can be solved for Co in terms of k and then substituted into equation 3: 292 /-Lmol/l = (409 umol /I / e-23.25k)([1 e- 432kl/[1 - e-72kj)e-49.5k (4) Simplifying equation 4 and then graphically solving for k, the elimination rate constant is 0.0218. This equates to an intravitreal half-life of 32 hours. By substituting this into equation 4 the maximum concentration after the first dose is 678 umol Zl. which yields an apparent volume of distribution of 5.9 ml. These values for half-life and volume of distribution are more agreeable with the clearance of other similar compounds. Foscarnet is a relatively hydrophilic compound and as such would not be expected to bind to lipid membranes within the eye. It also has relatively low protein binding in serum. Because of these factors we would expect the volume of distribution to be similar to the anatomic volume (approximately 5 ml). Additionally, in the absence of active transretinal transport, we would expect the half-life to be similar to other small, hydrophilic compounds such as gentamicin, which are presumably cleared via an anterior pathway (that is, via aqueous flow). Reported half-life data for gentamicin are approximately 32 hours.v' which is similar to the value calculated for foscarnet by using a multiple dosing design. Determination of intravitreal half-life and volume of distribution are important for developing appropriate dosing regimens and in the development of sustained delivery systems. Based on these data, after the administration of 1200 /-Lg of foscarnet, the intravitreal con-
Durham, North Carolina PAUL ASHTON, Ph.D.
Lexington, Kentucky References 1. Sawchuck, R. J., Zaske, D. E., CipoIle, R. J., Wargin, W. A., and Strate, R. G.: Kinetic model for gentamicin dosing with the use of individual patient parameters. Clin. Pharmacol. Ther. 21:362, 1977. 2. Gibaldi, M., and Perrier, D.: Pharmacokinetics, ed. 2. New York, Marcel Dekkar Inc., 1982, pp. 113-118. 3. Cobo, L. M., and Forster, R.: The clearance of intravitreal gentamicin. Am. J. Ophthalmol. 92:59, 1981. 4. Barza, M., Kane, A., and Baurn, J.: Pharmacokinetics of intravitreal carbenicillin, cefazolin, and gentamicin in rhesus monkeys. Invest. Ophthalmol. Vis. Sci. 24:1602, 1983.
_ _ _ _ _ _ _ Reply
_
EDITOR:
We agree with Drs. Pearson, Jaffe, and Ashton about the use of the approach described by Gibaldi and Perrier' to calculate pharmacokinetic parameters after multiple dosing as being better than doing calculations with the model proposed by Sawchuck and associates." However, establishing exact pharmacokinetic conclusions from two data sets is never completely correct. Additionally, intravitreal half-life in this case served only as an orientation point as a first approximation in addressing the problem. Conversely, by incorporating the suggestions made by Pearson, Jaffe, and Ashton related to the pharmacokinetics of foscarnet, the regimen of clinical administration of foscarnet is not modified. M. DiAZ-LLOPIS, M.D. E. CHIPONT, M.D. E. SANCHEZ, Pharm.D. E. ESPANA, M.D. A. NAVEA, M.D. J. L. MENEZO, M.D.
Valencia, Spain
AMERICAN JOURNAL OF OPHTHALMOLOGY
2. Souza-Dias. C: Additional consequences of muscle co-contraction in Duane's syndrome. In Souza-?ias, C (ed.): Smith-Kettlewell Symposium on Basic Sciences in Strabismus (Anex to the V Congress of the CL.A.D.E.). Sao Paulo, Edicoes Loyola, 1976, pp. 93-101. 3. Huber, A.: Duane's retraction syndrome. Considerations on pathogenesis and etiology of the different forms of Duane's retraction syndrome. In Huber, A. (ed.): Strabismus, London, H. Kimpton, 1970, pp. 36-43.
_ _ _ _ _ _ _ Reply
_
EDITOR:
I appreciate the comments of Dr. SouzaDias. His and Dr. Scott's excellent and innovative explanations of the up- and downshoot in Duane's syndrome and their suggestions for treatment were cited and referenced in my article and in an earlier report on this subject. I Dr. Souza-Dias disagrees with my statement that posterior fixation and recession of both horizontal recti muscles work similarly. Yet, he writes that "the principle of both techniques, with regard to the vertical anomalous movements, is the same." I see no disagreement here because the remainder of the sentence in my article, of which Dr. Souza-Dias cites only the beginning, expresses essentially the same view. It is theoretically correct that retraction of the globe should respond more favorably to recession than to posterior fixation of the horizontal recti muscles because the retraction effect of co-contraction is not lessened by posterior fixations. However, the postoperative photographs of the patient described in my article still show retraction on attempted adduction, despite a 6-mm recession of the medial rectus muscle and an 8-mm recession of the lateral rectus muscle. Perhaps, even larger recessions are necessary to decrease retraction significantly.
G. K. VON NOORDEN, M.D.
Houston, Texas
Reference 1. von Noorden. G. K., and Murray, E. M.: Up- and downshoot in Duane's retraction syndrome. J. Pediatr. Ophthalmol. Strabismus 23:212, 1986.
May, 1993
Intravitreal Foscarnet for Cytomegalovirus Retinitis in a Patient With Acquired Immunodeficiency Syndrome EDITOR:
We read with interest the article, "Intravitreal foscarnet for cytomegalovirus retinitis in a patient with acquired immunodeficiency syndrome," by M. Diaz-Llopis, E. Chipont, S. Sanchez, E. Espana, A. Navea, and J. L. Menezo (Am. J. Ophthalmol. 114:742, December 1992), and we commend the authors for their investigation of an alternate method of delivering foscarnet to the eye in the treatment of cytomegalovirus retinitis. We have been investigating alternate delivery techniques for a variety of compounds. Part of this work has centered around the clearance of drugs after intravitreal injection. We were surprised by their conclusion that the half-life of foscarnet is 54 hours. The authors have based their calculation of distribution volume and half-life on a model proposed by Sawchuck and associates in 1977. 1 In this work, Sawchuck and associates described the calculation of the distribution volu.me and elimination rate constant of gentamiCIn after an intravenous infusion. It would appear that Diaz-Llopis and associates have misinterpreted this work and have applied a formula which, although appropriate for Sawchuck and associates' study, does not adequately describe their own experimental conditions. Diaz-Llopis and associates have apparently used the data point 23.25 hours after the first intravitreal injection and the data point 49.5 hours after the sixth injection to calculate the half-life and distribution volume by using a simple nonlinear regression. To use regression analysis in this situation the essential assumption is that all of the drug was cleared from the eye during the interval between injections. Complete clearance will only occur if the dosing interval is much longer than the half-life. Based on the half-life that the authors themselves report, it is apparent that this is not true and that significant and measurable amounts of foscarnet remain in the eye 72 hours after application (the dosing interval). Pharmacokinetic parameters after multiple dosing can be readily calculated by using the approach described by Gibaldi and Perrier.? For a single compartment model, the concen-
687
Correspondence
Vol. 115, No.5
tration of drug at any time during a dosing interval can be determined by using the equation:
centration would fall below the mean 50% inhibition level for cytomegalovirus approximately 41 hours after a single dose. P. ANDREW PEARSON, M.D. GLENN J. JAFFE, M.D.
(1)
where C, is the drug concentration at time T (elapsed time since dose, N), Co is the maximum concentration after dose administration, N is the number of the dose, k is the elimination rate constant, and t is the dosing interval. Using the data provided in the article (409 umol /I 23.25 hours after the first dose and 292 umol Zl 49.5 hours after the sixth dose), equation 1 simplifies to: 409 urnolyl = Co e-23.25k (2) and: 292 umoly] = Co ([1 - e- 432kJ/ [l - e-72kj)e-49.5k (3)
Equation 2 can be solved for Co in terms of k and then substituted into equation 3: 292 /-Lmol/l = (409 umol /I / e-23.25k)([1 e- 432kl/[1 - e-72kj)e-49.5k (4) Simplifying equation 4 and then graphically solving for k, the elimination rate constant is 0.0218. This equates to an intravitreal half-life of 32 hours. By substituting this into equation 4 the maximum concentration after the first dose is 678 umol Zl. which yields an apparent volume of distribution of 5.9 ml. These values for half-life and volume of distribution are more agreeable with the clearance of other similar compounds. Foscarnet is a relatively hydrophilic compound and as such would not be expected to bind to lipid membranes within the eye. It also has relatively low protein binding in serum. Because of these factors we would expect the volume of distribution to be similar to the anatomic volume (approximately 5 ml). Additionally, in the absence of active transretinal transport, we would expect the half-life to be similar to other small, hydrophilic compounds such as gentamicin, which are presumably cleared via an anterior pathway (that is, via aqueous flow). Reported half-life data for gentamicin are approximately 32 hours.v' which is similar to the value calculated for foscarnet by using a multiple dosing design. Determination of intravitreal half-life and volume of distribution are important for developing appropriate dosing regimens and in the development of sustained delivery systems. Based on these data, after the administration of 1200 /-Lg of foscarnet, the intravitreal con-
Durham, North Carolina PAUL ASHTON, Ph.D.
Lexington, Kentucky References 1. Sawchuck, R. J., Zaske, D. E., CipoIle, R. J., Wargin, W. A., and Strate, R. G.: Kinetic model for gentamicin dosing with the use of individual patient parameters. Clin. Pharmacol. Ther. 21:362, 1977. 2. Gibaldi, M., and Perrier, D.: Pharmacokinetics, ed. 2. New York, Marcel Dekkar Inc., 1982, pp. 113-118. 3. Cobo, L. M., and Forster, R.: The clearance of intravitreal gentamicin. Am. J. Ophthalmol. 92:59, 1981. 4. Barza, M., Kane, A., and Baurn, J.: Pharmacokinetics of intravitreal carbenicillin, cefazolin, and gentamicin in rhesus monkeys. Invest. Ophthalmol. Vis. Sci. 24:1602, 1983.
_ _ _ _ _ _ _ Reply
_
EDITOR:
We agree with Drs. Pearson, Jaffe, and Ashton about the use of the approach described by Gibaldi and Perrier' to calculate pharmacokinetic parameters after multiple dosing as being better than doing calculations with the model proposed by Sawchuck and associates." However, establishing exact pharmacokinetic conclusions from two data sets is never completely correct. Additionally, intravitreal half-life in this case served only as an orientation point as a first approximation in addressing the problem. Conversely, by incorporating the suggestions made by Pearson, Jaffe, and Ashton related to the pharmacokinetics of foscarnet, the regimen of clinical administration of foscarnet is not modified. M. DiAZ-LLOPIS, M.D. E. CHIPONT, M.D. E. SANCHEZ, Pharm.D. E. ESPANA, M.D. A. NAVEA, M.D. J. L. MENEZO, M.D.
Valencia, Spain