HIV AND AIDS Edited by S. Diane Goodwin and Courtney V. Fletcher
This month we initiate a column dedicated to issues surrounding HIV-infected patients. It will serveas a forumthrough whicha broad rangeof AIDS and HIV topicscan be regularlypresented. The column is intended to reflectthe multipleaspectsof this area and draw attention to the manyways in whichwe have impacted or can impact the HIV-infected population. Some forthcoming topics include: Treatmentof HerpesVirus Infections in HIV-Infected Patients,Adjunctive Corticosteroid Therapy for Pneumocystis carinii Pneumo-
nia, and The Role of FolinicAcid in Patientson Trimethoprirn/Sulfamethoxazole. Potential authors are encouraged to sharetheirknowledge. insight, and experience in caring for the HIV patientby submitting reviews, commentary, and otherpertinent material. The editorsshould be contactedto avoidduplication of topics. HEDv A A. BARENHOLTZ.Pharm.D. HARVEY A.K. WHITNEY. JR., M.S.Pharm.
DIDANOSINE MarkJ. Shelton, Alice M.O'Donnell, and Gene D. Morse
OBJECTIVE: To review the chemistry, intracellularmetabolism. pharmacokinetics. and clinical experience with didanosine (2'.3'dideoxyinosine [ddI]). English-language articles and conference proceedings (indexing terms were didanosine, 2',3'-dideoxyinosine, andddI).
DATA SOURCES:
STUDY SELECIlON:
Available Phase I studies and abstracts determined to have clinical significance were included. DATA EXTRACOON: Clinical experience with ddI is limited to uncontrolled Phase I studies and a large "expanded-access" program. The primary outcome parameters used to evaluate ddl were the IDV surrogate markers: CD4+ lymphocytes and p24 antigen. Thus, the clinical data reviewed here must be evaluated critically and be considered preliminary until the results of studies comparing ddl with zidovudine (ZDV) and combination studies are available. DATA SYNTHESIs: Didanosine has been approved for the treatment of IDV infection in patients who are unable to tolerate ZDV because of
adverse effects (e.g., anemia and neutropenia) or who experience clinical or immunologic deterioration while receiving ZDV. Compared with ZDV, ddl has a long intracellularhalf-life and negligible bone-marrow toxicity. It also has in vitro activity against ZDV-resistant strains of IDV. Phase I studies indicate that ddl has a beneficial effect on the CD4+ cell counts and IDV p24 antigen concentrations. As a result of the acid-labile nature of ddI, oral formulations are buffered or must be mixed with antacid to neutralize gastric pH. Bioavailabilitythen averages 20-40 percent, depending on the dose and formulation given. The plasma half-life, total body clearance, and volume of distribution of ddl are one to two hours, 0.7-1 L/kg/h, and 0.8-1 L/kg, respectively. Painful peripheral neuropathy and pancreatitis (dose-limitingtoxicities of ddI) occurred in 34 and 9 percent of patients in Phase I studies, respectively. CONCLUSIONS: Didanosine has demonstrated preliminary efficacy in the treatment of late-stage IDV infection; however, its effect on patient survival, its efficacy relative to ZDV, and its utility in combination with other agents are still under evaluation.
Ann Pharmacother 1992;26:660-70. MARK J. SHELTON, Pharm.D., is an ACCP Fellow in Infectious Disease Pharmacotherapy, Center for Clinical Pharmacy Research, State University of New York at Buffalo; ALICE M. O'DONNELL, Pharm.D., is a Scholar of the American Foundation for AIDS Research, Center for Clinical Pharmacy Research, State University of New York at Buffalo; and GENE D. MORSE, Pharm.D.. FCCP, is an Associate Professor of Pharmacy, Center for Clinical Pharmacy Research, State University of New York at Buffalo; a Co-investigator, University of Rochester AIDS Clinical Trials Unit, and a Member, Department of Pharmaceutical Services, Erie County Medical Center, Buffalo, NY. Reprints: Gene D. Morse, Pharm.D., FCCP, State University of New York at Buffalo, Erie County Medical Center, 462 Grider St., Buffalo, NY 14215.
S. DIANE GOODWIN, Pharm.D., is an Assistant Professor, Division of Pharmacy Practice, School of Pharmacy, University of Colorado Health Sciences Center, Box C238,4200 E. Ninth Ave., Denver, CO 80262; and COURTNEY V. FLETCHER, Pharm.D., is an Associate Professor, Department of Pharmacy Practice, College of Pharmacy, University of Minnesota, 7-115 HSUF, 308 Harvard St. S.E., Minneapolis, MN 55455.
Thisanicle is approved for continuing educationcredit
660 • The Annals ofPharmacotherapy •
(2',3'-dideoxyinosine [ddI]) is the second antiretroviral agent approved by the Food and Drug Administration (FDA) for the treatment of lllV infection. Prior to the approval of ddI, zidovudine (ZDV) was the only licensed antiretroviral agent. Like ZDV, ddl underwent an accelerated approval process, taking three years from the onset of initial clinical studies to reach approval status. Ramifications of rapid approval can be seen from the postmarketing changes that have occurred with ZDV: a dose reduction from 250 to 100 mg every four hours.P and expansion of the indicated patient population to include asymptomatic lllV-positive patients with CD4+ cell counts consistently below 500 cells/mrn'.' The currently published data supporting the efficacy of ddl are limited to uncontrolled Phase I trials. However, ddl DIDANOSINE
1992 May, Volume 26
Downloaded from aop.sagepub.com at CORNELL UNIV on August 2, 2016
had an impressive effect on surrogate markers of HIV-disease activity (p24 antigenemia, CD4+ cell counts) without bone marrow suppression (a limiting toxicity of ZDV). Because of the lethal nature of HIV disease and the availability of only one treatment, ddI was made available to more than 20 000 patients in "expanded-access" (EA) protocols prior to its full approval. Clinical efficacy data used for the approval of ddI are derived from the Phase I studies (-170 patients) and the EA program (-7800 patients evaluated), which were not designed to evaluate efficacy. Therefore, ddI represents an alternative to ZDV for a subset of HIV-infected patients, but its long-term efficacy and criteria for optimal use remain to be determined.'
Endogenous Nucleosides
Dideoxyn ucleosides o
N~N
Adenosine:
(, .i..
HOCH2
N
r~o
This month we initiate a column dedicated to issues surrounding HIV-infected patients. It will serveas a forumthrough whicha broad rangeof AIDS and HIV topicscan be regularlypresented. The column is intended to reflectthe multipleaspectsof this area and draw attention to the manyways in whichwe have impacted or can impact the HIV-infected population. Some forthcoming topics include: Treatmentof HerpesVirus Infections in HIV-Infected Patients,Adjunctive Corticosteroid Therapy for Pneumocystis carinii Pneumo-
nia, and The Role of FolinicAcid in Patientson Trimethoprirn/Sulfamethoxazole. Potential authors are encouraged to sharetheirknowledge. insight, and experience in caring for the HIV patientby submitting reviews, commentary, and otherpertinent material. The editorsshould be contactedto avoidduplication of topics. HEDv A A. BARENHOLTZ.Pharm.D. HARVEY A.K. WHITNEY. JR., M.S.Pharm.
DIDANOSINE MarkJ. Shelton, Alice M.O'Donnell, and Gene D. Morse
OBJECTIVE: To review the chemistry, intracellularmetabolism. pharmacokinetics. and clinical experience with didanosine (2'.3'dideoxyinosine [ddI]). English-language articles and conference proceedings (indexing terms were didanosine, 2',3'-dideoxyinosine, andddI).
DATA SOURCES:
STUDY SELECIlON:
Available Phase I studies and abstracts determined to have clinical significance were included. DATA EXTRACOON: Clinical experience with ddI is limited to uncontrolled Phase I studies and a large "expanded-access" program. The primary outcome parameters used to evaluate ddl were the IDV surrogate markers: CD4+ lymphocytes and p24 antigen. Thus, the clinical data reviewed here must be evaluated critically and be considered preliminary until the results of studies comparing ddl with zidovudine (ZDV) and combination studies are available. DATA SYNTHESIs: Didanosine has been approved for the treatment of IDV infection in patients who are unable to tolerate ZDV because of
adverse effects (e.g., anemia and neutropenia) or who experience clinical or immunologic deterioration while receiving ZDV. Compared with ZDV, ddl has a long intracellularhalf-life and negligible bone-marrow toxicity. It also has in vitro activity against ZDV-resistant strains of IDV. Phase I studies indicate that ddl has a beneficial effect on the CD4+ cell counts and IDV p24 antigen concentrations. As a result of the acid-labile nature of ddI, oral formulations are buffered or must be mixed with antacid to neutralize gastric pH. Bioavailabilitythen averages 20-40 percent, depending on the dose and formulation given. The plasma half-life, total body clearance, and volume of distribution of ddl are one to two hours, 0.7-1 L/kg/h, and 0.8-1 L/kg, respectively. Painful peripheral neuropathy and pancreatitis (dose-limitingtoxicities of ddI) occurred in 34 and 9 percent of patients in Phase I studies, respectively. CONCLUSIONS: Didanosine has demonstrated preliminary efficacy in the treatment of late-stage IDV infection; however, its effect on patient survival, its efficacy relative to ZDV, and its utility in combination with other agents are still under evaluation.
Ann Pharmacother 1992;26:660-70. MARK J. SHELTON, Pharm.D., is an ACCP Fellow in Infectious Disease Pharmacotherapy, Center for Clinical Pharmacy Research, State University of New York at Buffalo; ALICE M. O'DONNELL, Pharm.D., is a Scholar of the American Foundation for AIDS Research, Center for Clinical Pharmacy Research, State University of New York at Buffalo; and GENE D. MORSE, Pharm.D.. FCCP, is an Associate Professor of Pharmacy, Center for Clinical Pharmacy Research, State University of New York at Buffalo; a Co-investigator, University of Rochester AIDS Clinical Trials Unit, and a Member, Department of Pharmaceutical Services, Erie County Medical Center, Buffalo, NY. Reprints: Gene D. Morse, Pharm.D., FCCP, State University of New York at Buffalo, Erie County Medical Center, 462 Grider St., Buffalo, NY 14215.
S. DIANE GOODWIN, Pharm.D., is an Assistant Professor, Division of Pharmacy Practice, School of Pharmacy, University of Colorado Health Sciences Center, Box C238,4200 E. Ninth Ave., Denver, CO 80262; and COURTNEY V. FLETCHER, Pharm.D., is an Associate Professor, Department of Pharmacy Practice, College of Pharmacy, University of Minnesota, 7-115 HSUF, 308 Harvard St. S.E., Minneapolis, MN 55455.
Thisanicle is approved for continuing educationcredit
660 • The Annals ofPharmacotherapy •
(2',3'-dideoxyinosine [ddI]) is the second antiretroviral agent approved by the Food and Drug Administration (FDA) for the treatment of lllV infection. Prior to the approval of ddI, zidovudine (ZDV) was the only licensed antiretroviral agent. Like ZDV, ddl underwent an accelerated approval process, taking three years from the onset of initial clinical studies to reach approval status. Ramifications of rapid approval can be seen from the postmarketing changes that have occurred with ZDV: a dose reduction from 250 to 100 mg every four hours.P and expansion of the indicated patient population to include asymptomatic lllV-positive patients with CD4+ cell counts consistently below 500 cells/mrn'.' The currently published data supporting the efficacy of ddl are limited to uncontrolled Phase I trials. However, ddl DIDANOSINE
1992 May, Volume 26
Downloaded from aop.sagepub.com at CORNELL UNIV on August 2, 2016
had an impressive effect on surrogate markers of HIV-disease activity (p24 antigenemia, CD4+ cell counts) without bone marrow suppression (a limiting toxicity of ZDV). Because of the lethal nature of HIV disease and the availability of only one treatment, ddI was made available to more than 20 000 patients in "expanded-access" (EA) protocols prior to its full approval. Clinical efficacy data used for the approval of ddI are derived from the Phase I studies (-170 patients) and the EA program (-7800 patients evaluated), which were not designed to evaluate efficacy. Therefore, ddI represents an alternative to ZDV for a subset of HIV-infected patients, but its long-term efficacy and criteria for optimal use remain to be determined.'
Endogenous Nucleosides
Dideoxyn ucleosides o
N~N
Adenosine:
(, .i..
HOCH2
N
r~o
