Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials. 1992

G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
Department of Medicine, University of Maryland School of Medicine, Baltimore.

The objective of this study was to determine the population pharmacokinetic parameters and the extent of absorption of 2',3'-dideoxyinosine, a nucleoside analog with activity against human immunodeficiency virus in vitro and in vivo, after oral and intravenous administration through the use of NON-linear Mixed Effects Modeling. The data were drawn from the pharmacokinetics section of an open-label, multicenter phase I study. One center administered ddI on a once-daily schedule. The other centers administered the drug once every 12 h. Drug was administered intravenously, and the plasma concentration-time profile was determined. Patients were then given the drug orally at twice the dose used in the intravenous portion of the study, and the pharmacokinetic profile was again determined. A 40-fold range of doses was examined. Forty-six human immunodeficiency virus-infected patients were studied. Concentrations in plasma were determined by high-pressure liquid chromatography. Clearance of the drug from plasma was 47.7 liters/h/70 kg of body weight. The terminal half-life was 1.4 h. The volume of distribution in the central compartment was 18.8 liters/70 kg. Absorption was rapid, with an absorption half-life of 0.52 h. Bioavailability with once-daily administration was 27%. For twice-daily administration, bioavailability rose to 36%. This difference was significant (P much less than 0.01). For doses of less than or equal to 5.1 mg/kg given every 12 h (10.2 mg/kg/day), bioavailability was 41%. We conclude that once-daily administration results in lower mean bioavailability, probably because of a saturation of the absorption process similar to that seen with acyclovir. This difference in bioavailability on the basis of the administration schedule explains the different short-term maximal tolerated doses identified in phase I trials of this agent.

UI MeSH Term Description Entries
D007275 Injections, Intravenous Injections made into a vein for therapeutic or experimental purposes. Intravenous Injections,Injection, Intravenous,Intravenous Injection
D004361 Drug Tolerance Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from DRUG RESISTANCE wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from MAXIMUM TOLERATED DOSE and NO-OBSERVED-ADVERSE-EFFECT LEVEL. Drug Tolerances,Tolerance, Drug,Tolerances, Drug
D006207 Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Halflife,Half Life,Half-Lifes,Halflifes
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000163 Acquired Immunodeficiency Syndrome An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive T-lymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. AIDS,Immunodeficiency Syndrome, Acquired,Immunologic Deficiency Syndrome, Acquired,Acquired Immune Deficiency Syndrome,Acquired Immuno-Deficiency Syndrome,Acquired Immuno Deficiency Syndrome,Acquired Immuno-Deficiency Syndromes,Acquired Immunodeficiency Syndromes,Immuno-Deficiency Syndrome, Acquired,Immuno-Deficiency Syndromes, Acquired,Immunodeficiency Syndromes, Acquired,Syndrome, Acquired Immuno-Deficiency,Syndrome, Acquired Immunodeficiency,Syndromes, Acquired Immuno-Deficiency,Syndromes, Acquired Immunodeficiency
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
D001682 Biological Availability The extent to which the active ingredient of a drug dosage form becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action. Availability Equivalency,Bioavailability,Physiologic Availability,Availability, Biologic,Availability, Biological,Availability, Physiologic,Biologic Availability,Availabilities, Biologic,Availabilities, Biological,Availabilities, Physiologic,Availability Equivalencies,Bioavailabilities,Biologic Availabilities,Biological Availabilities,Equivalencies, Availability,Equivalency, Availability,Physiologic Availabilities
D016049 Didanosine A dideoxynucleoside compound in which the 3'-hydroxy group on the sugar moiety has been replaced by a hydrogen. This modification prevents the formation of phosphodiester linkages which are needed for the completion of nucleic acid chains. Didanosine is a potent inhibitor of HIV replication, acting as a chain-terminator of viral DNA by binding to reverse transcriptase; ddI is then metabolized to dideoxyadenosine triphosphate, its putative active metabolite. 2',3'-Dideoxyinosine,Dideoxyinosine,ddI (Antiviral),NSC-612049,Videx,2',3' Dideoxyinosine,NSC 612049,NSC612049
D017321 Clinical Trials, Phase I as Topic Works about studies performed to evaluate the safety of diagnostic, therapeutic, or prophylactic drugs, devices, or techniques in healthy subjects and to determine the safe dosage range (if appropriate). These tests also are used to determine pharmacologic and pharmacokinetic properties (toxicity, metabolism, absorption, elimination, and preferred route of administration). They involve a small number of persons and usually last about 1 year. This concept includes phase I studies conducted both in the U.S. and in other countries. Clinical Trials, Phase I,Drug Evaluation, FDA Phase I,Evaluation Studies, FDA Phase I,Human Microdosing Trial,Phase 1 Clinical Trial,Phase I Clinical Trial,Phase I Clinical Trials,Clinical Trials, Phase 1,Drug Evaluation, FDA Phase 1,Drug Evaluation, FDA Phase I as Topic,Evaluation Studies, FDA Phase 1,Human Microdosing Trials,Microdosing Trials, Human,Phase 1 Clinical Trials,Microdosing Trial, Human,Trial, Human Microdosing,Trials, Human Microdosing

Related Publications

G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
January 1990, Reviews of infectious diseases,
G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
October 2012, Clinical cancer research : an official journal of the American Association for Cancer Research,
G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
February 1993, Journal of the National Cancer Institute,
G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
March 2021, Contemporary clinical trials communications,
G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
January 2000, The hematology journal : the official journal of the European Haematology Association,
G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
April 2005, Contemporary clinical trials,
G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
September 1988, Journal of chromatography,
G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
January 2012, Journal of veterinary internal medicine,
G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
April 2021, The international journal of biostatistics,
G L Drusano, and G J Yuen, and G Morse, and T P Cooley, and M Seidlin, and J S Lambert, and H A Liebman, and F T Valentine, and R Dolin
May 1992, Chemical & pharmaceutical bulletin,
Copied contents to your clipboard!