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

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 us...

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Main Authors: Drusano, G L, Yuen, G J, Morse, G, Cooley, T P, Seidlin, M, Lambert, J S, Liebman, H A, Valentine, F T, Dolin, R
Formato: Artigo
Idioma:en
Publicado em: 1992
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Research Article
Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC190332/
https://ncbi.nlm.nih.gov/pubmed/1416828
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spelling pubmed-1903322003-12-01 Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials. Drusano, G L Yuen, G J Morse, G Cooley, T P Seidlin, M Lambert, J S Liebman, H A Valentine, F T Dolin, R Antimicrob Agents Chemother Research Article 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. 1992-06 /pmc/articles/PMC190332/ /pubmed/1416828 Text en
institution US National Library of Medicine
collection PubMed Central
language en
format Article
topic Research Article
spellingShingle Research Article
Drusano, G L
Yuen, G J
Morse, G
Cooley, T P
Seidlin, M
Lambert, J S
Liebman, H A
Valentine, F T
Dolin, R
Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.
description 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.
author Drusano, G L
Yuen, G J
Morse, G
Cooley, T P
Seidlin, M
Lambert, J S
Liebman, H A
Valentine, F T
Dolin, R
author_facet Drusano, G L
Yuen, G J
Morse, G
Cooley, T P
Seidlin, M
Lambert, J S
Liebman, H A
Valentine, F T
Dolin, R
author_sort Drusano, G L
title Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.
title_short Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.
title_full Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.
title_fullStr Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.
title_full_unstemmed Impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase I trials.
title_sort impact of bioavailability on determination of the maximal tolerated dose of 2',3'-dideoxyinosine in phase i trials.
publishDate 1992
url https://ncbi.nlm.nih.gov/pmc/articles/PMC190332/
https://ncbi.nlm.nih.gov/pubmed/1416828
_version_ 1759041450178248704

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