TITLE

Pharmacokinetic optimisation of the treatment of cancer with high dose zidovudine

AUTHOR(S)
Danesi, R.; Falcone, A.; Conte, P.F.; Tacca, M.D.; Del Tacca, M
PUB. DATE
February 1998
SOURCE
Clinical Pharmacokinetics;1998, Vol. 34 Issue 2, p173
SOURCE TYPE
Academic Journal
DOC. TYPE
journal article
ABSTRACT
The thymidine analogue zidovudine is currently used for the treatment of HIV-infected patients, as the early development of the drug as an anticancer agent yielded modest results. A comprehensive preclinical analysis, however, showed that inhibitors of de novo thymidylate synthesis, including fluorouracil and methotrexate, enhanced the antiproliferative activity of zidovudine in cancer cells. Significant inhibition of tumour growth was obtained in mice bearing human colon cancer xenografts and given intraperitoneal zidovudine 300 to 600 mg/kg weekly in combination with methotrexate 87.5 mg/kg or intraperitoneal fluorouracil 85 mg/kg, and in pharmacokinetic studies high peak drug plasma concentrations (Cmax) of zidovudine were obtained, ranging from 610.3 to 1698.8 mumol/L. In order to exploit the therapeutic activity of zidovudine, phase I and II clinical studies were designed in combination with fluorouracil and the pharmacokinetic-pharmacodynamic profile of zidovudine was investigated. Clinical responses were obtained in patients treated intravenously with bolus fluorouracil 500 mg/m2, leucovorin and short (90 to 120 minutes) infusions of high dose zidovudine (up to 10 g/m2), generating drug Cmax similar to those obtained in preclinical models. However, in chemotherapy-pretreated patients receiving high dose zidovudine by the oral route (1 to 9 g/m2/day) or 48-hourly continuous intravenous infusion (2 to 20 g/m2/day) in combination with fluorouracil and leucovorin, treatment failures were observed despite high systemic exposure, described as the area under the plasma concentration-time curve and the occurrence of DNA strand breaks in peripheral blood mononucleated cells, the biological expression of zidovudine activity. In conclusion, preclinical and clinical evidence suggest that the schedule of administration of zidovudine is a requisite for the expression of its activity, indicating the importance of concentration-monitored trials to optimise chemotherapy dose administration in patients. The likelihood of tumour response appears to be related to the achievement of high peak plasma concentrations of zidovudine, and constant infusions appear less likely to produce clinical results.
ACCESSION #
9592763

 

Related Articles

  • Pharmacokinetics of Antiretroviral Drug Varies With Formulation in the Target Population of Children With HIV-1. Kasirye, P; Kendall, L; Adkison, K K; Tumusiime, C; Ssenyonga, M; Bakeera-Kitaka, S; Nahirya-Ntege, P; Mhute, T; Kekitiinwa, A; Snowden, W; Burger, D M; Gibb, D M; Walker, A S // Clinical Pharmacology & Therapeutics;Feb2012, Vol. 91 Issue 2, p272 

    The bioequivalence of formulations is usually evaluated in healthy adult volunteers. In our study in 19 HIV-1-infected Ugandan children (1.8-4 years of age, weight 12 to <15 kg) receiving zidovudine, lamivudine, and abacavir solutions twice a day for ≥24 weeks, the use of scored tablets...

  • Population pharmacokinetic analysisof lamivudine, stavudine and zidovudine in controlled HIV-infected patients on HAART. Panhard, Xavière; Legrand, Mayeule; Taburet, Anne-Marie; Diquet, Bertrand; Goujard, Cécile; Mentré, France // European Journal of Clinical Pharmacology;Nov2007, Vol. 63 Issue 11, p1019 

    This work aimed at building a population pharmacokinetic (PK) model for lamivudine (LMV), stavudine (STV) and zidovudine (ZDV), estimating their inter and intraindividual PK variability and investigating the influence of different covariates. Population PK of LMV, STV and ZDV was separately...

  • Reducing the dosage of AZT in children. Pinkowish, Mary Desmond // Patient Care;5/15/1996, Vol. 30 Issue 9, p184 

    Summarizes an article entitled `Randomized Study of the Tolerance and Efficacy of High-Versus Low-Dose Zidovudine in Human Immunodeficiency Virus-Infected Children with Mild to Moderate Symptoms,' by M.T. Brady, N. McGrath, et al, published in issue number 173 of the `Journal of Infectious...

  • MCV clue in zidovudine patient. Page, George E.; H.C.N. // Cortlandt Forum;3/25/95, Vol. 8 Issue 3, p103 

    Comments that an HIV-positive patient with normal corpuscular volume (MCV) is probably not taking his or her zidovudine.

  • Zidovudine and didanosine for HIV infection in children. Andolsek, Kathryn M. // American Family Physician;1/1/1998, Vol. 57 Issue 1, p132 

    Presents information on the use of zidovudine for children infected with human immunodeficiency virus (HIV) which is usually acquired by perinatal exposure. Recommendation of zidovudine for symptomatic children; Investigation conducted by Englund and associates on the use of zidovudine,...

  • Is AZT affecting my ability to build muscle?. Cohan, Gary R. // Advocate;10/5/93, Issue 639, p34 

    Discusses the possible effect of AZT to the ability of an HIV-positive man to build muscle. Clarification that AZT is not linked to any problem with muscle formation; Citation of a condition known as hypogonadism as the possible ailment affecting muscle development among HIV-infected persons.

  • An Update on Drug Interactions with Zidovudine. Piscitelli, Stephen C.; Polis, Michael A. // AIDS Patient Care & STDs;Sep98, Vol. 12 Issue 9, p687 

    Looks at the drug interaction of Zidovudine in patients with HIV infection. Concomitant medications which alter the plasma concentrations of zidovudine; Categories drug interactions are divided into; Details on the pharmacokinetic drug interactions with zidovudine; How drug interactions can be...

  • Postural hypotension related to zidovudine in a patient infected with HIV. Loke, Richard H.T.; Murray-Lyon, Lain M.; Carter, Graham D. // BMJ: British Medical Journal (International Edition);1/20/90, Vol. 300 Issue 6718, p163 

    Examines the relationship between postural hypotensions and patients infected with HIV. Side effects of zidovudine; Application of ketoconazole for the treatment of oral candidiasis; Reduction of CD4 lymphocytes count.

  • After Concorde. Gazzard, B.G. // BMJ: British Medical Journal (International Edition);4/17/93, Vol. 306 Issue 6884, p1016 

    Examines the effectiveness of zidovudine as sole treatment for asymptotic HIV positive patients in Great Britain. Susceptibility of HIV to antiviral drugs; Increase in CD4 antigen count after early treatment; Rate of the development of viral isolates in patients.

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics