Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections

Gene D. Morse, Margaret A Fischl, Mark J. Shelton, Marie T. Borin, Mary R. Driver, Mary DeRemer, Kelly Lee, Charles P. Wajszczuk

Research output: Contribution to journalArticle

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Abstract

Atevirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type I and is currently in phase II clinical trials. Atevirdine is most soluble at a pH of <2, and therefore, normal gastric acidity is most likely necessary fur optimal bioavailability. Because of the rapid development of resistance in vitro, atevirdine is being evaluated in combination with didanosine and/or zidovudine in both two- and three-drug combination regimens. To examine the influence of concurrent didanosine (buffered tablet formulation) on the disposition of atevirdine, 12 human immunodeficiency virus type 1-infected subjects (mean CD4+ cell count, 199 cells per mm3; range, 13 to 447 cells/mm3) participated in a three-way, partially randomized, crossover, single-dose study to evaluate the pharmacokinetics of didanosine and atevirdine when each drug was given alone (treatments A and B, respectively) versus concurrently (treatment C). Concurrent administration of didanosine and atevirdine significantly reduced the maximum concentration of atevirdine in serum from 3.45 ± 2.8 to 0.854 ± 0.33 μM (P = 0.004). Likewise, the mean atevirdine area under the concentration-time curve from 0 to 24 h after administration of the combination was reduced to 6.47 ± 2.2 μM · h (P = 0.004) relative to a value of 11.3 ± 4.8 μM · h for atevirdine alone. Atevirdine had no statistically significant effect on the pharmacokinetic parameters of didanosine. Concurrent administration of single doses of atevirdine and didanosine resulted in a markedly lower maximum concentration of atevirdine in serum and area under the concentration-time curve, with a minimal effect on the disposition of didanosine. It is unknown whether an interaction of similar magnitude would occur under steady-state conditions; thus, combination regimens which include both atevirdine and didanosine should be designed so that their administration times are separated. Since the duration of the buffering effect of didanosine formulations is unknown, atevirdine should be given prior to didanosine.

Original languageEnglish
Pages (from-to)767-771
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume40
Issue number3
StatePublished - Mar 1 1996

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Didanosine
Virus Diseases
HIV
atevirdine
Pharmacokinetics
Phase II Clinical Trials
Reverse Transcriptase Inhibitors
Zidovudine
Drug Combinations
CD4 Lymphocyte Count
Serum
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Morse, G. D., Fischl, M. A., Shelton, M. J., Borin, M. T., Driver, M. R., DeRemer, M., ... Wajszczuk, C. P. (1996). Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections. Antimicrobial Agents and Chemotherapy, 40(3), 767-771.

Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections. / Morse, Gene D.; Fischl, Margaret A; Shelton, Mark J.; Borin, Marie T.; Driver, Mary R.; DeRemer, Mary; Lee, Kelly; Wajszczuk, Charles P.

In: Antimicrobial Agents and Chemotherapy, Vol. 40, No. 3, 01.03.1996, p. 767-771.

Research output: Contribution to journalArticle

Morse, GD, Fischl, MA, Shelton, MJ, Borin, MT, Driver, MR, DeRemer, M, Lee, K & Wajszczuk, CP 1996, 'Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections', Antimicrobial Agents and Chemotherapy, vol. 40, no. 3, pp. 767-771.
Morse, Gene D. ; Fischl, Margaret A ; Shelton, Mark J. ; Borin, Marie T. ; Driver, Mary R. ; DeRemer, Mary ; Lee, Kelly ; Wajszczuk, Charles P. / Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections. In: Antimicrobial Agents and Chemotherapy. 1996 ; Vol. 40, No. 3. pp. 767-771.
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abstract = "Atevirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type I and is currently in phase II clinical trials. Atevirdine is most soluble at a pH of <2, and therefore, normal gastric acidity is most likely necessary fur optimal bioavailability. Because of the rapid development of resistance in vitro, atevirdine is being evaluated in combination with didanosine and/or zidovudine in both two- and three-drug combination regimens. To examine the influence of concurrent didanosine (buffered tablet formulation) on the disposition of atevirdine, 12 human immunodeficiency virus type 1-infected subjects (mean CD4+ cell count, 199 cells per mm3; range, 13 to 447 cells/mm3) participated in a three-way, partially randomized, crossover, single-dose study to evaluate the pharmacokinetics of didanosine and atevirdine when each drug was given alone (treatments A and B, respectively) versus concurrently (treatment C). Concurrent administration of didanosine and atevirdine significantly reduced the maximum concentration of atevirdine in serum from 3.45 ± 2.8 to 0.854 ± 0.33 μM (P = 0.004). Likewise, the mean atevirdine area under the concentration-time curve from 0 to 24 h after administration of the combination was reduced to 6.47 ± 2.2 μM · h (P = 0.004) relative to a value of 11.3 ± 4.8 μM · h for atevirdine alone. Atevirdine had no statistically significant effect on the pharmacokinetic parameters of didanosine. Concurrent administration of single doses of atevirdine and didanosine resulted in a markedly lower maximum concentration of atevirdine in serum and area under the concentration-time curve, with a minimal effect on the disposition of didanosine. It is unknown whether an interaction of similar magnitude would occur under steady-state conditions; thus, combination regimens which include both atevirdine and didanosine should be designed so that their administration times are separated. Since the duration of the buffering effect of didanosine formulations is unknown, atevirdine should be given prior to didanosine.",
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