Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects

Paul J. Cimoch, James Lavelle, Richard B Pollard, Kay Gaines Griffy, Rodney Wong, Thomas L. Tarnowski, Sandra Casserella, Donald Jung

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The aim of this study was to determine whether oral ganciclovir interacted pharmacokinetically with zidovudine (AZT), didanosine (ddl), or probenecid. A multicenter, open-label, randomized, crossover pharmacokinetic study with four phases was undertaken at an outpatient private research center and at university research clinics. Twenty-six HIV-infected adults (23 men, 3 women) with cytomegalovirus (CMV) seropositivity and CD4+ T- lymphocyte count ≤100 cells/μl were studied. Patients had to be stable on antiretroviral therapy for at least 4 weeks. Patients with a history of opportunistic infection or gastrointestinal symptoms were excluded. Measurements included serial blood and urine samples during the dosing intervals at steady state. The steady-state pharmacokinetics of ganciclovir were determined after the participants had stabilized and were tolerating AZT or ddI therapy. When a 1000-mg dose of oral ganciclovir was taken every 8 hours, there was a significant mean increase in C(max) and dosing interval area under the serum concentration time curve over a dosing interval (AUC) for the two antiretroviral drugs: for AZT, 61.6% and 19.5%, respectively; for ddI when administered sequentially (2 hours before ganciclovir), 116.0% and 114.6%; and for ddI administered simultaneously with ganciclovir. 107.9% and 107,1%, respectively. There was no significant change in renal clearance for either antiretroviral drug, suggesting that the interaction did not occur through a renal mechanism. There was no significant change in mean ganciclovir C(max) and AUC0-8 when coadministered with AZT. Mean increases in C(max) and AUC0-8 of oral ganciclovir averaged 40.1% and 52.5%, respectively, when coadministered with probenecid, but decreased by 22.1% and 22.7%, respectively, when oral ganciclovir was administered 2 hours after ddI. There was no change in the mean ganciclovir C(max) or AUC0-8 when administered simultaneously with ddI. The mean renal clearance of oral ganciclovir was not affected by AZT or ddI coadministration intake, but there was a mean decrease of 19% when coadministered with probenecid. We conclude the increased serum concentration and reduced renal clearance of ganciclovir suggests competition with probenecid for secretion at the renal tubule. The mechanism of the interaction of oral ganciclovir with either AZT or ddI remains to be determined. The magnitude of the effect of oral ganciclovir on ddI pharmacokinetics may result in an increase in ddI concentration-related toxicities. Similarly, the small but significant decrease in ganciclovir concentration with sequential combination ddI therapy may impair the efficacy of oral ganciclovir. For HIV-infected patients receiving ganciclovir and ddI, clinicians should recommend administering the two drugs simultaneously, and patients should be monitored closely for ddI-associated toxicities.

Original languageEnglish (US)
Pages (from-to)227-234
Number of pages8
JournalJournal of Acquired Immune Deficiency Syndromes and Human Retrovirology
Volume17
Issue number3
StatePublished - Mar 1 1998
Externally publishedYes

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Didanosine
Probenecid
Ganciclovir
Zidovudine
Pharmacokinetics
HIV
Kidney
Opportunistic Infections

Keywords

  • Didanosine (ddI)
  • Ganciclovir
  • HIV-1
  • Pharmacokinetics
  • Zidovudine (AZT)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Virology

Cite this

Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects. / Cimoch, Paul J.; Lavelle, James; Pollard, Richard B; Griffy, Kay Gaines; Wong, Rodney; Tarnowski, Thomas L.; Casserella, Sandra; Jung, Donald.

In: Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, Vol. 17, No. 3, 01.03.1998, p. 227-234.

Research output: Contribution to journalArticle

Cimoch, Paul J. ; Lavelle, James ; Pollard, Richard B ; Griffy, Kay Gaines ; Wong, Rodney ; Tarnowski, Thomas L. ; Casserella, Sandra ; Jung, Donald. / Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects. In: Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 1998 ; Vol. 17, No. 3. pp. 227-234.
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abstract = "The aim of this study was to determine whether oral ganciclovir interacted pharmacokinetically with zidovudine (AZT), didanosine (ddl), or probenecid. A multicenter, open-label, randomized, crossover pharmacokinetic study with four phases was undertaken at an outpatient private research center and at university research clinics. Twenty-six HIV-infected adults (23 men, 3 women) with cytomegalovirus (CMV) seropositivity and CD4+ T- lymphocyte count ≤100 cells/μl were studied. Patients had to be stable on antiretroviral therapy for at least 4 weeks. Patients with a history of opportunistic infection or gastrointestinal symptoms were excluded. Measurements included serial blood and urine samples during the dosing intervals at steady state. The steady-state pharmacokinetics of ganciclovir were determined after the participants had stabilized and were tolerating AZT or ddI therapy. When a 1000-mg dose of oral ganciclovir was taken every 8 hours, there was a significant mean increase in C(max) and dosing interval area under the serum concentration time curve over a dosing interval (AUC) for the two antiretroviral drugs: for AZT, 61.6{\%} and 19.5{\%}, respectively; for ddI when administered sequentially (2 hours before ganciclovir), 116.0{\%} and 114.6{\%}; and for ddI administered simultaneously with ganciclovir. 107.9{\%} and 107,1{\%}, respectively. There was no significant change in renal clearance for either antiretroviral drug, suggesting that the interaction did not occur through a renal mechanism. There was no significant change in mean ganciclovir C(max) and AUC0-8 when coadministered with AZT. Mean increases in C(max) and AUC0-8 of oral ganciclovir averaged 40.1{\%} and 52.5{\%}, respectively, when coadministered with probenecid, but decreased by 22.1{\%} and 22.7{\%}, respectively, when oral ganciclovir was administered 2 hours after ddI. There was no change in the mean ganciclovir C(max) or AUC0-8 when administered simultaneously with ddI. The mean renal clearance of oral ganciclovir was not affected by AZT or ddI coadministration intake, but there was a mean decrease of 19{\%} when coadministered with probenecid. We conclude the increased serum concentration and reduced renal clearance of ganciclovir suggests competition with probenecid for secretion at the renal tubule. The mechanism of the interaction of oral ganciclovir with either AZT or ddI remains to be determined. The magnitude of the effect of oral ganciclovir on ddI pharmacokinetics may result in an increase in ddI concentration-related toxicities. Similarly, the small but significant decrease in ganciclovir concentration with sequential combination ddI therapy may impair the efficacy of oral ganciclovir. For HIV-infected patients receiving ganciclovir and ddI, clinicians should recommend administering the two drugs simultaneously, and patients should be monitored closely for ddI-associated toxicities.",
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T1 - Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects

AU - Cimoch, Paul J.

AU - Lavelle, James

AU - Pollard, Richard B

AU - Griffy, Kay Gaines

AU - Wong, Rodney

AU - Tarnowski, Thomas L.

AU - Casserella, Sandra

AU - Jung, Donald

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N2 - The aim of this study was to determine whether oral ganciclovir interacted pharmacokinetically with zidovudine (AZT), didanosine (ddl), or probenecid. A multicenter, open-label, randomized, crossover pharmacokinetic study with four phases was undertaken at an outpatient private research center and at university research clinics. Twenty-six HIV-infected adults (23 men, 3 women) with cytomegalovirus (CMV) seropositivity and CD4+ T- lymphocyte count ≤100 cells/μl were studied. Patients had to be stable on antiretroviral therapy for at least 4 weeks. Patients with a history of opportunistic infection or gastrointestinal symptoms were excluded. Measurements included serial blood and urine samples during the dosing intervals at steady state. The steady-state pharmacokinetics of ganciclovir were determined after the participants had stabilized and were tolerating AZT or ddI therapy. When a 1000-mg dose of oral ganciclovir was taken every 8 hours, there was a significant mean increase in C(max) and dosing interval area under the serum concentration time curve over a dosing interval (AUC) for the two antiretroviral drugs: for AZT, 61.6% and 19.5%, respectively; for ddI when administered sequentially (2 hours before ganciclovir), 116.0% and 114.6%; and for ddI administered simultaneously with ganciclovir. 107.9% and 107,1%, respectively. There was no significant change in renal clearance for either antiretroviral drug, suggesting that the interaction did not occur through a renal mechanism. There was no significant change in mean ganciclovir C(max) and AUC0-8 when coadministered with AZT. Mean increases in C(max) and AUC0-8 of oral ganciclovir averaged 40.1% and 52.5%, respectively, when coadministered with probenecid, but decreased by 22.1% and 22.7%, respectively, when oral ganciclovir was administered 2 hours after ddI. There was no change in the mean ganciclovir C(max) or AUC0-8 when administered simultaneously with ddI. The mean renal clearance of oral ganciclovir was not affected by AZT or ddI coadministration intake, but there was a mean decrease of 19% when coadministered with probenecid. We conclude the increased serum concentration and reduced renal clearance of ganciclovir suggests competition with probenecid for secretion at the renal tubule. The mechanism of the interaction of oral ganciclovir with either AZT or ddI remains to be determined. The magnitude of the effect of oral ganciclovir on ddI pharmacokinetics may result in an increase in ddI concentration-related toxicities. Similarly, the small but significant decrease in ganciclovir concentration with sequential combination ddI therapy may impair the efficacy of oral ganciclovir. For HIV-infected patients receiving ganciclovir and ddI, clinicians should recommend administering the two drugs simultaneously, and patients should be monitored closely for ddI-associated toxicities.

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