Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS clinical trials group protocol 062)

K. H.P. Moore, R. H. Raasch, K. L.R. Brouwer, K. Opheim, S. H. Cheeseman, M. Elaine Eyster, S. M. Lemon, C. M. Van der Horst

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    Abstract

    The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over an 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 ± 192 ng · h/ml), maximum concentration of drug in serum (1,751 ± 180 ng/ml), and half-life (2.04 ± 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 ± 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 ± 1,222 ng · h/ml) and maximum concentration of drug in serum (5,220 ± 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2,79 ± 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 ± 0.15 in HIV-infected patients with mild hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy- proven cirrhosis, our results suggest that ZDV could accumulate in HIV- infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.

    Original languageEnglish (US)
    Pages (from-to)2732-2737
    Number of pages6
    JournalAntimicrobial Agents and Chemotherapy
    Volume39
    Issue number12
    DOIs
    StatePublished - Jan 1 1995

    Fingerprint

    Zidovudine
    Virus Diseases
    Clinical Protocols
    Biological Availability
    Acquired Immunodeficiency Syndrome
    Pharmacokinetics
    Clinical Trials
    HIV
    Liver
    Area Under Curve
    Oral Administration
    Liver Diseases
    Healthy Volunteers
    Serum
    Pharmaceutical Preparations
    Half-Life
    Fibrosis
    High Pressure Liquid Chromatography
    Body Weight

    All Science Journal Classification (ASJC) codes

    • Pharmacology
    • Pharmacology (medical)
    • Infectious Diseases

    Cite this

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    title = "Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS clinical trials group protocol 062)",
    abstract = "The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over an 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 ± 192 ng · h/ml), maximum concentration of drug in serum (1,751 ± 180 ng/ml), and half-life (2.04 ± 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 ± 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 ± 1,222 ng · h/ml) and maximum concentration of drug in serum (5,220 ± 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2,79 ± 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 ± 0.15 in HIV-infected patients with mild hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy- proven cirrhosis, our results suggest that ZDV could accumulate in HIV- infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.",
    author = "Moore, {K. H.P.} and Raasch, {R. H.} and Brouwer, {K. L.R.} and K. Opheim and Cheeseman, {S. H.} and Eyster, {M. Elaine} and Lemon, {S. M.} and {Van der Horst}, {C. M.}",
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    Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS clinical trials group protocol 062). / Moore, K. H.P.; Raasch, R. H.; Brouwer, K. L.R.; Opheim, K.; Cheeseman, S. H.; Eyster, M. Elaine; Lemon, S. M.; Van der Horst, C. M.

    In: Antimicrobial Agents and Chemotherapy, Vol. 39, No. 12, 01.01.1995, p. 2732-2737.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS clinical trials group protocol 062)

    AU - Moore, K. H.P.

    AU - Raasch, R. H.

    AU - Brouwer, K. L.R.

    AU - Opheim, K.

    AU - Cheeseman, S. H.

    AU - Eyster, M. Elaine

    AU - Lemon, S. M.

    AU - Van der Horst, C. M.

    PY - 1995/1/1

    Y1 - 1995/1/1

    N2 - The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over an 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 ± 192 ng · h/ml), maximum concentration of drug in serum (1,751 ± 180 ng/ml), and half-life (2.04 ± 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 ± 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 ± 1,222 ng · h/ml) and maximum concentration of drug in serum (5,220 ± 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2,79 ± 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 ± 0.15 in HIV-infected patients with mild hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy- proven cirrhosis, our results suggest that ZDV could accumulate in HIV- infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.

    AB - The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over an 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 ± 192 ng · h/ml), maximum concentration of drug in serum (1,751 ± 180 ng/ml), and half-life (2.04 ± 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 ± 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 ± 1,222 ng · h/ml) and maximum concentration of drug in serum (5,220 ± 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2,79 ± 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 ± 0.15 in HIV-infected patients with mild hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy- proven cirrhosis, our results suggest that ZDV could accumulate in HIV- infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.

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