Valganciclovir in Adult Solid Organ Transplant Recipients View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2009-06

AUTHORS

Nancy Perrottet, Laurent A. Decosterd, Pascal Meylan, Manuel Pascual, Jerome Biollaz, Thierry Buclin

ABSTRACT

Valganciclovir and ganciclovir are widely used for the prevention of cytomegalovirus (CMV) infection in solid organ transplant recipients, with a major impact on patients’ morbidity and mortality. Oral valganciclovir, the ester prodrug of ganciclovir, has been developed to enhance the oral bioavailability of ganciclovir. It crosses the gastrointestinal barrier through peptide transporters and is then hydrolysed into ganciclovir. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of therapeutic drug monitoring.Based on currently available literature, ganciclovir pharmacokinetics in adult solid organ transplant recipients receiving oral valganciclovir are characterized by bioavailability of 66±10% (mean ± SD), a maximum plasma concentration of 3.1 ± 0.8 mg/L after a dose of 450 mg and of 6.6 ± 1.9 mg/L after a dose of 900 mg, a time to reach the maximum plasma concentration of 3.0±1.0 hours, area under the plasma concentration-time curve values of 29.1±5.3mg · h/L and 51.9±18.3mg · h/L (after 450 mg and 900 mg, respectively), apparent clearance of 12.4 ± 3.8 L/h, an elimination half-life of 5.3 ± 1.5 hours and an apparent terminal volume of distribution of 101 ±36 L. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Unexplained interpatient variability is limited (18% in apparent clearance and 28% in the apparent central volume of distribution). There is no indication of erratic or limited absorption in given subgroups of patients; however, this may be of concern in patients with severe malabsorption.The in vitro pharmacodynamics of ganciclovir reveal a mean concentration producing 50% inhibition (IC50) among CMV clinical strains of 0.7 mg/L (range 0.2–1.9 mg/L). Systemic exposure of ganciclovir appears to be moderately correlated with clinical antiviral activity and haematotoxicity during CMV prophylaxis in high-risk transplant recipients. Low ganciclovir plasma concentrations have been associated with treatment failure and high concentrations with haematotoxicity and neurotoxicity, but no formal therapeutic or toxic ranges have been validated.The pharmacokinetic parameters of ganciclovir after valganciclovir administration (bioavailability, apparent clearance and volume of distribution) are fairly predictable in adult transplant patients, with little interpatient variability beyond the effect of renal function and bodyweight. Thus ganciclovir exposure can probably be controlled with sufficient accuracy by thorough valganciclovir dosage adjustment according to patient characteristics. In addition, the therapeutic margin of ganciclovir is loosely defined. The usefulness of systematic therapeutic drug monitoring in adult transplant patients therefore appears questionable; however, studies are still needed to extend knowledge to particular subgroups of patients or dosage regimens. More... »

PAGES

399-418

References to SciGraph publications

  • 1995-04. Foscarnet and ganciclovir pharmacokinetics during concomitant or alternating maintenance therapy for AIDS‐related cytomegalovirus retinitis in CLINICAL PHARMACOLOGY & THERAPEUTICS
  • 2001-07. Ganciclovir in DRUGS
  • 2005-05. Pharmacokinetic Profile of Ganciclovir After its Oral Administration and From its Prodrug, Valganciclovir, in Solid Organ Transplant Recipients in CLINICAL PHARMACOKINETICS
  • 2001-02-01. Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan in BONE MARROW TRANSPLANTATION
  • 1998-04. Clinical Pharmacokinetics in the 21st Century in CLINICAL PHARMACOKINETICS
  • 1999-08. Pharmacokinetics of Valganciclovir and Ganciclovir Following Multiple Oral Dosages of Valganciclovir in HIV- and CMV-Seropositive Volunteers in CLINICAL PHARMACOKINETICS
  • 1998-01-01. Prophylactic oral ganciclovir after renal transplantation-dosing and pharmacokinetics in PEDIATRIC NEPHROLOGY
  • 2003-07-23. Pharmacokinetics of ganciclovir in pediatric renal transplant recipients in PEDIATRIC NEPHROLOGY
  • 2005-07-01. Initial experience with oral valganciclovir for pre-emptive cytomegalovirus therapy after lung transplantation in WIENER KLINISCHE WOCHENSCHRIFT
  • 2005-04. Valganciclovir in DRUGS
  • 1999-08-01. Ganciclovir-induced encephalopathy in a bone marrow transplant recipient in BONE MARROW TRANSPLANTATION
  • 2002-08-22. Pharmacokinetics of valganciclovir and ganciclovir in renal impairment in CLINICAL PHARMACOLOGY & THERAPEUTICS
  • Identifiers

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    http://scigraph.springernature.com/pub.10.2165/00003088-200948060-00006

    DOI

    http://dx.doi.org/10.2165/00003088-200948060-00006

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/19650679


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    25 schema:description Valganciclovir and ganciclovir are widely used for the prevention of cytomegalovirus (CMV) infection in solid organ transplant recipients, with a major impact on patients’ morbidity and mortality. Oral valganciclovir, the ester prodrug of ganciclovir, has been developed to enhance the oral bioavailability of ganciclovir. It crosses the gastrointestinal barrier through peptide transporters and is then hydrolysed into ganciclovir. This review aims to describe the current knowledge of the pharmacokinetic and pharmacodynamic characteristics of this agent, and to address the issue of therapeutic drug monitoring.Based on currently available literature, ganciclovir pharmacokinetics in adult solid organ transplant recipients receiving oral valganciclovir are characterized by bioavailability of 66±10% (mean ± SD), a maximum plasma concentration of 3.1 ± 0.8 mg/L after a dose of 450 mg and of 6.6 ± 1.9 mg/L after a dose of 900 mg, a time to reach the maximum plasma concentration of 3.0±1.0 hours, area under the plasma concentration-time curve values of 29.1±5.3mg · h/L and 51.9±18.3mg · h/L (after 450 mg and 900 mg, respectively), apparent clearance of 12.4 ± 3.8 L/h, an elimination half-life of 5.3 ± 1.5 hours and an apparent terminal volume of distribution of 101 ±36 L. The apparent clearance is highly correlated with renal function, hence the dosage needs to be adjusted in proportion to the glomerular filtration rate. Unexplained interpatient variability is limited (18% in apparent clearance and 28% in the apparent central volume of distribution). There is no indication of erratic or limited absorption in given subgroups of patients; however, this may be of concern in patients with severe malabsorption.The in vitro pharmacodynamics of ganciclovir reveal a mean concentration producing 50% inhibition (IC50) among CMV clinical strains of 0.7 mg/L (range 0.2–1.9 mg/L). Systemic exposure of ganciclovir appears to be moderately correlated with clinical antiviral activity and haematotoxicity during CMV prophylaxis in high-risk transplant recipients. Low ganciclovir plasma concentrations have been associated with treatment failure and high concentrations with haematotoxicity and neurotoxicity, but no formal therapeutic or toxic ranges have been validated.The pharmacokinetic parameters of ganciclovir after valganciclovir administration (bioavailability, apparent clearance and volume of distribution) are fairly predictable in adult transplant patients, with little interpatient variability beyond the effect of renal function and bodyweight. Thus ganciclovir exposure can probably be controlled with sufficient accuracy by thorough valganciclovir dosage adjustment according to patient characteristics. In addition, the therapeutic margin of ganciclovir is loosely defined. The usefulness of systematic therapeutic drug monitoring in adult transplant patients therefore appears questionable; however, studies are still needed to extend knowledge to particular subgroups of patients or dosage regimens.
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    31 schema:keywords CMV prophylaxis
    32 absorption
    33 accuracy
    34 activity
    35 addition
    36 adjustment
    37 administration
    38 adult solid organ transplant recipients
    39 adult transplant patients
    40 agents
    41 antiviral activity
    42 apparent clearance
    43 area
    44 available literature
    45 barriers
    46 bioavailability
    47 bodyweight
    48 characteristics
    49 clearance
    50 clinical strains
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    63 effect
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    65 ester prodrugs
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    68 filtration rate
    69 function
    70 ganciclovir
    71 ganciclovir exposure
    72 ganciclovir pharmacokinetics
    73 ganciclovir plasma concentrations
    74 gastrointestinal barrier
    75 glomerular filtration rate
    76 haematotoxicity
    77 high concentrations
    78 high-risk transplant recipients
    79 hours
    80 impact
    81 indications
    82 infection
    83 inhibition
    84 interpatient variability
    85 issues
    86 knowledge
    87 limited absorption
    88 literature
    89 little interpatient variability
    90 major impact
    91 malabsorption
    92 margin
    93 maximum plasma concentration
    94 mean concentration
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    96 morbidity
    97 mortality
    98 neurotoxicity
    99 oral bioavailability
    100 oral valganciclovir
    101 organ transplant recipients
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    104 patient characteristics
    105 patients
    106 peptide transporter
    107 pharmacodynamic characteristics
    108 pharmacodynamics
    109 pharmacokinetic parameters
    110 pharmacokinetics
    111 plasma concentration-time curve (AUC) values
    112 plasma concentrations
    113 prevention
    114 prodrug
    115 prophylaxis
    116 proportion
    117 range
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    119 recipients
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    121 renal function
    122 review
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    130 systematic therapeutic drug monitoring
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    137 transplant patients
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    140 treatment failure
    141 unexplained interpatient variability
    142 usefulness
    143 valganciclovir
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