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Clinical Pharmacokinetics and Population Pharmacokinetic Analysis of Voriconazole in Transplant Patients

Han, Kelong (2011) Clinical Pharmacokinetics and Population Pharmacokinetic Analysis of Voriconazole in Transplant Patients. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Transplant patients at high risk of invasive mold infections receive voriconazole for prophylaxis. Large variability in voriconazole exposure with a fixed dosing regimen was observed. Low exposure of voriconazole predisposes patients for infection. High concentrations are associated with toxicity.The objectives are to characterize the pharmacokinetics of voriconazole in transplant patients, to identify factors associated with the variability in the pharmacokinetics, and to develop adequate dosing guidelines for transplant patients.Liver, lung and pediatric bone marrow transplant (BMT) patients were enrolled. Multiple blood samples were collected within one dosing interval (totally 75 full pharmacokinetic profiles). Voriconazole plasma concentrations were measured using HPLC. Non-compartmental analysis was performed using WinNonlin. Population pharmacokinetic models were developed using NONMEM. Covariate models were built using a forward addition and reverse removal approach. Precision of parameter estimation was evaluated by bootstrapping. Adequate dosing regimens were developed using Monte Carlo simulations.There was a good correlation between AUCo-∞ and trough voriconazole plasma concentrations. Bioavailability of voriconazole is substantially reduced in lung transplant and BMT patients during the early post-transplant period. Pharmacokinetics of voriconazole is significantly associated with postoperative time, liver function and CYP2C19 genotype in liver transplant patients. Pharmacokinetics of voriconazole is significantly associated with postoperative time and cystic fibrosis in lung transplant patients. Pharmacokinetics of voriconazole is significantly associated with liver function in BMT patients. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability than non-CF patients. Donor characteristics had no significant correlation with pharmacokinetics of voriconazole in liver transplant patients. Bioavailability of voriconazole is similar between lung transplant and BMT patients. Compared to liver and lung transplant patients, BMT patients had significantly higher clearance and significantly lower volume of distribution.In conclusion, weight-adjusted or fixed dosing regimens resulted in highly variable exposure of voriconazole in liver transplant, lung transplant and BMT patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), voriconazole dose can be individualized based on trough concentrations. Population analysis demonstrated inadequacy of oral administration of voriconazole and adequacy of intravenous administration during the first few post-operative days, followed by oral doses for optimal drug exposure.


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    Item Type: University of Pittsburgh ETD
    ETD Committee:
    ETD Committee TypeCommittee MemberEmail
    Committee ChairVenkataramanan, Ramanrv@pitt.edu
    Committee MemberDay, Billybday@pitt.edu
    Committee MemberGoyal, RakeshRakesh.Goyal@chp.edu
    Committee MemberBies, Robertrrbies@iupui.edu
    Committee MemberXie, Wenwex6@pitt.edu
    Title: Clinical Pharmacokinetics and Population Pharmacokinetic Analysis of Voriconazole in Transplant Patients
    Status: Unpublished
    Abstract: Transplant patients at high risk of invasive mold infections receive voriconazole for prophylaxis. Large variability in voriconazole exposure with a fixed dosing regimen was observed. Low exposure of voriconazole predisposes patients for infection. High concentrations are associated with toxicity.The objectives are to characterize the pharmacokinetics of voriconazole in transplant patients, to identify factors associated with the variability in the pharmacokinetics, and to develop adequate dosing guidelines for transplant patients.Liver, lung and pediatric bone marrow transplant (BMT) patients were enrolled. Multiple blood samples were collected within one dosing interval (totally 75 full pharmacokinetic profiles). Voriconazole plasma concentrations were measured using HPLC. Non-compartmental analysis was performed using WinNonlin. Population pharmacokinetic models were developed using NONMEM. Covariate models were built using a forward addition and reverse removal approach. Precision of parameter estimation was evaluated by bootstrapping. Adequate dosing regimens were developed using Monte Carlo simulations.There was a good correlation between AUCo-∞ and trough voriconazole plasma concentrations. Bioavailability of voriconazole is substantially reduced in lung transplant and BMT patients during the early post-transplant period. Pharmacokinetics of voriconazole is significantly associated with postoperative time, liver function and CYP2C19 genotype in liver transplant patients. Pharmacokinetics of voriconazole is significantly associated with postoperative time and cystic fibrosis in lung transplant patients. Pharmacokinetics of voriconazole is significantly associated with liver function in BMT patients. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability than non-CF patients. Donor characteristics had no significant correlation with pharmacokinetics of voriconazole in liver transplant patients. Bioavailability of voriconazole is similar between lung transplant and BMT patients. Compared to liver and lung transplant patients, BMT patients had significantly higher clearance and significantly lower volume of distribution.In conclusion, weight-adjusted or fixed dosing regimens resulted in highly variable exposure of voriconazole in liver transplant, lung transplant and BMT patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), voriconazole dose can be individualized based on trough concentrations. Population analysis demonstrated inadequacy of oral administration of voriconazole and adequacy of intravenous administration during the first few post-operative days, followed by oral doses for optimal drug exposure.
    Date: 10 January 2011
    Date Type: Completion
    Defense Date: 10 August 2010
    Approval Date: 10 January 2011
    Submission Date: 29 November 2010
    Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-11292010-053634
    Uncontrolled Keywords: Population Pharmacokinetics; Transplant; Voriconazole
    Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
    Date Deposited: 10 Nov 2011 15:06
    Last Modified: 15 May 2012 12:06
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-11292010-053634/, etd-11292010-053634

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