Clinical Pharmacokinetics and Population Pharmacokinetic ...d- Pharmacokinetics and Population Pharmacokinetic Analysis ... Population Pharmacokinetic Analysis of Voriconazole

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  • Clinical Pharmacokinetics and Population Pharmacokinetic Analysis of Voriconazole in

    Transplant Patients

    by

    Kelong Han

    B.S. (equivalent), University of Gttingen, 2006

    Submitted to the Graduate Faculty of

    School of Pharmacy in partial fulfillment

    of the requirements for the degree of

    Doctor of Philosophy

    University of Pittsburgh

    2010

  • UNIVERSITY OF PITTSBURGH

    SCHOOL OF PHARMACY

    This dissertation was presented

    by

    Kelong Han

    It was defended on

    August 10, 2010

    and approved by

    Robert Bies, PharmD, PhD

    Billy Day, PhD

    Rakesh Goyal, MD

    Wen Xie, MD, PhD

    Dissertation Advisor: Raman Venkataramanan, PhD

    ii

  • Copyright by Kelong Han

    2010

    iii

  • Clinical Pharmacokinetics and Population Pharmacokinetic Analysis of Voriconazole in

    Transplant Patients

    Kelong Han

    University of Pittsburgh, 2010

    Transplant patients at high risk of invasive mold infections receive voriconazole for

    prophylaxis. Low exposure of voriconazole predisposes patients for infection. High

    concentrations are associated with toxicity. Large variability in voriconazole exposure with a

    fixed dosing regimen has been observed in transplant patients. 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.

    iv

  • 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 good correlation between AUCo- and trough voriconazole plasma

    concentrations in all patient groups. In liver transplant patients, CL/F and V/F of voriconazole

    significantly decreased with postoperative time, CL/F of voriconazole significantly increased

    with liver function, and CYP2C19*2 allele carriers exhibited significantly higher exposure.

    Donor characteristics had no significant association with pharmacokinetics of voriconazole in

    liver transplant patients. In lung transplant patients the bioavailability of voriconazole was

    substantially lower, but significantly increased with postoperative time, and patients with cystic

    fibrosis (CF) exhibited a significantly lower bioavailability and exposure than non-CF patients.

    Clearance of voriconazole significantly increased with liver function in BMT patients. BMT

    patients had significantly higher clearance and significantly lower volume of distribution

    compared to liver and lung transplant patients, but bioavailability was similar to lung transplant

    patients.

    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

    v

  • 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.

    vi

  • vii

    TABLE OF CONTENTS

    PREFACE . xvii

    Chapter I Introduction................................................................................................................. 1

    1.1 Voriconazole and its use in transplant patients............................................................... 1

    1.2 Clinical pharmacokinetic properties of voriconazole ..................................................... 2

    1.2.1 Absorption............................................................................................................... 3

    1.2.2 Distribution ............................................................................................................. 3

    1.2.3 Metabolism and elimination ................................................................................... 4

    1.2.4 Nonlinear pharmacokinetics ................................................................................... 5

    1.3 Variability in the pharmacokinetics of voriconazole ...................................................... 6

    1.3.1 Age.......................................................................................................................... 6

    1.3.2 Hepatic dysfunction ................................................................................................ 6

    1.3.3 Food effect .............................................................................................................. 7

    1.3.4 Drug-drug interactions ............................................................................................ 7

    1.3.5 Other factors............................................................................................................ 7

    1.4 Variability in the pharmacokinetics of voriconazole in transplant patients.................... 8

    1.4.1 Variability in absorption ......................................................................................... 8

    1.4.2 Variability in elimination........................................................................................ 9

    1.4.3 Drug-drug interactions .......................................................................................... 10

    1.5 Therapeutic drug monitoring of voriconazole .............................................................. 10

    1.5.1 Adverse events ...................................................................................................... 10

  • viii

    1.5.2 Correlation between voriconazole exposure and efficacy/toxicity....................... 11

    1.5.3 Application of correlation between voriconazole exposure and efficacy/toxicity to

    therapeutic drug monitoring.................................................................................................. 12

    1.6 Preliminary data ............................................................................................................ 13

    1.7 Study populations.......................................................................................................... 18

    1.8 Hypotheses.................................................................................................................... 18

    Chapter II Methods................................................................................................................. 20

    2.1 Pharmacokinetic modeling............................................................................................ 20

    2.2 Classical pharmacokinetic modeling ............................................................................ 21

    2.3 Population pharmacokinetic modeling ......................................................................... 21

    2.3.1 General approaches............................................................................................... 21

    2.3.2 Model building...................................................................................................... 21

    2.3.3 Covariate evaluation ............................................................................................. 23

    2.3.4 Model evaluation and validation........................................................................... 24

    Chapter III Pharmacokinetics of Voriconazole in Liver Transplant Patients.......................... 26

    3.1 Abstract ......................................................................................................................... 26

    3.2 Introduction................................................................................................................... 29

    3.3 Methods......................................................................................................................... 32

    3.3.1 Patients.................................................................................................................. 32

    3.3.2 Blood Sample Collection ...................................................................................... 32

    3.3.3 Genotyping............................................................................................................ 33

    3.3.4 Analytical Assay ................................................................................................... 33

    3.3.5 Non-compartmental Pharmacokinetic Analysis ................................................... 34

  • ix

    3.3.6 Statistical Analysis................................................................................................ 35

    3.3.7 Population Pharmacokinetic Analysis .................................................................. 36

    3.3.8 Model Evaluation.................................................................................................. 38

    3.3.9 External Val