A pharmacokinetic-pharmacodynamic model for remifentanil ... 1.2 Pharmacokinetics and pharmacodynamics

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  • POLITECNICO DI MILANO Scuola di Ingegneria Industriale e dell’Informazione

    Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”

    Corso di Laurea Magistrale in Ingegneria Chimica

    A pharmacokinetic-pharmacodynamic model for remifentanil administration in anesthesia

    Supervisor: prof. Davide MANCA

    Master degree thesis of:

    Adriana SAVOCA, 837204

    Cristina VERGANI, 832889

    Academic Year 2015 – 2016

  • 1

    Contents Figures ................................................................................................................................. 5

    Tables ................................................................................................................................ 15

    Acronyms .......................................................................................................................... 23

    Symbols ............................................................................................................................. 25

    Abstract ............................................................................................................................. 27

    Estratto .............................................................................................................................. 29

    1. INTRODUCTION............................................................................................................. 31

    1.1 Research context and objectives of the thesis ......................................................... 31

    1.2 Pharmacokinetics and pharmacodynamics ............................................................. 35

    1.2.1 Pharmacokinetics .............................................................................................. 36

    1.2.2 Pharmacodynamics ........................................................................................... 41

    1.3 Analgesics and anesthesiology ................................................................................ 43

    1.4 Remifentanil............................................................................................................. 45

    1.4.1 Introduction and physiochemical characteristics ............................................. 45

    1.4.2 Mechanism of action......................................................................................... 47

    1.4.3 Pharmacokinetics of remifentanil ..................................................................... 48

    1.4.4 Pharmacodynamics of remifentanil .................................................................. 49

    1.4.5 Clinical uses and dosage ................................................................................... 51

    2. PHARMACOKINETICS .................................................................................................... 53

    2.1 Pharmacokinetics modeling: focus on Physiologically Based Pharmacokinetics

    models ........................................................................................................................... 53

    2.2 Abbiati et al. (2016) PBPK model ............................................................................. 55

    2.3 Six-parameter PK model .......................................................................................... 66

    2.4 Model validation and comparison with Abbiati et al. (2016) work ......................... 69

    2.4.1 Case-study 1: Egan et al. (1996) ....................................................................... 69

    2.4.2 Case-study 2: Westmoreland et al. (1993) ....................................................... 77

    2.4.3 Case-study 3: Pitsiu et al. (2004) ....................................................................... 79

    2.4.4 Case-study 4: Glass et al. (1993) ....................................................................... 82

    2.4.5 Conclusions ....................................................................................................... 83

    2.5 Akaike Information Criterion ................................................................................... 83

  • 2

    2.6 Limitations of the model .......................................................................................... 84

    2.7 Dose dependence ..................................................................................................... 87

    2.7.1 Variation of the protein binding ....................................................................... 88

    2.7.2 Saturation of enzymes ...................................................................................... 91

    2.7.3 Results and discussion ....................................................................................... 93

    2.8 Temperature dependence ...................................................................................... 105

    2.8.1 Temperature dependence model .................................................................... 107

    2.8.2 Results and discussion -Case-study 1: Davis et al. (1999) ............................... 111

    2.8.3 Results and discussion - Case-study 2: Sam et al. (2009) ................................ 113

    2.8.4 Conclusions ...................................................................................................... 115

    3. PHARMACODYNAMICS ............................................................................................... 117

    3.1 Pharmacodynamic modeling of remifentanil ........................................................ 117

    3.2 Pharmacological effects ........................................................................................ 119

    3.2.1 Blood pressure ................................................................................................. 119

    3.2.2 Heart rate ........................................................................................................ 121

    3.2.3 Minute ventilation ........................................................................................... 122

    3.2.4 Bispectral index ............................................................................................... 123

    3.3 Modeling approach ................................................................................................ 124

    3.3.1 𝑀𝐴𝑃 and 𝑆𝐴𝑃 model ......................................................................................... 131

    3.3.2 𝐻𝑅 model ............................................................................................................ 133

    3.4 Results and discussion – 𝑆𝐴𝑃 model ..................................................................... 138

    3.4.1 Case-study 1: Lee et al. (2012) ........................................................................ 138

    3.4.2 Case-study 2: O’Hare et al. (1999) .................................................................. 139

    3.4.3 Case-study 3: Park et al. (2011) ...................................................................... 140

    3.4.4 Case-study 4: Nora et al. (2007) ..................................................................... 141

    3.4.5 Conclusions ...................................................................................................... 142

    3.5 Results and discussion – 𝑀𝐴𝑃 model .................................................................... 143

    3.5.1 Case-study 1: Hall et al. (2000) ....................................................................... 143

    3.5.2 Case-study 2: Alexander et al. (1999) ............................................................. 144

    3.5.3 Case-study 3: Batra et al. (2004)..................................................................... 145

    3.5.4 Conclusions ...................................................................................................... 146

    3.6 Results and discussion – 𝐻𝑅 model ....................................................................... 146

  • 3

    3.6.1 Case-study 1: Lee et al. (2012) ........................................................................ 146

    3.6.2 Case-study 2: Park et al. (2011) ...................................................................... 147

    3.6.3 Case-study 3: Nora et al. (2007) ..................................................................... 147

    3.6.4 Case-study 4: Hall et al. (2000) ....................................................................... 148

    3.6.5 Case-study 5: Maguire et al. (2001) ................................................................ 149

    3.6.6 Case-study 6: Shajar et al. (1999) ................................................................... 150

    3.6.7 Conclusions ..................................................................................................... 150

    3.7 Limitations of the PD model .................................................................................. 151

    4. A COMBINED PK-PD MODEL ...................................................................................... 153

    4.1 Combined models and effect-site compartment ................................................... 153

    4.2 Evaluation of the distribution rate constant 𝑘𝑒0 .................................................. 155

    4.3 Application to 𝑆𝐴𝑃 ..............................