Conditions: Systemic Fungal Infections
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
The purpose of this study is to try to find out how critically ill patients receiving the anti fungal medication, posaconazole, process it in their body. Investigators would like to study if the recommended doses of posaconazole achieve adequate concentrations in the patients blood to treat fungal infections.The disease process in critically ill patients can profoundly influence the concentration of anti fungal medication in the blood. The process by which a drug travels through the body in blood, how it is broken down and removed by the body is called pharmacokinetics (PK).

This information is important to know because if antifungal levels are low in the blood, the fungal infection has an opportunity to become resistant to the antifungal medication which can lead to the medication being less effective against the fungal infection potentially exposing future patients with infection to a limited range of effective antifungals.

Investigators can measure the PK by taking blood samples at specific times after the anti fungal medication is given.

This study will enroll 8 patients who are admitted to the intensive care unit and are being treated with an antifungal medication for a fungal infection. Patients will be consented and given a single dose of posaconazole and serial blood samples will be collected just prior to the dose and at 15, 45,75 minutes during the infusion and at 3, 5, 8, 12, 18, 24, 30 36 and 48 hours . Information about the patients stay in the ICU will also be collected including blood pressure, temperature, blood test results.

Detailed description:
Posaconazole is a new extended spectrum triazole active against a range of yeasts and molds including Aspergillus, Candida, Coccidioides, Cryptococcus neoformans, Fusarium, and Zygomycetes. It may be used for the prevention of invasive fungal infections in immunocompromised patients including febrile neutropenic patients and those receiving immunosuppressant drugs for graft-vs-host disease during stem cell transplantation. It may also be used for treatment of systemic fungal infections.The use of posaconazole in ICU patients has been limited to stable patients to ensure reliable bioavailability from the oral formulations. Oral formulations have important limitation in that they cannot be used in critically ill patients who may be unable to take oral doses or bioavailability may be compromised due to erratic absorption. Recently, an intravenous (IV) formulation has been developed to address these limitations. Initial pharmacokinetic (PK) investigations of the IV formulation were conducted in hematology patients, with further data in other patient populations still forthcoming; particularly in the critically ill where the IV formulation would probably be used most frequently.

Most of the available PK data for posaconazole is from non-critically ill patients who received the oral formulation. Although the absorption phase of the kinetics is not relevant for the IV formulation, data on the distribution, metabolism and elimination properties would still be informative of the IV kinetics. The tissue distribution of posaconazole is extensive with a very large volume of distribution owing to its high lipophilicity. It is highly bound to plasma proteins (98-99%) and therefore very likely to be affected by the variable changes in plasma protein concentration in critically ill patients. The major elimination pathway of posaconazoleis through biliary excretion (about 77%) of mainly the unchanged parent compound and the rest through renal execration of as a glucuronide conjugate.

A number of studies have described PK variability of posaconazole due to altered absorption/bioavailability which can frequently result in sub-therapeutic plasma concentrations, forming strong case for therapeutic drug monitoring. Nonetheless, it is unclear whether the observed low concentrations can also be explained, at least in part, by other factors such as disease-related PK changes or if the obvious plausibility of altered absorption has masked such investigations. Most population PK models described so far are based on one compartment models, which do not reveal if the observed variability in concentrations is due to changes in PK parameters such as volume of distribution or clearances. The influence of disease state on these PK parameters has been extensively described for several antimicrobials in the critically ill patient populations. Although data on the new IV formulation of posaconazole in this patient population is lacking, there is evidence from previous PK studies on the oral formulation that PK variability not observed in healthy study participants was observed in patients with invasive fungal infections, although it was explained primarily in relation to altered bioavailability from the oral formulation. In surgical ICU patients low plasma concentration of posaconazole were observed, after administration via nasogastric tube. Similar findings were reported in general ICU patients. Although the explanation in these reports was again the irregular absorption, the influence of other pathologic changes remains to be investigated. A PK evaluation of IV posaconazole in critically ill patients, not confounded by the absorption factor, would reveal if there is any pathophysiology-induced PK alteration. Such a study will also give insight into the dose-exposure relationships and optimal treatment regimen.

Arms:
arm 1: The study will enrol eight patients with presumed or confirmed systemic fungal infections, who are admitted to ICU

Interventions: intervention 1: Posaconazole
Intervention descriptions: intervention 1: A single dose of 300mg intravenous posaconazole will be administered and blood samples will be taken prior to start of infusion, at 15,45,75minutes, 3,5,8,12,18,24,30,36 and 48 hours.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
Study title:  Single Dose Population Pharmacokinetics 
of Intravenous Posaconazole in Critically Ill Patients 
 
ID: HREC/16/QRBW/377 
 
NCT number: NCT02968134 


 
 
 
 
Single dose population pharmacokinetics of 
intravenous posaconazole in critically ill 
patients 
Research Protocol                                                                
Version 02                                                                               
Dated 20 July 2016 
 
 
 
Principal Investigator :     Prof. Jason Roberts 
 
Associate Investigator:      Prof. Jeffrey Lipman 
                                           
 
 
 
 


Prof. Jason Roberts 
Posaconazole PK 
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Contents 
1. INTRODUCTION ................................................................................................................................... 1 
2. CLINICAL HYPOTHESES ........................................................................................................................ 3 
3. OBJECTIVES ......................................................................................................................................... 3 
4. STUDY DESIGN ..................................................................................................................................... 4 
5. STUDY PROCEDURES ........................................................................................................................... 5 
5.1 Patient screening .......................................................................................................................... 5 
5.2 Patient enrolment ......................................................................................................................... 6 
5.3 Drug administration ...................................................................................................................... 6 
5.4 Sample collections ........................................................................................................................ 7 
5.5 Clinical data collection .................................................................................................................. 7 
5.6 Sample assay ................................................................................................................................. 8 
6. PHARMACOKINETIC ANALYSIS ............................................................................................................ 8 
6.1 Initial non-compartmental analysis .............................................................................................. 8 
6.2 Population pharmacokinetic analysis ........................................................................................... 9 
7. STATISTICAL ANALYSIS AND SAMPLE SIZE JUSTIFICATION ............................................................... 10 
8. STUDY DURATION ............................................................................................................................. 10 
9. STUDY DRUG SUPPLY ........................................................................................................................ 10 
10. FUNDING AND INDEMNITY ............................................................................................................. 10 
11. MONITORING AND REPORTING SAE AND SUSAR ........................................................................... 10 
12. ETHICAL CONSIDERATIONS ............................................................................................................. 11 
13. CONFIDENTIALITY AND PRIVACY..................................................................................................... 12 
14. CONSENT ......................................................................................................................................... 12 
15. REFERENCES .................................................................................................................................... 14 
 
 
 
 
 
 


Prof. Jason Roberts 
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1. INTRODUCTION  
 
Treatment of fungal infections remains a significant challenge to clinicians, particularly for patients 
requiring intensive care unit (ICU) management where the incidence of invasive fungal infections and 
associated mortality rate are distinctly high[1]. Response to antifungal therapy is generally sub-
optimal despite the emergence of extended spectrum novel anti-fungals like the echinocandins and 
triazoles. Although the relative incidence of invasive fungal infection is low, and hence therapeutic 
anti-fungal  dosing is relatively less frequent, prophylactic use of oral/systemic antifungal agents has 
become a very common indication due to the increasing use  immunosuppressants during critical care, 
cancer chemotherapy and organ transplantation [2,3].  This has led to a wide systemic exposure to 
antifungal drugs in considerable number of patients. In parallel, such widespread use increases the 
risk of emergence of resistant fungi, unless adequate exposure is defined and ensured during clinical 
use of the drugs. Unfortunately, it has been a challenge to explicitly describe the dose-exposure-
response relationships in all target patient populations, especially for new antimicrobials prior to their 
wide clinical application.  
 
Posaconazole is a new extended spectrum triazole active against a range of yeasts and molds 
including Aspergillus, Candida, Coccidioides, Cryptococcus neoformans, Fusarium, and  
Zygomycetes[4]. It may be used for the prevention of invasive fungal infections in 
immunocompromised patients including febrile neutropenic patients and those receiving 
immunosuppressant drugs for graft-vs-host disease during stem cell transplantation[5]. It may also be 
used for treatment of systemic fungal infections [6].The use of posaconazole in ICU patients has been 
limited to stable patients to ensure reliable bioavailability from the oral formulations [7].Oral 
formulations have important limitation in that they cannot be used in critically ill patients who may be 
unable to take oral doses or bioavailability may be compromised due to erratic absorption. Recently, 
an intravenous (IV) formulation has been developed to address these limitations[8]. Initial 
pharmacokinetic (PK) investigations of the IV formulation were conducted in hematology patients 
[8], with further data in other patient populations still forthcoming; particularly in the critically ill 
where the IV formulation would probably be used most frequently.  
 
Most of the available PK data for posaconazole is from non-critically ill patients who received the 
oral formulation. Although the absorption phase of the kinetics is not relevant for the IV formulation, 
data on the distribution, metabolism and elimination properties would still be informative of the IV 
kinetics. The tissue distribution of posaconazole is extensive with a very large volume of distribution 
owing to its high lipophilicity[9]. It is highly bound to plasma proteins (98-99%) and therefore very 
likely to be affected by the variable changes in plasma protein concentration in critically ill patients. 
The major elimination pathway of posaconazoleis through biliary excretion (about 77%) of mainly the 


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unchanged parent compound and the rest through renal execration of as a glucuronide conjugate 
[9,10]. Thus, posaconazole PK is expected to be hardly affected in patients with renal impairment 
including those undergoing haemodialysis[11,12]. The extent of hepatic metabolism is also limited 
that the influence of hepatic dysfunction on the PK of posaconazole appears minimal; existing studies 
have not indicated a need for dosing adjustment in hepatic impairment although monitoring plasma 
concentration is advocated [10,13]. Other factors such as demographic variables including age, sex 
and race reportedly have no clinically relevant influence on the PK of posaconazole in healthy adults 
[14] suggesting no need of dose titration for these covariates.  
 
However, a number of studies have described PK variability due to altered absorption/bioavailability 
which can frequently result in sub-therapeutic plasma concentrations, forming strong case for 
therapeutic drug monitoring [15,16]. Nonetheless, it is unclear whether the observed low 
concentrations can also be explained, at least in part, by other factors such as disease-related PK 
changes or if the obvious plausibility of altered absorption has masked such investigations. Most 
population PK models described so far are based on one compartment models, which do not reveal if 
the observed variability in concentrations is due to changes in PK parameters such as volume of 
distribution or clearances [17]. The influence of disease state on these PK parameters has been 
extensively described for several antimicrobials in the critically ill patient populations [18,19]. 
Although data on the new IV formulation of posaconazole in this patient population is lacking, there 
is evidence from previous PK studies on the oral formulation that PK variability not observed in 
healthy study participants was observed in patients with invasive fungal infections, although it was 
explained primarily in relation to altered bioavailability from the oral formulation[10]. In surgical 
ICU patients, Störzingeret al.[7]observed low plasma concentration of posaconazole, which was 
administered via nasogastric tube. Similar findings were reported in general ICU patients[20]. 
Although the explanation in these reports was again the irregular absorption, the influence of other 
pathologic changes remains to be investigated. A PK evaluation of IV posaconazole in critically ill 
patients, not confounded by the absorption factor, would reveal if there is any pathophysiology-
induced PK alteration. Such a study will also give insight into the dose-exposure relationships and 
optimal treatment regimen, although the pharmacodynamic (PD, exposure-response relation) of 
posaconazole is yet to be clarified.  
 
Posaconazloe is thought to exhibit both concentration and time dependent antimicrobial activity, 
which can be described by the ratio of AUC/MIC[21,22]. However, PD studies are limited and 
inconsistent that the optimal dosing target is yet to be described[17]. Generally maintaining higher 
concentrations may be necessary to improve patient outcomes[6,15,17,23]. Some guideline 
recommendations are steady state trough concentrations greater than 0.7 mg/L may be required for 
prophylaxis and greater than 1mg/L for treatment of invasive fungal infections[3]. Clearly, more data 


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is required to accurately describe optimal plasma concentration-response relationships as there is 
inconsistency between studies/authors in the recommended trough concentrations [3,10,15]. However, 
it is also clear that the clinical efficacy is well correlated with plasma concentration [15]. It is, 
therefore, essential to describe the relationship between dosing regimens and subsequent exposure 
through a thorough PK analysis, particularly for the new IV formulations, which pharmacokinetically 
may behave differently from the oral formulations that have been investigated so far. Such PK 
analysis would provide the foundation for the design of optimal dosing regimens for ICU patients, 
through PK/PD based modelling and clinical trial simulations. The application of population PK 
models also extends to the determination of susceptibility breakpoints through analysis of dosing 
simulations data [24]. This would be invaluable given the limited clinical experience of posaconazole 
in the ICU settings and that, previous break points which correspond to the oral dosing regimens 
[24,25], may not be relevant to the applications of the IV formulation in ICU patients. 
This prospective, observational, pharmacokinetic study of posaconazole aims to describe the 
population PK of posaconazole after a single IV dose administration in the critically ill. It will assess 
the influence of pathophysiologic changes including altered plasma protein concentrations/binding in 
the critically ill on the PK of posaconazole. 
2. CLINICAL HYPOTHESES  
 Pharmacokinetic properties of the new intravenous posaconazole formulation will be distinct 
as compared to the previous oral formulations   
 Dose-exposure relationships from the new formulation may be different in intensive care unit 
patients as compared to general wards patients, due to  disease-related factors 
 Changes in plasma protein concentration or binding capacity in the critically ill may affect the 
pharmacokinetics of posaconazole 
3. OBJECTIVES 
 To describe the pharmacokinetics of intravenous posaconazole in critically ill patients 
 To assess the influence of critical illness on the pharmacokinetics of posaconazole 
administered via intravenous infusion 
 To assess the impact of altered plasma protein concentrations/binding in the critically ill on 
the pharmacokinetics of posaconazole 
 


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4. STUDY DESIGN 
This is a prospective, observational, pharmacokinetic study. The study will enrol eight patients with 
presumed or confirmed systemic fungal infections, who are admitted to ICU. Patients aged greater 
than 18 years with established central venous access for drug administration and no history of allergy 
for triazole antifungals will be approached for enrolment if they have not taken posaconazole within 
two weeks of time and if they are not pregnant. A single dose of 300mg IV posaconazole will be 
administered to eight study participants. Serial blood samples will be collected at pre-defined time 
points for determination of both total and unbound plasma concentrations. Structured data collection 
sheets will be used to collect other clinical data. The data generated will be subject to population 
pharmacokinetic analysis using computer software. Monte Carlo simulations will be performed to 
describe dose-exposure relationships. 
Recruitment 
Inclusion Criteria
•Age 18
•ICU Admission
•Fungal infection
•CVC access
Exclusion Criteria
•Age < 18 
•Pregnancy
•Drug interaction
•Prior Noxafil Rx
•Drug allergy 
Drug Administration 
&
Sample Collections 
Dosage 
•Single dose-300mg IV
•90 min infusion
Sample timing
•Just before dose
•At 15, 45, 75 min during 
infusion
•After line flushing/end 
of infusion
• 3h, 5h, 8h, 12h, 18h, 
24h, 30h, 36h and 48h 
Population 
PK Analysis 
using  
NONMEM 
Overview of the study 
 
Figure 1. Study flow chart 
 
 
 


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5. STUDY PROCEDURES 
5.1 Patient screening  
All patients admitted to the ICU at the Royal Brisbane and Women’s Hospital (RBWH) during the 
study period with suspected or confirmed fungal infections and receiving/requiring systemic 
antifungal therapy will be screened for eligibility to participate in this study based on the under listed 
inclusion and exclusion criteria.  
Inclusion criteria 
 
Age   18 years 
 
Admission for ICU care  
 
The presence of suspected or confirmed fungal infection requiring systemic antifungal 
therapy  
 
Presence of central venous access for drug administration 
Exclusion criteria  
 
Age < 18 years  
 
Pregnancy  
 
Prescription of drugs that are known to interact with posaconazole 
 
Oral posaconazole use within the last two week prior to enrolment  
 
Documented history of drug reaction to the triazole antifungal medications  
A decision to prescribe an anti-fungal therapy will occur as part of the routine care by the attending 
clinicians. After such a decision has been made by the doctors treating the patient, the study will use 
the opportunity of this clinical condition that requires treatment with systemic anti-fungal 
medications, to investigate the pharmacokinetics of the study anti-fungal medication (a new 
intravenous formulation of posaconazole). Therefore, this study does not aim to initiate treatment for 
a suspected or proven systemic fungal infection for the study purpose, and will recruit patients only 
after such a decision is made by the doctors treating the patients.  
The usual circumstances for the diagnosis of a suspected systemic fungal infection that requires 
treatment with systemic anti-fungal medications are non-specific and involve empiric assessment of 
the patient’s clinical condition, assessment of potential risk factors as well as clinical interpretation of 
various diagnostic mycological and radiological investigations. Proven systemic fungal infections are 
those confirmed by presence of hyphae in a histological or cytological specimen with further evidence 
of tissue damaged seen in histological examinations, or positive culture for a clinical specimen with a 
clinical or radiological sign of infection at the site from which specimen was taken. Serologic tests 


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(mainly for Aspergillus, Blastomyces, Candida, Coccidioides, Cryptococcus, and Histoplasma) are 
also used to confirm fungal infections. The diagnosis of either a suspected or confirmed systemic 
fungal infection by the doctors treating the patient warrants treatment with systemic anti-fungal 
medications.  
5.2 Patient enrolment  
Patients that meet all the inclusion criteria and none of the exclusion criteria will be approached for 
informed consent. Investigators of the study will explain the procedures of the study verbally in 
addition to the structured patient information sheet that will be provided for the participants prior to 
consenting. The participants’ next of kin will be approached if any of the participants are not in a 
position to give consent due to medical sedation or unconsciousness or severe illness. A total of 8 
patients will be enrolled.   
5.3 Drug administration  
All patients enrolled in the study will receive the usual treatment with anti-fungal agent(s) as per the 
standards of practice at the study hospital. The usual care for suspected or confirmed systemic fungal 
infections will be at the discretion of the clinical team treating the patient and in accordance with the 
local guidelines and standards of practice. The typical initial empiric therapy for suspected or proven 
invasive fungal infections in patients at the Royal Brisbane and Women’s Hospital is fluconazole. 
Voriconazole or amphotericin B may also considered as an alternative initial agent in 
immunocompromised patients if invasive aspergillosis is confirmed or if there is a high suspicion of a 
mould infection. In non-neutropenic patients with invasive candidiasis, fluconazole may be used if the 
organism is deemed susceptible. For fluconazole-resistant candidiasis in non-neutropenic patients, 
caspofungin is the agent most likely to be used. For suspected or proven acute invasive aspergillosis, 
voriconazole is first-line therapy although amphotericin B or caspofungin may also be used.  
In addition to the drugs given as part of the usual care as described above, a single dose of 
posaconazole will be administered for the study purpose. A single dose of 300 mg intravenous 
posaconazole solution, diluted with 0.9% sodium chloride or 5% dextrose in water, will be 
administered to each study participant by slow infusion over 90 minutes through a central venous 
access. The drug will be infused through a 0.22 micron polyethersulfone (PES) or polyvinylidene 
difluoride (PVDF) filter. The magnitude of the single dose chosen for this study is in accordance with 
with the approved maintenance dosing regimen.  


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5.4 Sample collections 
Serial blood samples will be collected just before and after administration of the single dose of 
posaconazole. The first sample will be collected immediately before commencing of the posaconazole 
infusion. The next three samples will be collected during drug infusion at 15 min, 45min and 75 
minutes after commencing the infusion. The fifth sample will be taken at the end of line flushing (15-
20min) after the 90 minutes infusion. The next samples will be taken at 3h, 5h, 8h, 12h, 18h, 24h, 30h, 
36h and 48h after the commencement of drug infusion. The actual time of collection for individual 
samples will be recorded and used for analysis. Lithium heparin tubes will be used for sample 
collection. The volume of each blood samples will be 2-3ml. The plasma will be separated by 
centrifugation (3000 rpm for 10 minutes) and frozen under - 80C for storage until the subsequent 
assay of total and unbound posaconazole concentration. 
5.5 Clinical data collection 
Patients’ electronic and paper based medical records will be reviewed to collect clinical data including 
demographic characteristics, list of diagnosis, microbiological data, vital signs, and clinical 
haematological and chemistry data. A structured data collection sheet will be used to collect these 
patient specific clinical data, which will include the following: 
 
Physical examination including vital signs 
 
ICU and Hospital admission and discharge dates and times 
 
Acute Physiology and Chronic Health Evaluation II [APACHE II] score and risk of death at 
ICU admission, APACHE II diagnosis upon recruitment  
 
Sequential Organ Failure Assessment [SOFA] score at ICU admission and daily during ICU 
antibiotic course 
 
Presence of shock on days of sampling 
 
Presence of mechanical ventilation 
 
Serum creatinine concentrations 
 
Urinary creatinine clearance (if available) 
 
Hepatic function markers (alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alanine phosphatase ALP), gamma glutamyl transferase (GGT), international 
normalised ratio (INR), bilirubin 
 
Medication list on days of sampling 
 
Antimicrobial Data: type, dose, dosing interval, duration of infusion 
 
RRT data: 
o Filter type, filter size, filter age at time of sampling 


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o Blood flow rates 
o Dialysate dose 
o Haematocrit 
o Pre/post dilution dose 
o Patient fluid balance on day of sampling and targeted hourly fluid removal  
o Changes made to settings during sampling interval 
o Transmembrane pressure 
 
Infection data: 
o Organisms isolated and sample type, 
o Minimum inhibitory concentration if available 
All case report forms and other data (including without limitation, written, printed, graphic, video and 
audio material, and information contained in any computer database or computer readable form) created 
or developed in connection with the Study will be owned by the Principal Investigator. All data will be 
collected by study research staff. 
5.6 Sample assay   
An LC-MS/MS method for determination of total and unbound posaconazole concentrations in human 
plasma will be developed, validated and used for analysis of patient samples. Previously, we have 
successfully developed and utilized LC-MSMS methods for the determination of unbound drug 
concentration using plasma protein ultrafiltration technique for sample preparation. A similar 
approach will be employed to develop a method for determination of unbound posaconazole 
concentration. Our bio-analytical laboratory has state-of-the-arts technology with highly qualified 
analytical chemists who have developed and validated assay methods for various antimicrobials. 
Therefore, it is highly likely that a validated method will be available at our laboratory when the study 
progresses and samples are available for analysis. However, if the need arises, samples can be 
analysed at Pathology Queensland, Royal Brisbane and Women’s Hospital, where a validated LC-
MS/MS method for posaconazole assay exists.  
6. PHARMACOKINETIC ANALYSIS  
Pharmacokinetic data analysis will be performed on both the total concentration and unbound plasma 
posaconazole concentration following the procedures described below. 
6.1 Initial non-compartmental analysis 
The plasma concentration-time data will be subject to non-compartmental pharmacokinetic analysis 
using computer software applications such as PK-Solver or WinNonlin. The linear trapezoidal rule 


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will be followed for computation of area under the concentration-time curve. Results will be 
summarized for preliminary description of the single dose PK parameters, which will be utilized as 
initial estimates in the subsequent population PK analysis.  
6.2 Population pharmacokinetic analysis  
NONMEM software (version 7.3, GloboMax LLC, Hanover, MD) will be used for population PK 
analysis. A stepwise approach will be following in the model building process:  (i) determination of 
the structural base model; (ii) selection of the best fit statistical error model (iii) development of 
covariate model, (iv) and finally model evaluation. 
(i) Determination of the structural base model: Different structural models based on one, two or 
three compartment will be fitted to the concentration-time data using NOMEMEM subroutines. Both 
linear and/or Michaelis–Menten kinetics will be assessed for elimination and distribution of the drug. 
Also linear and/or non-linear binding to plasma proteins will be considered.  
ii) Selection of statistical error models: Inter-individual variability will be assumed to follow a log-
normal distribution. For the residual error model additive, proportional and a combination of additive 
and proportional models will be tested.  
(iii) Development of covariate model: Available clinical covariates will be assessed for biological 
plausibility and subsequently evaluated in the covariate analysis. Selected covariates will be tested on 
the structural model parameters (volume(s) of distribution and clearance). Standard covariate 
evaluation algorithms will be followed through forward addition and backward elimination or a 
combination of forward addition and backward elimination in a stepwise fashion.  
(iv)Model evaluation: Diagnostic plots and statistical examination through objective function values 
will be used for comparison of models. Diagnostic plots will include scatter plot of residuals versus 
predicted values, scatter plot of observed values versus predicted values and scatter plot of weighted 
residuals versus explanatory variables. Objective functions will include log-likelihood ratio test for 
nested model. A decrease in objective function value by greater than 3.84 (which corresponds to p 
<0.05 based on chi-square test) will be considered statistically significant. Other objective function 
values also, Akaike Information Criterion (AIC) or Bayesian Information Criterion (BIC) will be 
examined.Finally, the stability of the final model will be assessed by the nonparametric bootstrapping 
method.  
v) Dosing Simulation: Subsequent to population PK analysis, Monte Carlo simulations will be 
performed using either CLSI or EUCAST MIC interpretive criteria for the presumed or confirmed 
etiologic organisms, or specific MICs if available. 


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7. STATISTICAL ANALYSIS AND SAMPLE SIZE JUSTIFICATION 
All data analysis will be performed by the investigator and his research team. Power calculation is not 
applicable for this prospective initial pharmacokinetic investigation in ICU patients. The planed 
pharmacokinetic data analysis and associated statistical considerations are as described above under 
the study procedures. We have performed previous studies with the proposed sample size for similar 
antimicrobial agents and have provided clinically meaningful results. 
8. STUDY DURATION 
The study will be conducted over 12-18 months from date of hospital approval. 
9. STUDY DRUG SUPPLY 
Merck Sharpe and Dohme (MSD) (Australia) Pty Limited shall make available sufficient quantities of 
Study drug free of charge to carry out the study. The sponsor (University of Queensland) and the 
Principal Investigator shall be responsible for the maintenance of appropriate records and assure 
appropriate supply, handling, storage, distribution and usage of the Study Drug in accordance with the 
Protocol. The supplied Study Drug will not be used for any other purpose other than stated in the 
protocol. There will be no cost to the study participants. 
10. FUNDING AND INDEMNITY 
MSD has provided The University of Queensland (Sponsor) with funding in support of this study. The 
University of Queensland will contract with the Intensive Care Services Research Office at the Royal 
Brisbane and Women’s Hospital to conduct the study within the ICU. These payments are for services 
provided by the Principal Investigator and third party entities i.e. research staff at Royal Brisbane and 
Women’s Hospital. MSD will also provide prosaconazole free of charge for study participants. 
Indemnity will be provided by the University of Queensland and Metro North Hospital Health 
Services District. 
11. MONITORING AND REPORTING SAE AND SUSAR  
Serious Adverse Events (SAEs) are defined as any untoward medical occurrence that meets one or 
more of the following criteria: 
 Results in death; 


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 Is life-threatening; 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation; 
 Results in persistent or significant disability/incapacity; 
 Is a congenital anomaly/birth defect; or 
 Is an important medical event which may require intervention to prevent one of the  
previously listed outcomes 
Suspected Unexpected Serious Adverse Reaction (SUSAR) is any SAE, the nature, severity or 
frequency of which is not consistent with information in the most current most current Summary of 
Product Characteristics (SPC) or Package insert. 
Monitoring the safety of study participant and the progress of the study will be made at two levels. 
Firstly, the ICU research management forum at the study site, which is attended by all intensive care 
specialists, will be used for a comprehensive appraisal of the study protocol including assessment of 
risk to study participants. Monthly meetings of this forum will be used to evaluate the progress of the 
conduct of the study based on firsthand experience during the conduct of the study.  
Secondly, on a day to day basis participants will be monitored for potential serious adverse reactions 
(ADRs) and serious unexpected suspected adverse reactions (SUSAR). This monitoring will be done 
by nursing staff, doctors treating the patient and the research team. The clinical staff at the study site 
(nurses and doctors) will be aware when a patient is enrolled in the study and will be requested to 
remain vigilant for any ADRs or SUSAR. Nurses look after the patients in the ICU 24 hours per day 
(one nurse for one patient) and this provides a constant monitoring of the patients. In addition doctors 
will visit the patient multiple times per day. Further to these, the clinical pharmacists and research 
team will provide additional reviews of the patient. Following these reviews, investigators of the 
study will report any ADRs or SUSARs related to the study drug both to the HREC and the sponsors. 
The SAE reports will be forwarded to the HREC in accordance with local requirements. Investigators 
of the study are consultant intensive care clinicians and have all the required expertise to assist and 
advice the HREC about reports of serious adverse events. The Principal Investigator will forward to 
MSC Global Safety Group (fax number: +1-215-993-1220) any SAE and SUSAR information within 
2 business days of learning of the information. 
12. ETHICAL CONSIDERATIONS 
This study is to be performed in accordance with the ethical principles of the Declaration of Helsinki 
and all relevant national and local guidelines on the ethical conduct of research. Prior to 
commencement, the study protocol will be presented to the Human Research Ethics Committee at the 
Royal Brisbane and Women’s Hospital for approval.Local governance approval will then be sought. 


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The Principal Investigator will be responsible for submitting progress reports, adverse event reports 
and any other required documentation to the HREC in accordance with their guidelines. Copies of all 
HREC and research governance correspondence will be kept with the study investigator files. 
13. CONFIDENTIALITY AND PRIVACY 
Patients enrolled will be allocated a unique study number. The Research Coordinator will compile an 
enrolment log including the patient’s name, date of birth, hospital identification number, unique study 
number and date and time of enrolment. Subsequent data will be identified by the unique study 
number only. The enrolment log and study data will be kept separately. All patient details and study 
data will be kept in a locked office at the study site. No identifying data will be entered into the 
electronic data base. 
Study data will be entered into a secure computer maintaining confidentiality in accordance with local 
legislation on privacy and use of health data. When archiving or processing data pertaining to the 
investigator/and or patients, the coordinating centre will take all appropriate measures to safeguard 
and prevent access to this data by any unauthorised party. 
The site principal investigator will maintain the confidentiality of all study documentation, and take 
measures to prevent accidental or premature destruction of these documents. The site principal 
investigator will retain the study documents at least fifteen years after the completion or 
discontinuation of the study. The investigator will be notified prior to the destruction of any study 
essential documents following the study completion or discontinuation. If the investigator's personal 
situation is such that archiving can no longer be ensured by him/her, the investigator shall inform the 
sponsor and MSD and the relevant records shall be transferred to a mutually agreed designee. 
14. CONSENT 
The principal investigator or the nominated delegate will obtain written informed consent from any 
conscious and comprehending patient, prior to enrolment in the study. Obtaining written and informed 
consent directly from patients in the ICU prior to enrolment in a clinical trial is frequently not possible 
because these patients are often unconscious, sedated, intubated and too ill to understand information 
relating to study participation. Under these circumstances, the approach to obtaining consent in this 
study will be based on that developed from the guidelines of the Australian NHMRC National 
Statement. 


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Where it is possible for a conscious and comprehending patient to give informed consent to take part 
in this study before project related activities are undertaken, the study will be explained verbally to 
that patient by the principle investigator or their nominated delegate. The patient will be given the 
opportunity to read the participant information sheet and ask any questions prior to deciding on 
participation in the study. Intensive care physicians are highly experienced at caring for critically ill 
patients and also evaluating the competence of their patients to understand their illness and consent 
for therapeutic interventions. If the patient is deemed competent and consents to participate, they will 
be given a copy of the signed and dated consent form and the participant information sheet and any 
other documentation discussed through the consent process. 
If a potential participant lacks the capacity to give consent because of their medical condition, consent 
will be obtained from an authorised representative. The procedure for obtaining consent from the 
authorised representative will be approved by the local HREC prior to use. Authorised representatives 
will be given a verbal explanation of the study and the information sheet to read. They will be given 
opportunity to ask questions prior to deciding on participation of the participant. If the authorised 
representative consents to the participant’s participation in the study they will be given a copy of the 
signed Information and consent form. 
All interaction between research staff and potential or actual participants and their relatives will take 
into consideration the stress or emotional factors associated with critical illness and ensure that the 
dependency of potential participants and their relatives on medical personnel providing treatment does 
not compromise the freedom of decision making to participate. 


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