Pharmacokinetic Drug-Drug Interaction Study of Voriconazole With Clarithromycin.
Phase: PHASE4
Conditions: Healthy
Sponsor: Abdul Wali Khan University Mardan

PHARMACOKINETIC DRUG-DRUG INTERACTION STUDY OF 
VORICONAZOLE WITH CLARITHROMYCIN 
BY 
MEHWISH MUSHTAQ  
 
Synopsis submitted to Abdul Wali Khan University Mardan in the partial 
fulfillment of the requirements for the degree of 
M.Phill pharmaceutical sciences 
 
 
 
M.PHIL IN PHARMACEUTICAL SCIENCES 
DEPARTMENT OF PHARMACY 
 
 
 
 
 
 
 
 
 
 
 
DEPARTMENT OF PHARMACY 
PHARMACY 
ABDUL WALI KHAN UNIVERSITY MARDAN 
Session (2017 – 19) 
 
 

PHARMACOKINETIC DRUG-DRUG INTERACTION 
STUDY OF VORICONAZOLE WITH CLARITHROMYCIN 
By 
MEHWISH MUSHTAQ  
 
Approved by 
 
Supervisory Committee: 
 
Name: Dr. Yasar Shah                                    Supervisor 
Department Name:  
Department of Pharmacy 
 
Name: Dr. Muhammad Abbas 
               Member of Supervisory Committee 
Department Name 
Department of Pharmacy  
 
Name: Dr. Omer Shehzad 
 
 Member of Supervisory Committee 
 
Department Name 
 
Department of Pharmacy  
 
Name: Prof. Dr. Haroon  
               Convener, Graduate Studies Committee        
Department Name 
Department of Pharmacy                              
 
Name: Prof. Dr. Salimullah Khan                    Convener, Board of Studies 
Department Name 
Department of Pharmacy                              
 
Name: Prof. Dr. Zahid Ali Khan                      Director Academics/ASRB 
Director ASRB 
Abdul Wali Khan University Mardan 
 
Name: Prof. Dr. Sultan Ayaz Khattak              Dean Faculty of Chemical & Life Sciences 
Department Name 
Department of Biochemistry                              
 
 
DEPARTMENT OF PHARMACY 
FACULTY OF CHEMICAL & LIFE SCIENCES 
ABDUL WALI KHAN UNIVERSITY MARDAN 
SESSION (2017-19) 

 
RESEARCH PROPOSAL FOR M. PHIL IN PHARMACY 
TOPIC: PHARMACOKINETIC DRUG-DRUG INTERACTION 
STUDY OF VORICONAZOLE WITH CLARITHROMYCIN 
 
 
 
Submitted by: 
Mehwish Mushtaq  
Reg. No. 
AWKUM-16002974 
 
Session admitted in: 
(2017-2019). 
Current semester: 
2nd semester. 
Admission Score & 
date cleared: 
40.   8th Feb 2017 
 
Approval of BOS 
Ref. No/ Pharm/AWKUM 2018/917 
Minutes of the 07th Meeting of the Board of Studies Held on 07-09-2018 in 
the Department of Pharmacy, Abdul Wali Khan University Mardan 
(AWKUM). 
Approval of ASRB 
Dir/A&R/AWKUM/2018/1408 
 
ASRB Meeting No: 19th Meeting of Advance Studies and Research Board 
(ASRB). 
Date:  September 28, 2018 
Remarks 
Approved 
 
 
DEPARTMENT OF PHARMACY 
ABDUL WALI KHAN UNIVERSITY, MARDAN 
 
 
 
 
 
Supervisor 
Dr. Yasar Shah 
Co-Supervisor 
Nill 

1. INTRODUCTION 
Drug-drug interaction (DDI) occurs when one drug (perpetrator drug) varies the 
plasma concentration and the biological outcomes of the second drug (victim drug). 
Pharmacokinetic drug-drug interaction (PK-DDI) may occur at the level of 
absorption, distribution, metabolism, or excretion when a co-exposed drug may 
result in alteration of blood-concentration vs. times profile of one or both drugs. 
Induction of CYP450 enzymes by the co-administered drug results in a decrease in 
substrate drug concentration leading to in-efficacy or inhibition of CYP450 
enzymes by another drug resulting in prolonged half-lives and/or higher substrate 
drug concentration that may enhance the potential for side effects. Drug 
transporters also play a vital role in drug disposition when both co-exposed drugs 
have an affinity for the same binding site of the transporter, while age, gender, 
nutritional status, various diseases, genetic polymorphisms, and ontogeny of the 
metabolic enzyme may also affect the drug metabolism (Müller and Fromm, 
2011, Michalets, 1998). 
Voriconazole is synthetically derived from fluconazole antifungal. Voriconazole 
(Fig. 1), chemically is ([2R, 3S]-2- [2, 4-difluorophenyl]-3-[5-fluro-4pyrimidinyl]-
1- [1 H -1, 2, 4-trizole-1-yl]-2-butanol) and has a broad spectrum categorized as 
second-generation triazole antifungal. Voriconazole is also called a 14-alpha-sterol 
demethylase inhibitor, broadly used to manage invasive Aspergillosis and other 
serious fungal infections. Voriconazole binds to the rate-limiting enzyme and 
inhibits the CYP450 enzyme, leading to inhibition of ergosterol synthesis and 
deposition of 14-alpha-methyl sterols such as lanosterol, so the structure of fungi 
cell membrane disrupts. Voriconazole is a strong inhibitor of CYP51 (fungal CYP 
enzyme) as compared to fluconazole.  It has additional activity against Candida 
Albicans, Candida kurusei Scedosporium, Fusarium, and certain other emerging 
pathogens. Usually, the first oral administered dose of voriconazole is 400mg, 
followed by a maintenance dose of 200mg at a 12hr dosing interval, and in some 
conditions, the loading dose is maintained at 9mg/kg, twice a day (BD). 
Voriconazole is rapidly absorbed and has mostly 96% oral bioavailability. The 
Peak plasma concentration (Cmax) of voriconazole is 5.27mg/L at 400mg and the 

target is achieved in 1-2hr after drug administration. Both Cmax and AUC are dose-
proportional over the range of (200mg-400mg). The volume of distribution is 
4.6L/Kg and plasma protein binding is 58%. Terminal elimination half-life (t1/2) 
ranged from 8hr to 15hr and there is no effect over the steady- pharmacokinetics 
of voriconazole by variation in the timings of administration of dose (morning or 
evening). Voriconazole is highly metabolized by the hepatic enzyme CYP2C19 
and forms a voriconazole-N-oxide as a major inactive metabolite, which has only 
minimal antifungal activity. Other metabolites also formed such as hydroxyl 
voriconazole and dihydroxy-voriconazole. Voriconazole shows first pass by 
enzymes present in enterocytes as well as hepatocytes and major systemic 
metabolisms occur by cytochrome-P450 enzymes such as CYP2C19, CYP2C9, 
CYP3A4, CYP3A5, and the 25% metabolism occurs by Flavin containing mono-
oxygenase FMO-1 and FMO-3. Renal and Biliary excretion of voriconazole 
(metabolized form) is about 75%-80% and 20%-25% respectively, whereas, the 
remaining 2% is excreted in urine as unchanged form. Voriconazole is a potent 
inhibitor of CYP2C19, CYP2C9, CYP2B6, and CYP3A4 enzymes, present in 
hepatocytes as well as enterocytes. Voriconazole is a p-glycoprotein (ABCB1) 
substrate at different levels (intestinal, hepatic, and renal levels) and also it is a 
weak inhibitor of this transporter. Being a lipophilic drug, Voriconazole would be 
in the un-ionized form as the pH of the formulation shifts towards a neutral value 
resulting in enhanced permeation (Mohanty et al., 2013, Vanhove et al., 2017, 
Mikus et al., 2011, Herbrecht, 2004).  
Clarithromycin 
(6-O-Methylerthromycin) 
is 
a 
semi-synthetic 
macrolide 
antibacterial agent with a 14-membered ring. The oral bioavailability of 
clarithromycin parent drug is 52-53% and terminal elimination half-life (t1/2) is 8hr 
(Logan et al., 1994). The usually recommended dose in adults of Clarithromycin 
is 250mg-500mg (P/O) twice a day for 7-14 days in various conditions and in some 
conditions are also given a single dose of 1000mg. About 53% of a single dose of 
clarithromycin is excreted in the urine and 40% in feces. The volume of distribution 
of clarithromycin is estimated to be 191 to 309L and plasma protein binding ranges 
from 42-72%. Clarithromycin is extensively metabolized by hepatic CYP3A4 and 

forms a 14-R-hydroxyclarithromycin active metabolite and inactive metabolite N-
desmethyl-clarithromycin (Rodvold, 1999). Clarithromycin is an intense inhibitor 
of CYP3A4 and has the average inhibitory activity of CYP2C19, CYP2D6, and 
CYP1A2 enzymes at hepatic as well as the intestinal levels (Furuta et al., 1999, 
Michalets, 1998). 
At different levels (intestinal, hepatic, and renal levels), several transporters 
(ABCB1, ABCC2, OATP2B1, and OATP1A2)are substrates of clarithromycin 
(Müller and Fromm, 2011). Voriconazole is an inhibitor of several transporters 
like breast cancer resistance protein (BCRP), p-glycoprotein,  multidrug resistance-
associated protein (MRP-1, MRP-2, MRP-4, and MRP-5), and bile salt export 
pump (BSEP), but exhibited an inhibitory activity of less than 60% (Lempers et 
al., 2016, Mikus et al., 2011). Clarithromycin is also an inhibitor of p-glycoprotein 
at enterocytes (luminal), hepatocytes (canalicular), and renal (luminal) sites as well 
as an inhibitor of OATP1B1 and OATP1B3 at hepatocytes (sinusoidal) and 
intestinal level (Müller and Fromm, 2011). Strong inhibitory (Ic50) activity of 
OATP4C1 has also been observed by clarithromycin at intestinal and renal sites 
(Sato et al., 2017). Clarithromycin is a potent inhibitor of the taurocholate uptake 
in rat OATP1A5-transfected Madin-Darby canine kidney cells, the nearest analog 
to human OATP1A2 (Garver et al., 2008). According to the BCS classification, 
voriconazole and clarithromycin both are class-II drugs (Kumar et al., 2014, 
Kristin et al., 2017). Nature and pKa of both interacting drugs (i.e., clarithromycin 
weakly basic in nature with 8.76 pKa and voriz exhibiting both sets of pKa values 
i.e., basic: 1.76 pKa as well as acidic pKa values: 4.36 and 12.7) make these drugs 
better candidates for possible potential PK-DDIs. 
Keeping in view the nature of voriconazole and clarithromycin a pharmacokinetic 
drug-drug interaction may likely be possible. 
 

 
 
 
 
 
 
 
 
 
                         Fig.1: Chemical structure of voriconazole 
 
2. OBJECTIVES 
The main objectives of this study will be 
1. To develop a sophisticated, robust, and sensitive quantification method using 
HPLC for the determination of voriconazole in biological fluids. 
2. To measure the pharmacokinetic parameters [i.e., Cmax, Tmax, T1/2, AUC, etc.] 
of voriconazole in healthy volunteers of Pakistan. 
3. To evaluate the PK-DDI of voriconazole with clarithromycin and to study 
the impact of clarithromycin co-administration on the pharmacokinetic 
parameters of voriconazole. 
4. To interpret the data statistically.  
 
3. LITERATURE REVIEW 
Co-administration of a precipitant drug with an object drug may alter the object 
drug’s response in the patient. Some drug interactions are clinically significant and 
beneficial, so it is desirable to use their simultaneous administration for better 
therapeutic response and reduced potential ADRs. The majority of drug 
interactions are not clinically significant and may be detrimental resulting in 
adverse events. Voriconazole’s drug interactions can be categorized into: 
contraindicated, needing dose adjustment, monitoring levels, and no adjustment 
required (Herbrecht, 2004). Many DDI of voriconazole is well documented in the 

literature. Purkins and his co-workers performed an open-label, randomized, and 
cross-over study on 12 healthy volunteers. Effect of cimetidine on pharmacokinetic 
parameters of voriconazole has been evaluated and an insignificant increase in 
AUC and Cmax of voriconazole has been observed, so only monitoring the 
voriconazole concentration in the body in long term use for toxicity is sufficient 
(Purkins et al., 2003b). Another study is conducted on voriconazole and ritonavir, 
in which a serious DDI has been reported. Cmax of voriconazole is decreased by 
150% because ritonavir is (CYP2C19 and CYP2C9) enzyme inducer, so an 
alternative therapy or contraindication along with ritonavir (400mg BID) has been 
suggested (Liu et al., 2007). 
Drug interaction of voriconazole with phenytoin has also been reported in the 
literature. The AUC and Cmax of voriconazole decreased by150% because 
phenytoin is a (CYP2C19 and CYP2C9) enzymes inducer so increased 
maintenance dose and TDM of voriconazole have been recommended (Purkins et 
al., 2003a). Andrew and his fellow researchers have performed a DDI study of 
voriconazole with ethinyloestradiol and norethindrone. This study reported 
increased AUC and Cmax of voriconazole by 100% because ethinyloestradiol is a 
CYP2C19 enzyme inhibitor. They have reported that this one is significant 
interaction and concurrent use of voriconazole, ethinyloestradiol, and 
norethindrone medications are well-tolerated (Andrews et al., 2008). The effect of 
efavirenz on voriconazole pharmacokinetics has also been studied. This study 
reported a decrease in AUC by150% because efavirenz is CYP2C19 and CYP2C9 
enzymes inducer (Damle et al., 2008). 
In recent research conducted on voriconazole with flucloxacillin co-administration 
in patients having chronic granulomatous disease and influenza-associated 
aspergillosis, a decrease in plasma voriconazole concentration has been reported. 
Flucloxacillin induced CYP3A4 enzyme resulting in decreased Cmax. In this 
study, the researchers have suggested close monitoring of plasma concentration of 
voriconazole and avoidance of the combination if possible (Muilwijk et al., 2017). 
A case study of pulmonary aspergillosis patients reported a decrease in 
voriconazole plasma concentration by co-administration with darunavir (non-

peptidic HIV protease inhibitor). This study report suggested that voriconazole, 
ritonavir, and darunavir should be given cautiously or combination is avoided 
(Becker et al., 2015).  
Many DDIs occur because voriconazole has variable and non-linear 
pharmacokinetic behavior. Voriconazole is a CYP2C19 and CYP3A4 enzymes 
inhibitor as well as a substrate of these enzymes. Enzyme CYP2C19 has genetic 
polymorphism: poor, moderate, and extensive metabolizers (Bahar et al., 2017). 
Asian peoples are mostly poor CYP2C19 metabolizers so DDI may be possible in 
this region and voriconazole may show variable Cmax because of non-linearity 
(Mikus et al., 2011).  Clarithromycin is CYP3A4 and CYP2C19 enzymes inhibitor 
and voriconazole are also a substrate and inhibitor of these two enzymes (Furuta 
et al., 1999).  Both drugs share the same enzyme pathway so DDI may be possible. 
To our knowledge, no work has been done for the evaluation of the effect of 
clarithromycin on pharmacokinetic parameters of voriconazole to date. 
 
4. METHODOLOGY  
This study will be designed in the following three steps. 
Step-1: Development of Quantification Method and Its Validation 
In the first phase of the current study, we will develop an HPLC method and 
validation according to standard guidelines for the quantification of voriconazole 
in a biological matrix. The first phase of the study will comprise of development 
and validation of the HPLC method for the identification as well as determination 
of voriconazole in biological fluids. 
Step-2: Evaluation of Pharmacokinetic Drug-Drug Interaction 
During the second step, sample collection will be carried out and blood samples 
will be collected in EDTA or heparinized tubes from the enrolled human 
volunteers, administered with voriconazole alone or co-administered with 
clarithromycin at specified periods. Further processing of the sample will be done 
for extractions and subsequent analysis with the developed analytical method. 
Evaluation of possible pharmacokinetic drug-drug interaction will be carried out 
through a comparison of pharmacokinetic parameters. 

Study Design and Subject 
A study designed for drug interaction will be a single oral dose, open-label, 
randomized, cross-over study of healthy volunteers. The ethical approval of the 
protocol will be taken from the local ethical committee of the Pharmacy 
department, Abdul Wali Khan University, Mardan before initiation. This study will 
follow the “ethical principles of the Helsinki declaration for medical research 
involving human subjects” and “good clinical practice guidelines”. Written 
consent will be obtained from all included volunteers in the DDI study. The study 
will be comprised of two treatment sequences with a two-week washout period i.e., 
given in Table-I; 
 
Sequence 
 
Treatment-1 
Group-I  
         (n= 12) 
Treatment-2 
Group- II 
           (n = 12) 
Sequence-1 
Voriconazole alone (Vfend® Oral 
Two Tab, strength of 200mg)  
Voriconazole 
+ 
clarithromycin 
(Vfend® 
Oral Two Tab, Strength of 
200mg with klaricid® Oral 
Tab, Strength of 500mg) 
Two Week Washout Period 
 
Treatment-2 
Treatment-1 
 
Sequence-2 
Voriconazole + clarithromycin 
(Vfend® Oral sTwo Tab, strength 
of 200mg with klaricid® Oral Tab, 
Strength of 500mg)   
Voriconazole alone (Vfend® 
Oral Two Tab, Strength of 
200mg) 
Table-1: Two Treatment Sequence, Open Labeled, Cross-Over Study Design for the 
Pharmacokinetic DDI-Study of Voriconazole with Clarithromycin 
 
Inclusion Criteria 
Male Pakistani volunteers in good health aged 18-35 years will be enrolled as 
participants in this study. The selection will be based on: a complete detailed medical 

history, clinical examination, voriconazole hypersensitivity test, and evaluation of 
various biochemical tests like Blood Glucose Level, Hemoglobin (Hb) Level, Serum 
Glutamic-Pyruvic Transaminase (SGPT) Or Alanine Amino Transferase and 
Aspartate (ALT and AST, respectively) Level, Urine Test, BUN Level, Albumin to 
Creatinine Ratio (ACR) Test, Glomerular Filtration Rate (GFR) Level, etc. 
Exclusion Criteria  
Those volunteers who have a history of voriconazole hypersensitivity reaction, 
deviation from normal values in the biochemical test report, having any pathology 
like chronic renal disease, hepatic impairment, and having any cardiovascular, 
gastrointestinal tract, hematopoietic disorders will be excluded from the study. 
Alcohol addicted, smokers and volunteers who cannot sign the permission consent 
form will be excluded from the study. 
Collection of Blood-Samples 
Blood samples (approximately 3cc) will be collected from overnight fasting inducted 
volunteers in heparinized tubes at specific time intervals of 0.0 (pre-dose), 0.5, 1.0, 
1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours after administration of two tablets of 
voriconazole (200mg) either alone or co-administration with clarithromycin 
(500mg). After taking blood samples, immediately these samples will be centrifuged 
to separate plasma from blood (RBC) and will be stored at -800C until analysis. 
Samples Analysis 
We will develop an RP-HPLC/UV-Vis method for the measurement of voriconazole 
concentration in biological fluid. The stored samples will be brought back to room 
temperature by thawing technique and the drug will be extracted from plasma 
samples with already established extraction solvents and subsequently analyzed with 
the developed method. 
Step-3:  Data Assessment and Analysis 
In this phase, pharmacokinetic parameters used for PK-DDI assessment will be 
analyzed statistically using compartment and/or non-compartmental approaches. 
Assorted pharmacokinetic parameters like Cmax (µg/ml), Tmax (hrs), T1/2 (hrs), 
[AUC]0-t (µg.h/ml), AUMC (µg.h/ml), MRT (hrs), and Vd (L) will be determined 

from plasma drug concentration Vs. time profile. All pharmacokinetic parameters 
will be evaluated using different pharmacokinetic software like PK-Summit® etc., 
and for graphical data analysis MS-Excel, Minitab, etc. will be used. Appropriate 
statistical tests like t-test and analysis of variance (ANOVA) will be performed and 
data will be presented graphically. 
 
5. TENTATIVE TIME 
Literature Survey: one month 
Research: 06 month 
Thesis writing: 06 month  
 
6. REFERENCE 
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M., LEDUC, D. & LEGOUT, L. 2015. Drug interactions between voriconazole, 
darunavir/ritonavir and tenofovir/emtricitabine in an HIV-infected patient treated for 
Aspergillus candidus lung abscess. International journal of STD & AIDS, 26, 672-675. 
3. DAMLE, B., LABADIE, R., CROWNOVER, P. & GLUE, P. 2008. Pharmacokinetic interactions 
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M., KOSUGE, K., HANAI, H. & CHIBA, K. 1999. Effects of clarithromycin on the metabolism 
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5. GARVER, E., HUGGER, E. D., SHEARN, S. P., RAO, A., DAWSON, P. A., DAVIS, C. B. & HAN, 
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Title: Pharmacokinetic Drug-Drug Interaction Study of Voriconazole with Clarithromycin  
ASRB Approval Date of Study and Study-Title: September 28 2018 
  
CONSENT FORM  
PHARMACOKINETIC DRUG-DRUG INTERACTION STUDY OF VORICONAZOLE WITH 
CLARITHROMYCIN  
  
Name of the participant: _______________________________________  
Name of the principal (Co-) Investigator: __________________________  
Name of the institution: _______________________________________  
  
Documentation of the informed consent  
I, __________________________, have read the information in this form (or it has been read to me). I was free 
to ask any questions and they have been answered. I am over 18 years of age and, exercising my free power of 
choice, hereby give my consent to be included as a participant in  
“_______________________________________________________________” (title of study)  
1. I have read and understood this consent form and the information provided to me.  
2. I have had the consent document explained to me.  
3. I have been explained about the nature of the study.  
4. I have been advised about the risks associated with my participation in the study.  
5. I have informed the investigator of all the treatments I am taking or have taken in the 
past_______________ months including any desi (alternative) treatments.  
6. I agree to cooperate with the investigator and I will inform him/her immediately if I suffer unusual 
symptoms.  
7. I have not participated in any research study within past ___________ month(s).  
8. I am also aware that the investigators may terminate my participation in the study at any time, for any 
reason, without my consent.  
9. I hereby give permission to the investigator to release the information obtained from me as a result of 
participation in this study to the sponsors, regulatory authorities, government agencies, and ethics 
committee. I understand that they may inspect any original records.  
10. My identity will be kept confidential if my data are publicly presented.  
11. I have had my questions answered to my satisfaction.  
12. I have decided to be in the research study.  
  
Participant’s initials:  
Name and signature / thumb impression of the participant  
Name: __________________        Signature: ________________   Date: ____________   Time: ________  
Address and contact number of the impartial witness: _________________________________________ 
_____________________________________________________________________________________  
Name and signature of the investigator or his representative obtaining consent:  
Name: __________________      Signature: ______________ Date: _______________  
  
Investigator certificate  
I certify that all the elements including the nature, purpose and possible risks of the above study as described in 
this consent document have been fully explained to the subject. In my judgment, the participant possesses the 
legal capacity to give the informed consent to participate in this research and is voluntarily and knowingly giving 
informed consent to participate,  
Signature of the investigator: ______________       Date: ____________________  
Name of investigator: