University of Groningen
Towards personalized management of drug interactions: from interaction to
drug-drug-gene-interaction
Bahar, Akbar
DOI:10.33612/diss.112160601
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Publication date: 2020
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Bahar, A. (2020). Towards personalized management of drug interactions: from drug-drug-interaction to drug-drug-gene-interaction. University of Groningen. https://doi.org/10.33612/diss.112160601
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Summary
Samenvatting
Acknowledgment
About the author
List of manuscripts produced during PhD study
Summary
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Summary
Drug-drug interactions (DDIs) are still one of the main problems hindering the optimization of pharmacotherapy since it may lead to ineffectiveness or deleterious side effects. DDI alerting systems have been employed, at the time of drug prescription and before drug dispensing, in order to prevent potential negative impact of such DDIs. However, despite the presence of the DDI surveillance systems, potential DDIs are still frequently observed in clinical practice. One of the main weaknesses of the DDI alerts is that some of them are still programmed to detect potential DDIs with unclear clinical significance. Potential DDIs are not always manifested as real DDIs or as clinically relevant DDIs with abilities to pose drawbacks on the pharmacotherapeutic management plan. Intrinsic and extrinsic factors might influence the clinical magnitude of DDIs, for example via production of complex DDIs such as drug-drug-gene-interactions (DDGIs) and therefore, inter-individual variabilities in the extent of DDIs severity exist. Consequently, the management of potential DDIs should address the variation and importantly provide personalized recommendation based on the available risk factors as well as potential severity. In this thesis, we aimed to estimate the burden of overlooked potential DDIs, to provide additional evidence for one of the most frequently observed potential DDIs as well as to assess its clinical relevance, and to describe the influence of genetic polymorphisms on the impact of DDIs and DDGIs.
In part A, we investigated the burden and management of potential DDIs which were still prescribed despite the presence of DDI alerting systems. In chapter 2, we explored the frequency of potentially interacting substrate and inhibitor of three main polymorphic metabolizing enzymes (CYP2D6, CYP2C19, and CYP2C19) co-prescriptions in the Dutch population within the Lifelines cohort cross-sectionally. Additionally, since the drug information was collected by using self-reported questionnaires, which are prone to recall bias, we investigated the concordance level of these drug information with prescription information from the University of Groningen prescription database IADB.nl which is representative for the Dutch population as a whole. We found that CYP2D6/2C19/2C9-mediated potential DDIs were frequent (1 to 2 per 100 users). Concordance of self-reported and prescription data varied by time window, type of interacting medication, sex and age. Time window of three months produced the highest kappa values of agreement i.e. 0.545 (95% CI: 0.544-0.545), 0.512 (95% CI: 0.511-0.512), and 0.374 (95% CI: 0.373-0.375), respectively, and potential DDIs involving two drugs used chronically had a better agreement level than those combinations involving at least one drug used occasionally. Future studies are urgently needed to determine the health impact of these combinations and preferably use a combination of self-reported and database information.
In chapter 3, we estimated the burden and management of one of the most prevalent combined potentially interacting drugs, metoprolol (a CYP2D6 substrate) and paroxetine/fluoxetine (a strong CYP2D6 inhibitor), among a high-risk population of older persons using the IADB.nl database. Even in the presence of alerting software, we observed that metoprolol-paroxetine/fluoxetine or reverse combinations are still highly prevalent among older Dutch inhabitants. After being co-dispensed, switching metoprolol or paroxetine/fluoxetine to a non-interacting drug was rarely found in the community pharmacies. Lastly, we also found that metoprolol prescription is mostly low-dosed in this population even without the presence of paroxetine/fluoxetine.
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In chapter 4, we then evaluated the impact of paroxetine/fluoxetine addition on metoprolol prescriptions among older persons using two proxy outcomes namely the early termination and dose modification of metoprolol. We found that compared with metoprolol and mirtazapine (no interaction) co-prescription, the combination of metoprolol-paroxetine/fluoxetine was significantly associated with the risk of early termination but not a dose modification of metoprolol, especially among female older persons.
Next, in chapter 5, we systematically reviewed outcomes of metoprolol and paroxetine/ fluoxetine drug-drug interactions. There were three case reports, four clinical studies and one cohort (retrospective) study reporting that the drug interactions may lead to metoprolol-induced side effects; however, a case control study presented a contradictory result. Despite conflicting research findings, most studies concluded that the DDI can lead to adverse clinical consequences. Therefore, because alternative antidepressants with comparable efficacy are available, this DDI should be avoided. Nevertheless, if the benefit of the combination outweighs the potential side effects, prescribing an adjusted dose of metoprolol and monitoring the appearance of potential side effects should be done especially in a high risk population.
One factor which might influence the severity of drug metabolizing enzyme mediated drug interactions is genetic polymorphism. Therefore, in part B, we evaluated the influence of CYP450 polymorphisms on the magnitude of drug interactions. In chapter 6, we performed a systematic review with the aim to describe the influence of genetic polymorphisms on the magnitude of not only CYP2C9, CYP2C19, and CYP2D6 (three main polymorphic drug-metabolizing enzymes) mediated DDIs but also complex DDGIs. We presented that the magnitude of DDIs and DDGIs depends on the number of functional CYP alleles with different clinical implications. Generally, NMs generate a greater extent of DDIs than IMs. Yet, the latter produces a greater extent of DDIs than PMs. The severity of DDGIs are also gene-dependent with PMs generating greater extent of DDGIs than IMs and followed by NMs.
In chapter 7, we then explored the impact of DDIs, DGIs, and DDGIs on one of the most prescribed antidepressants in clinical practice namely citalopram and escitalopram [(es)citalopram]. These drugs are metabolized by multiple catalytic enzymes i.e. CYP2C19, CYP3A4, and CYP2D6. Consequently, the biodegradation of these drugs might be altered either via one enzyme or multiple enzymes by perpetrator drugs (DDIs), genetic polymorphism (drug-gene interactions/ DGIs) or both of them (DDGIs). We performed an inception retrospective cohort study, as part of the PharmLines Initiative, among a Caucasian population (≥18 years old) from the Lifelines cohort (167,729 participants) with linked prescription data from the IADB.nl (730,000 participants). Their genetic information on CYP2C19/3A4 genotypes was available. We found that participants with DGIs involving predicted reduced catalytic activity of CYP2C19 had an increased risk of switching and/ or dose reduction of (es)citalopram. The co-presence of decreased function of CYP3A4 seemed to increase the impact of the DGIs. Meanwhile, there were trends towards increased risks of switching and/or dose reduction of (es)citalopram for participants with DDIs and DDGIs. However, these findings need to be confirmed with larger studies.
To pave the way for personalizing drug interaction management, pre-emptive multiple pharmacogene testing is one important step that needs to be implemented. The pharmacogene
Summary
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profiles as well as other clinically relevant information should be then incorporated in the computerized physician order which has been coupled with an advanced drug interaction alerting system. The surveillance system should be able to process the complex information in order to produce specific information regarding the severity of the potential drug interactions as well as tailored recommendation to manage the interaction. Therefore, research to provide evidence about the combined influence of various factors, internal and external factors, on the magnitude of drug interactions and the development of sophisticated drug interaction alerting system should be continuously encouraged.
Samenvatting
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Samenvatting
Interacties tussen geneesmiddelen (drug-drug interactions oftewel DDI’s) vormen nog steeds een groot probleem bij de optimalisatie van farmacotherapie. Deze DDIs kunnen namelijk leiden tot inefficiënte therapie of schadelijke bijwerkingen. DDI controle-systemen in de apothekerssoftware worden geactiveerd op het moment dat een geneesmiddel wordt voorgeschreven en voordat het geneesmiddel wordt verstrekt om zo mogelijke negatieve effecten van de DDI’s te voorkomen. Echter, ondanks de aanwezigheid van deze controle-systemen, worden potentiële DDI’s nog steeds vaak waargenomen in de klinische praktijk. Een van de voornaamste zwaktes van de DDI controle-systemen is dat sommige nog steeds geprogrammeerd zijn om alle potentiële DDI’s, ook die met een onduidelijke klinische significantie, te detecteren. Potentiële DDI’s manifesteren zich niet altijd als echte DDI’s of als klinisch relevante DDI’s die consequenties hebben voor de farmacotherapeutische behandelplannen. Intrinsieke en extrinsieke factoren kunnen invloed hebben op de klinische relevantie van de DDI’s, bijvoorbeeld bij complexe DDI’s waarbij er een wisselwerking is tussen geneesmiddelen en genen, de zogenaamde drug-drug-gene-interactions (oftewel DDGI’s). Daarom zijn er inter-individuele variaties wat betreft de ernst van de DDI’s voor dezelfde behandeling. Derhalve zou het beleid ten aanzien van potentiële DDI’s zich moeten richten op de variatie van de risico’s. Nog belangrijker, er zou een geïndividualiseerde aanbeveling moeten kunnen worden gegeven op basis van de beschikbare risicofactoren en de mogelijke ernst. In deze dissertatie willen wij de geschatte belasting door enkele onopgemerkte potentiële DDI’s vaststellen, om aanvullend bewijs te leveren voor een van de meest frequent gevonden potentiële DDI’s en daarbij de klinische relevantie hiervan vaststellen. Daarnaast beschrijven we welke invloed genetische polymorfismen hebben op de impact van DDI’s en DDGI’s.
In het eerste deel onderzoeken we de belasting door en het beheer van potentiële DDI’s die nog steeds worden waargenomen ondanks de aanwezigheid van DDI controlesystemen. In hoofdstuk 2 kijken we in een dwarsdoorsnelde van het Lifelines cohort onderzoek naar het voorkomen van recepten voor mogelijk interagerende substraten en remmers van de drie belangrijkste polymorfe metabole enzymen, namelijk CYP2D6, CYP2C19 en CYP2C9, in de Nederlandse populatie. Omdat de informatie van de geneesmiddelen verzameld was met behulp van zelfgerapporteerde vragenlijsten, die altijd neigen naar vertekening door gebrekkige herinnering (recall bias), onderzochten we de mate van overeenstemming van gegevens uit deze informatiebron over de voorgeschreven geneesmiddelen met de informatie in de IADB.nl, de apothekersdatabase van de Universiteit van Groningen. Deze database is representatief voor de Nederlandse populatie. We vonden dat potentiële DDI’s op basis van CYP2D6/2C19/C9 vaak voorkwamen (bij 1 tot 2 per 100 gebruikers) op een willekeurig moment (basismeting Lifelines). Overeenstemming met zelfgerapporteerde en voorgeschreven data toonde variaties in tijdsbestek, type interagerend geneesmiddel, geslacht en leeftijd. Een tijdsbestek van 3 maanden gaf de hoogste kappa waardes van overeenstemming, namelijk respectievelijk 0.545 (95% CI: 0.544-0.545), 0.512 (95% CI: 0.511-0.512), en 0.374 (95% CI: 0.373-0.375), en potentiële DDI’s waarbij twee medicijnen chronisch gebruikt werden, hadden een beter overeenstemmingsniveau dan de combinaties waarbij tenminste een medicijn alleen sporadisch werd gebruikt. Toekomstige onderzoeken zijn hard nodig om vast
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te stellen wat voor gezondheidseffecten deze combinaties hebben. Het onderzoek kan het best gebaseerd worden op een combinatie van zelfgerapporteerde- en database informatie, met name als het om acute medicaties gaat.
In hoofdstuk 3 stellen we vast hoe groot de belasting door en het beheer is van een van de meest gangbare combinaties van mogelijk interagerende geneesmiddelen, metoprolol (een CYP2D6 substraat) en paroxetine/fluoxetine (een sterke CYP2D6 remmer). Dit onderzochten we bij een hoog-risico populatie van ouderen met behulp van de database IADB.nl. Zelfs bij het gebruik van DDI controle-software kunnen we zien dat metoprolol-paroxetine/fluoxetine of omgekeerde combinaties nog steeds zeer veel voorkomen bij oudere Nederlanders. Na het voorschrijven van beide middelen kwam switchen van metoprolol of paroxetine/fluoxetine naar een niet interagerend geneesmiddel weinig voor in de openbare apotheken. Ten slotte kunnen we ook aantonen dat metoprolol vaak in lage dosering wordt voorgeschreven voor deze oudere groep, zelfs zonder de aanwezigheid van paroxetine/fluoxetine.
In hoofdstuk 4 kijken we naar de impact van paroxetine/fluoxetine toevoeging aan metoprolol voorschriften onder oudere mensen waarbij we twee surrogaat uitkomsten gebruiken, namelijk het vroegtijdig stoppen en doseringsaanpassing van metoprolol. We vonden dat, in vergelijking met een co-prescriptie van metoprolol en mirtazapine (geen interactie), de combinatie van metoprolol-paroxetine/fluoxetine significant geassocieerd was met het risico van vroegtijdig stoppen, maar niet met doseringsaanpassing van metoprolol, met name onder de vrouwelijke deelnemers.
Verder kijken we in hoofdstuk 5 systematisch naar de resultaten van metoprolol en paroxetine/ fluoxetine DDI’s. Er waren drie case reports, vier klinische onderzoeken en een (retrospectief) cohort onderzoek die aangaven dat de geneesmiddel interacties mogelijk kunnen leiden tot bijwerkingen veroorzaakt door metoprolol; er was echter ook een patient-controle onderzoek dat het tegenovergestelde resultaat gaf. Ondanks deze tegenstrijdige onderzoeksuitkomsten concluderen de meeste onderzoeken dat de DDI kan leiden tot negatieve klinische consequenties. Omdat alternatieve antidepressiva met vergelijkbare werkzaamheid beschikbaar zijn, zouden deze DDI’s voorkomen kunnen worden. Maar als de voordelen van deze combinatie opwegen tegen de mogelijke bijwerkingen, dan zal een aangepaste dosis van metoprolol voorgeschreven moeten worden en zal het monitoren van mogelijke bijwerkingen goed bijgehouden moeten worden, met name bij hoog-risico groepen.
Een factor die misschien van invloed kan zijn op de intensiteit van geneesmiddelinteracties gebaseerd op geneesmidel-metaboliserende enzymen is genetisch polymorfisme. Daarom kijken we in deel B naar de invloed van CYP450 polymorfismen op de geneesmiddel-interacties. In hoofdstuk 6 voeren we een systematische review uit met als doel om de invloed van genetische polymorfismen te beschrijven op DDI’s, niet alleen gebaseerd op CYP2C9, CYP2C19, en CYP2D6 (de drie belangrijkste polymorfe geneesmiddel-metaboliserende enzymen), maar ook op complexe DDGI’s. We laten zien dat de klinische implicaties van DDI’s en DDGI’s afhangt van de hoeveelheid functionele CYP-allelen. Over het algemeen genereren Normal Metabolisers (NM’s) meer DDI’s dan Intermediate Metabolisers (IM’s). Maar die laatsten produceren weer meer DDI’s dan Poor Metabolisers (PM’s). Het optreden van de DDGI’s is ook gen-afhankelijk met PM’s die meer DDGI’s genereren dan IM’s, gevolgd door NM’s.
Samenvatting
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In hoofdstuk 7 bekijken we de impact van DDI’s, DGI’s en DDGI’s op een van de meest voorgeschreven antidepressiva in de klinische praktijk, namelijk citalopram en escitalopram [(es) citalopram]. Deze geneesmiddelen worden omgezet door meerdere enzymen zoals CYP2C19, CYP3A4, and CYP2D6. De biologische afbraak van deze geneesmiddelen kan veranderd worden door een geneesmiddel (DDI’s) via een of meerdere enzymen door genetische polymorfismen (drug-gene interactions/DGI’s) of door allebei (DDGI’s). We hebben een retrospectief inceptiecohort onderzoek uitgevoerd binnen het PharmLines Initatief, bij een blanke populatie (≥18 jaar oud) van de Lifelines groep (167.729 deelnemers) met gekoppelde voorschrift-data van de IADB.nl (1.7 miljoen deelnemers). De genetische informatie van CYP2C19/3A4 genotypes was voor een deel beschikbaar. Wij ontdekten dat de deelnemers met DGI’s gebaseerd op een voorspelde verminderde enzymactiviteit van CYP2C19 een verhoogd risico hadden om te switchen en/of de dosering van (es) citalopram te verlagen. Indien tevens de functie van CYP3A4 was verminderd leek de impact van de DGI’s te verhogen. Bovendien was er een trend in toename van het risico op switchen en of dosisverlaging van (es)citalopram bij deelnemers met DDI’s en DDGI’s. Deze resultaten moeten nog bevestigd worden door grotere klinische studies.
Om gepersonaliseerd geneesmiddel-interactie beleid mogelijk te maken, is vooraf genotyperen op meerdere farmacogenen een belangrijke stap die geïmplementeerd moet worden. De farmacogenetische profielen en andere klinisch relevante informatie zouden dan opgenomen moeten worden in het elektronisch voorschrijfsysteem dat gekoppeld is aan een geavanceerd geneesmiddel-interactie waarschuwingssysteem. Het controlesysteem zou in staat moeten zijn om complexe informatie te verwerken om specifieke informatie over de ernst van de potentiële geneesmiddel-interactie te kunnen geven naast op maat gemaakte aanbevelingen. Daarom is het aan te bevelen om meer onderzoek te doen om bewijs te leveren voor de gecombineerde invloed van zowel interne als externe factoren die te maken hebben met de ernst van de geneesmiddel-interacties. Hiermee wordt het mogelijk efficiënte geavanceerde controlesystemen voor geneesmiddel-interacties te ontwikkelen.
Acknowledgment
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Acknowledgment
First and foremost, I would like to send my greatest gratitude to Allah, the Almighty, who mercifully bestows upon me health, strength, determination and patience as well as supportive family, supervisors, and friends who enabled me to finish my PhD study as one of the most important stepping stone in my life.
This thesis would not be finished without immense supports from a lot of remarkable parties. Therefore, I would like to convey my sincere gratitude to those that have shaped my academic endeavor.
I would like to sincerely and specially thank my promotor, Prof. Bob Wilffert, who gave me a chance to work under his supervision. I could never thank you enough for it. Bob, I learnt a lot from you about how to always be optimistic in every situation and how to be a super supervisor. You always believe in my capacity as well as motivate me that I can finish all my PhD projects on time while I am struggling with my imposter syndrome. You are always accessible and very helpful when I have obstacles both substantially and financially related to my study. You also always remind me to have enough time with my family which is very important for me as a source of my motivation. Thank you very much for greeting me almost every day in four years in Bahasa Indonesia. Finally, I would like to say: Boss, I made it!
My deep and special gratitude also goes to my second promotor, Prof. Eelko Hak. Thank you very much for your continuous support and guidance over the years. I really appreciate all your contributions of time, ideas, and patience to guide me to be an independent researcher. I always admire your critical thinking and problem solving abilities. I also love your English revision on my manuscript and cover letter since you can always beautify and sharpen the sentences. Thank you for not only being a supportive supervisor but also a great teacher for me.
My sincere thanks to dr. Sander D. Borgsteede who gave me additional valuable supports to several chapters of my thesis especially in the field of drug-drug-interactions. Thank you for sharing your knowledge and thank you for becoming a challenging and enlightening discussion partner. I am also thankful to Jens H.J. Bos who helped and taught me a lot about SQL and IADB as well as helped the linkage process of the Pharmlines initiatives.
I want also to extend my profound gratitudes to all my co-authors who supported me generously to finish all my PhD projects. Thank you to Yuanyuan Wang; Aafje Dotinga, Rolinde A. Alingh, Jasper Kamp, Didik Setiawan, Prof. Rolf H. Sijmons, and Pauline Lanting for your valuable suggestions and corrections as well as great helps in the completion process of my thesis.
I also would like to thank you all the assessments committee: Prof. A. H. Maitland-van der Zee, Prof. D. J. Touw, and Prof. E. N. van Roon for their time to assess my thesis.
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I also thank all former and current members of Unit PTEE: Abrham, mbak Afifah, Adjie, Bert, Christian, Doti, Eva, Fajri, Felicia (for translating my English summary to Dutch), Hao, Heleen, Hugo,
mbak Ira, mas Ivan, Jens, Jurjen, Joy, mas Khairul, Lan, Linda, Lisette, mbak Lusi, Marcy, Monik, mbak Nelly, Nynke, Pepjin, Pieter, Qi, Riswandy, Simon, Sofa, mbak Sylvi, Taichi, Tanja, Thea, Talitha,
Thang, mbak Tia, kak Ury, Prof. Katja, and Prof. Maarten. Thank you for all scientific discussions in our group meetings, the random conversation in any occasions and for cheerful my days during my PhD. Special thanks to the members of room 3214.0454. Yuan, you are my first international friend in Groningen and I still remembered the first time we met. Thank you very much for everything and I am sorry for being a ‘not so nice’ officemate for you. Thank you for involving me in your projects.
Mas Ivan, thank you very much for all the lessons through our discussions about everything from
scientific matters, politics to daily life problems. Thank you for becoming a very good table tennis partner who made me rarely win. Mbak Sylvi, I did enjoy talking to you about many topics especially philosophical aspects of life. Thank you for becoming a good listener, and a very helpful and nice officemate. Mas Ivan and mbak Sylvi, thank you also for being available as my paranymphs.
I also would like to give my special gratitude to Jannie Schoonveld, our beloved secretary, who always helped me a lot during my PhD study and always had solutions for all my administrative problems. My deep gratitude also goes to mas Didik and Aizati who have become my role models during my study. Aizati, thank you for helping me to settle well during my first year of my PhD. Mas Didik, I remembered that you were the first Indonesian person I contacted to when I decided to continue my study in this University. You were also the one who spared your time to pick me up in the train station during my arrival and ever since had been becoming my ‘guru’ in Groningen.
I also would like to address my thank you to Riswandy, Cici, Mikail and Mikhayla for their help and support to me and my family. Thank you for being a more than friend to me. Our family shared a lot of beautiful moments here and hopefully we can continue to create more beautiful moments in Makassar.
My special thanks also goes to pak Asmoro and bu Rini families. Thank you for taking care and helping us. Thank you for being such a nice bude and oppa to Abdullah. Thank you for all the delicious foods.
Mas Adi, Mbak Ifa, and Mas Riffat, thank you for being good brothers and a sister for Abdullah.
Thank you for all the moments we spent together.
My sincere thanks also goes to kak Habibie, Ma’wa and Owi. As a family and friend, I could not thank you enough for having you here in Groningen. I believe that I could not finish my study without your great support for me and my family. Thank you for being always available to help us in every situation and condition. I am sorry if I and my family always put a burden on your family. Hopefully, we can soon re-unite again in Makassar.
Acknowledgment
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I am also indebted to all former and current sesepuh, friends and families in the Netherlands especially in Groningen, PPIG, and deGromiest who have been very kind, helpful and supportive to me and my family: Oom Archie-Tante Mary, budhe Nunung, oom Weno-Uwak Asiyah, oom Herman-Budhe Arie, pak Tatang and family, mas Salim-mbak Atika and family, mas Zakiyullah and family, mas Kus and family, bli Kadek and family, mas Hegar and family, mas Zainal and family, mas Azis and family, kang Bino and family, mbak Nur Qomariah, mas Fajar and family, mas Yudi and family, mas Amak and family, mas Khairul and family, mas Ivan and family, mas Mega and family, mas Lana and family, mas Ali Abdurrahman and family, mas Joko and family, mas Surya and family, mas Ristiono and family, mas Didin and family, mas Zaki and family, mas Krisna and family, mbak Tiur, mas Ali Syariati and family, mas Ucon, mas Azkario, mas Yoga, mbak May, mas Azka and family, mas Ade and family,
mas Agung and family, mas Latief and family, mas Wicaksosono, mbak Ira, mas Ronny, mas Luthfi, mas Adjie, mas Guntur and family, mas Fika and family, mas Chalis and family, mas Afif, mas Bhimo, mbak Inda and family, mas Budi and family, mas Zulfan and family, and all people who could not be
listed in this acknowledgement.
I would like also to thank the Group Haji Groningen 2017. Thank for helping us during the hajj ceremony. Thank you for becoming supportive travel mates for my little family.
I thank all friends in the big family of IKA Unhas-Belanda: Amy, Adlin, Alim, Amanda, Beby, Faqi, Fuad, Dodo, Hasan, Indry, kak Isdah, Karis, tante Lina, Miaa, kak Muthmainnah, Oka, kak Rahma, Riefqi, Richa, Rifaat, tante Seruni, kak Sidik, tante Sue, kak Sul, Taufik, tante Titi, Qalby, kak Yani, Arif, and others who cannot be listed here. Thank you for all the happiness and good times in many occasions.
I would like to express my great appreciation to Directorate General of Higher Education, the Ministry of Research, Technology and Higher Education of the Republic of Indonesia for providing the DIKTI scholarship which enabled me to continue my PhD education at the University of Groningen, the Netherlands. I would also like to thank the University of Groningen for providing me a scholarship to cover my last 1.5 year of my PhD study.
I would also to sincerely thank Prof. Dwia Aries Tina Pulubuhu as the Rector of Universitas Hasanuddin who allowed me to continue my PhD study here. I also owe a debt of gratitude to Prof. Elly Wahyudin and Prof. Gemini Alam, as the former and current Dean of the Faculty of Pharmacy, Universitas Hasanuddin, who supported and gave me permission to pursue a PhD study here. My special thanks also goes to Subehan, PhD as the one who opened a way for me to continue my study abroad. I am also grateful to all lecturers and staffs as well as my colleagues and friends in the Faculty of Pharmacy, Universitas Hasanuddin, who always gave me full support during my PhD study. Special thanks goes to Ismail and Muhammad Nur Amir who are always being available to take care all my administrative problems in the university.
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I would also like to acknowledge all my teachers in every step of my education. Thank you very much for teaching me well so that I can grow and be who I am right now.
To my brothers and sisters (also in-law) as well as my nephews: Muh. Akmal Bahar-Rikma-Muh. Syarkawi Akmal, Sitti Zakiyah Bahar-Sarjan Romdony-Muh. Aulal Hadi-Maryam Afifatul Ulya, Tuti Alawiyah-Sarwing, Andi Hudri-Andi Diana-Andi Ikram Rahmansyah, and Andi Shaleh, thank you very much for all the prayers and supports. Thank you for helping to take care our parents and Abdullah during my leave.
To my (late) father- and mother-in-law, Syamsul Bahri and Andi Dahlia, thank you very much for all your blessings, understanding, love, and supports for me. I am sorry for not always being there especially during your tough times.
To my father and mother, Muh. Bahar Paelori and Fatmawati Muhammad, thank you very much for your endless love, unconditional understanding and continuous prayers for me. Thank you for raising me up and always giving me the best education that you could afford. Thank you for all the trusts and supports for each decision that I take during my life. I am really sorry I missed a lot of special and important moments in our family.
To my wife, Andi Sri Wahyuni, I am so lucky to have you by my side as my love. Thank you very much for all your patience, understanding, encouragement and constant supports during my PhD study. I could not describe how hard it is for you to take care our active baby boy alone while you are dealing with your job. I am really proud of you and deeply appreciate how you manage everything in order. Thank you for believing in me and always motivating my days with your special sentence: ‘Selamat
Bersinar Matahari (Happy Shining my Sun)’.
To my shaleh and smart son, Abdullah Muhammad Akbar, thank you for all your smiles, patience and stories. I would like you to know that your presence changes your parents, lives a lot and since then, you have become our ultimate source of joy. I am sorry, nak, for not always being present during your stages of development. However, Ayah is finally coming home, nak, and we can play together again.
Alhamdulillah, barakallahu fiikum for all of you.
Groningen, 19-11-2019 Muh. Akbar Bahar
About the author
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About the author
Muh. Akbar Bahar (1986) was born in Ujung Pandang, South Sulawesi, Indonesia. He gained his bachelor (2007) and pharmacist degree (2008) from Universitas Hasanuddin, South Sulawesi, Indonesia. After his graduation, he worked as a pharmacist in the Labuang Badji Hospital (a district general hospital) before joining Pharmacology and Toxicology Laboratory, Faculty of Pharmacy, Universitas Hasanuddin, as a young lecturer and researcher (2009). Funded by the Ministry of Research, Technology and Higher Education of the Republic of Indonesia under the scheme of DIKTI scholarship, he continued his study in the Applied Pharmacology Laboratory, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan, and obtained a master degree in the field of pharmaceutical sciences (2013). In 2015, he got a research grant ‘RISBIN IPTEKDOK 2015’ from the Ministry of Health of Republic Indonesia for young researcher. In the end of 2015, he was then again awarded a DIKTI scholarship to start his PhD study in the Unit of PharmacoTherapy, -Epidemiology, and -Economis (PTEE), Groningen Research Institue of Pharmacy (GRIP), Universiy of Groningen, the Netherlands. After finishing his PhD study, he will go back to Indonesia and continue to work as a lecturer and researcher in the Pharmacology and Toxicology Laboratory, Faculty of Pharmacy, Universitas Hasanuddin, South Sulawesi, Indonesia.
List of manuscripts produced during PhD study
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List of manuscripts produced during PhD study
Bahar, M. A., Setiawan, D., Hak, E., & Wilffert, B. (2017). Pharmacogenetics of drug–drug interaction
and drug–drug–gene interaction: a systematic review on CYP2C9, CYP2C19 and CYP2D6.
Pharmacogenomics, 18(7), 701-739.
Bahar, M. A., Hak, E., Bos, J. H., Borgsteede, S. D., & Wilffert, B. (2017). The burden and management
of cytochrome P450 2D6 (CYP2D6)-mediated drug–drug interaction (DDI): co‐medication of metoprolol and paroxetine or fluoxetine in the elderly. Pharmacoepidemiology and drug safety, 26(7), 752-765.
Bahar, M. A., Wang, Y., Bos, J. H., Wilffert, B., & Hak, E. (2018). Discontinuation and dose
adjustment of metoprolol after metoprolol‐paroxetine/fluoxetine co‐prescription in Dutch elderly.
Pharmacoepidemiology and drug safety, 27(6), 621-629.
Bahar, M. A., Kamp, J., Borgsteede, S. D., Hak, E., & Wilffert, B. (2018). The impact of CYP2D6
mediated drug–drug interaction: a systematic review on a combination of metoprolol and paroxetine/fluoxetine. British journal of clinical pharmacology, 84(12), 2704-2715.
Wang, Y., Zijp, T. R., Bahar, M. A., Kocks, J. W., Wilffert, B., & Hak, E. (2018). Effects of prophylactic antibiotics on patients with stable COPD: a systematic review and meta-analysis of randomized controlled trials. Journal of Antimicrobial Chemotherapy, 73(12), 3231-3243.
Wang, Y.*, Bahar, M. A.*, Jansen, A. M., Kocks, J. W., Alffenaar, J. W. C., Hak, E., Wilffert, B., & Borgsteede, S. D. (2019). Improving antibacterial prescribing safety in the management of COPD exacerbations: systematic review of observational and clinical studies on potential drug interactions associated with frequently prescribed antibacterials among COPD patients. Journal of Antimicrobial
Chemotherapy, 74(10), 2848-2864.
*Equal contribution.
Bahar, M. A., Bos, J. H., Borgsteede, S. D., Dotinga, A., Alingh, R. A., Wilffert, B., & Hak, E. Prevalence
and accuracy of information on CYP2D6, CYP2C19, and CYP2C9 related substrate and inhibitor co-prescriptions in the general population: a cross-sectional descriptive study as part of the PharmLines Initiative. Submitted.
Bahar, M. A., Lanting, P., Bos, J. H., Sijmons, R.H., Hak, E., & Wilffert, B. Impact of
drug-gene-interaction, drug-drug-drug-gene-interaction, and drug-drug-gene-interaction on switching, dose adjustment and early discontinuation of (es)citalopram: an explorative cohort study within the PharmLines initiative. Submitted.
ADDENDUM
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Irawati, S., Wasir, R., Bahar, MA., Hak, E., Wilffert, B., Taxis, K., Postma, MJ., Buskens, E. The burden of cardiovascular diseases and trend of claim reimbursement for statin prescription in Indonesia after the implementation of the National Health Insurance (Jaminan Kesehatan Nasional, JKN): 2014-2016. In preparation.
Kambira, P. F. A.*, Bahar, MA.*, Wilffert, B. Polymorphism of CYP450 in Indonesia: A Systematic Review. In preparation.
