Assessing drug-drug interactions through therapeutic drug monitoring when administering oral second-generation antipsychotics

ABSTRACT

Introduction: Second-generation antipsychotics (SGAs) are frequently co-prescribed with drug metabolic inducers and inhibitors. SGA pharmacokinetic drug-drug interactions (DDIs) with inducers and inhibitors have not received enough attention in the literature but can be studied in by using therapeutic drug monitoring (TDM).

Areas covered: The limited information available on oral SGA pharmacokinetic DDIs is reviewed. A systematic literature search on the available oral SGA TDM studies is completed. By integrating TDM studies with the information on in vitro metabolism studies, case report/series and prospective studies, a table is provided to manage average SGA patients taking inducers or inhibitors by using TDM and/or dose SGA changes. Adding an inhibitor or discontinuing an inducer may increase plasma concentrations and cause adverse drug reactions (ADRs) on clozapine or risperidone. Quetiapine and lurasidone, which are very sensitive to decreases of plasma concentrations by induction, should not be administered with potent inducers. Prescribing sertindole with TDM may make its use safer.

Expert opinion: Reading our article may encourage: 1) clinicians using these combinations to publish TDM case reports/series to demonstrate whether our dose indications are correct or not, in their patients with DDIs; and 2) pharmacokinetic researchers to study these DDIs in prospective and retrospective ways using large TDM databases.

KEYWORDS:

• Drug interactions
• inhibitors
• inducers
• pharmacokinetics
• second-generation antipsychotics
• therapeutic drug monitoring

Article highlights

• The SGA literature on DDIs is limited and psychiatric textbooks and drug package inserts provide few recommendations to clinicians on how to manage them.

• A review of the literature on oral SGA TDM studies is integrated with the information on in vitro metabolism studies, case report/series, and prospective studies to provide our best interpretation of what to expect in the average SGA patient taking inducers or inhibitors by providing suggestions of when to use TDM and/or dose SGA corrections.

• Clozapine and risperidone are narrow therapeutic window drugs; adding an inhibitor or discontinuing an inducer may be particularly prone to cause ADRs in clozapine or risperidone patients.

• Quetiapine and lurasidone, which are very sensitive to decreases in plasma concentrations by induction, should not be administered with potent inducers.

• Amisulpride and ziprasidone, which bring about little CYP metabolism, even in conditions of induction, may not need dosages changes in the presence of potent inducers.

• Sertrindole data is limited but prescribing it under TDM control appears a good idea due to (1) its possible narrow therapeutic window with risk for QTc prolongation and (2) being influenced by CYP2D6 genetic polymorphism, CYP2D6 inhibitors, CYP3A4 inhibitors, and CYP3A4 inducers.

This box summarizes key points contained in the article.

Acknowledgments

The authors acknowledge Lorraine Maw, M.A., at the Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA, who helped in editing the article.

Declaration of interest

No commercial organizations had any role in the writing of this paper for publication.

In the past few years, E Spina has participated in speakers/advisory boards and lectured, supported by AstraZeneca, Bristol-Myers, Eli Lilly & Co, Janssen Pharmaceuticals, Lundbeck and Pfizer. C Hiemke has received speaker´s or consultancy fees from the following pharmaceutical companies: Pfizer, Lilly and Servier. C Hiemke is managing director of the psiac GmbH which provides an internet based drug-drug interaction program. He declares to have no conflict of interest with this article. J de Leon personally develops his presentations for lecturing, has never lectured using any pharmaceutical or pharmacogenetic company presentations, and has never been a consultant for pharmacogenetic or pharmaceutical companies. In the past, J Leon received researcher-initiated grants from Eli Lilly (one ended in 2003 and the other, as co-investigator, ended in 2007); from Roche Molecular Systems, Inc. (ended in 2007); and, in a collaboration with Genomas, Inc., from the NIH Small Business Innovation Research program (ended in 2010). J Leon has been on the advisory boards of Bristol-Myers Squibb (2003/04) and AstraZeneca (2003). Roche Molecular Systems supported one of his educational presentations, which was published in a peer-reviewed journal (2005). His lectures were supported once by Sandoz (1997), twice by Lundbeck (1999 and 1999), twice by Pfizer (2001 and 2001), three times by Eli Lilly (2003, 2006, and 2006), twice by Janssen (2000 and 2006), once by Bristol-Myers Squibb (2006), and seven times by Roche Molecular Systems, Inc. (once in 2005 and six times in 2006).