Complex Drug–Drug–Gene–Disease Interactions Involving Cytochromes P450: Systematic Review of Published Case Reports and Clinical Perspectives

Abstract

Drug pharmacokinetics (PK) is influenced by multiple intrinsic and extrinsic factors, among which concomitant medications are responsible for drug-drug interactions (DDIs) that may have a clinical relevance, resulting in adverse drug reactions or reduced efficacy. The addition of intrinsic factors affecting cytochromes P450 (CYPs) activity and/or expression, such as genetic polymorphisms and diseases, may potentiate the impact and clinical relevance of DDIs. In addition, greater variability in drug levels and exposures has been observed when such intrinsic factors are present in addition to concomitant medications perpetrating DDIs. This variability results in poor predictability of DDIs and potentially dramatic clinical consequences. The present review illustrates the issue of complex DDIs using systematically searched published case reports of DDIs involving genetic polymorphisms, renal impairment, cirrhosis, and/or inflammation. Current knowledge on the impact of each of these factors on drug exposure and DDIs is summarized and future perspectives for the management of such complex DDIs in clinical practice are discussed, including the use of advanced Computerized Physician Order Entry (CPOE) systems, the development of model-based dose optimization strategies, and the education of healthcare professionals with respect to personalized medicine.

Physiologically‐Based Pharmacokinetic Modeling for the Prediction of CYP2D6‐Mediated Gene–Drug–Drug Interactions

“…Storelli et al polymorphisms. 4 As an example, the extent in the increase of area under the curve (AUC) for venlafaxine when coadministered with quinidine can vary by a 20-fold factor in normal metabolizers of CYP2D6. 5 Therefore, it seems crucial to identify other covariables responsible for this huge variability.…”

“…Despite the development of DDI prediction tools integrated in computerized physician order entry systems, it still remains difficult to predict the clinical relevance of potential DDIs, as shown by the significant discrepancy between the high prevalence of potential DDIs and the low prevalence of actual DDIs leading to clinical harm . Indeed, a large interindividual variability exists in the extent of CYP‐mediated DDIs, which might be explained by intrinsic factors, such as age, sex, comorbidities, and genetic polymorphisms . As an example, the extent in the increase of area under the curve (AUC) for venlafaxine when coadministered with quinidine can vary by a 20‐fold factor in normal metabolizers of CYP2D6 .…”

“…2 Despite the development of DDI prediction tools integrated in computerized physician order entry systems, it still remains difficult to predict the clinical relevance of potential DDIs, as shown by the significant discrepancy between the high prevalence of potential DDIs and the low prevalence of actual DDIs leading to clinical harm. 3 Indeed, a large interindividual variability exists in the extent of CYP-mediated DDIs, which might be explained by intrinsic factors, such as age, sex, comorbidities, and genetic 1 Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland; 2 Geneva-Lausanne School of Pharmacy, Geneva University, Geneva, Switzerland; 3 Faculty of Medicine, Geneva University, Geneva, Switzerland; 4…”

An analysis of selected factors influencing the efficacy of psoriasis therapy

“…Next, genetic polymorphism plays a key role in obtaining adequate response to applied therapeutic strategy. With regards to psoriasis pharmacotherapy, the importance of the polymorphism of the following genes is emphasized: TNF, MTHR, SLC19A1, MTRR, CGH, ABCB1, VNTR, IL1B, IL1RN, KIR2DS2, KIR2DL2, CHST11, AMPD1, ITPA, MTHFD1, FCGR3A, BAFF-871, IL-6, as well as the following enzymatic protein-coding genes that participate in drug biotransformation: CYP39A1, CYP2D6, CYP1A2, CYP2D6, SLC22A2, SLC7A7, ALDH2 [43][44][45].…”

“…Poza tym polimorfizm genetyczny odgrywa niezmiernie ważną rolę w uzyskaniu adekwatnej odpowiedzi na stosowaną strategię terapeutyczną. W odniesieniu do farmakoterapii łuszczycy podkreśla się znaczenie polimorfizmu genów: TNF, MTHR, SLC19A1, MTRR, CGH, ABCB1, VNTR, IL1B, IL1RN, KIR2DS2, KIR2DL2, CHST11, AMPD1, ITPA, MTHFD1, FCGR3A, BAFF-871, IL-6 oraz genów kodujących białka enzymatyczne uczestniczące w biotransformacji leków: CYP39A1, CYP2D6, CYP1A2, CYP2D6, SLC22A2, SLC7A7, ALDH2 [43][44][45].…”