title: Managing the Risk of CYP3A Induction in Drug Development: A Strategic Approach.
abstract: Induction of cytochrome P450 (P450) can impact the efficacy and safety of drug molecules upon multiple dosing with coadministered drugs. This strategy is focused on CYP3A since the majority of clinically relevant cases of P450 induction are related to these enzymes. However, the in vitro evaluation of induction is applicable to other P450 enzymes; however, the in vivo relevance cannot be assessed because the scarcity of relevant clinical data. In the preclinical phase, compounds are screened using pregnane X receptor reporter gene assay, and if necessary structure-activity relationships (SAR) are developed. When projects progress toward the clinical phase, induction studies in a hepatocyte-derived model using HepaRG cells will generate enough robust data to assess the compound's induction liability in vivo. The sensitive CYP3A biomarker 4β-hydroxycholesterol is built into the early clinical phase I studies for all candidates since rare cases of in vivo induction have been found without any induction alerts from the currently used in vitro methods. Using this model, the AstraZeneca induction strategy integrates in vitro assays and in vivo studies to make a comprehensive assessment of the induction potential of new chemical entities. Convincing data that support the validity of both the in vitro models and the use of the biomarker can be found in the scientific literature. However, regulatory authorities recommend the use of primary human hepatocytes and do not advise the use of sensitive biomarkers. Therefore, primary human hepatocytes and midazolam studies will be conducted during the clinical program as required for regulatory submission.
authors: Oncology Innovative Medicines and Early Development Biotech Unit (B.C.J.) and Drug Safety and Metabolism (H.R.), AstraZeneca, Cambridge, United Kingdom; Quantitative Clinical Pharmacology (S.J.), and Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit (K.P.K., T.B.A.), AstraZeneca, Mölndal, Sweden; Quantitative Clinical Pharmacology, AstraZeneca, Hertfordshire, United Kingdom (C.L.); Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts (K.V.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.). Barry.Jones1@astrazeneca.com.
authors: Barry C
authors: BC
authors: Jones
authors: Oncology Innovative Medicines and Early Development Biotech Unit (B.C.J.) and Drug Safety and Metabolism (H.R.), AstraZeneca, Cambridge, United Kingdom; Quantitative Clinical Pharmacology (S.J.), and Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit (K.P.K., T.B.A.), AstraZeneca, Mölndal, Sweden; Quantitative Clinical Pharmacology, AstraZeneca, Hertfordshire, United Kingdom (C.L.); Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts (K.V.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.).
authors: Helen
authors: H
authors: Rollison
authors: Oncology Innovative Medicines and Early Development Biotech Unit (B.C.J.) and Drug Safety and Metabolism (H.R.), AstraZeneca, Cambridge, United Kingdom; Quantitative Clinical Pharmacology (S.J.), and Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit (K.P.K., T.B.A.), AstraZeneca, Mölndal, Sweden; Quantitative Clinical Pharmacology, AstraZeneca, Hertfordshire, United Kingdom (C.L.); Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts (K.V.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.).
authors: Susanne
authors: S
authors: Johansson
authors: Oncology Innovative Medicines and Early Development Biotech Unit (B.C.J.) and Drug Safety and Metabolism (H.R.), AstraZeneca, Cambridge, United Kingdom; Quantitative Clinical Pharmacology (S.J.), and Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit (K.P.K., T.B.A.), AstraZeneca, Mölndal, Sweden; Quantitative Clinical Pharmacology, AstraZeneca, Hertfordshire, United Kingdom (C.L.); Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts (K.V.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.).
authors: Kajsa P
authors: KP
authors: Kanebratt
authors: Oncology Innovative Medicines and Early Development Biotech Unit (B.C.J.) and Drug Safety and Metabolism (H.R.), AstraZeneca, Cambridge, United Kingdom; Quantitative Clinical Pharmacology (S.J.), and Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit (K.P.K., T.B.A.), AstraZeneca, Mölndal, Sweden; Quantitative Clinical Pharmacology, AstraZeneca, Hertfordshire, United Kingdom (C.L.); Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts (K.V.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.).
authors: Craig
authors: C
authors: Lambert
authors: Oncology Innovative Medicines and Early Development Biotech Unit (B.C.J.) and Drug Safety and Metabolism (H.R.), AstraZeneca, Cambridge, United Kingdom; Quantitative Clinical Pharmacology (S.J.), and Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit (K.P.K., T.B.A.), AstraZeneca, Mölndal, Sweden; Quantitative Clinical Pharmacology, AstraZeneca, Hertfordshire, United Kingdom (C.L.); Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts (K.V.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.).
authors: Karthick
authors: K
authors: Vishwanathan
authors: Oncology Innovative Medicines and Early Development Biotech Unit (B.C.J.) and Drug Safety and Metabolism (H.R.), AstraZeneca, Cambridge, United Kingdom; Quantitative Clinical Pharmacology (S.J.), and Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit (K.P.K., T.B.A.), AstraZeneca, Mölndal, Sweden; Quantitative Clinical Pharmacology, AstraZeneca, Hertfordshire, United Kingdom (C.L.); Quantitative Clinical Pharmacology, AstraZeneca, Waltham, Massachusetts (K.V.); and Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (T.B.A.).
authors: Tommy B
authors: TB
authors: Andersson
mesh_terms: D001681:Biological Assay; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions / Q000201:enzymology / Q000209:etiology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A