Minireview Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper

ABSTRACT An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs

Title Page Mechanisms and Predictions of Drug-Drug Interactions of the Hepatitis C Virus 3-Direct Acting Antiviral (3D) DMD # 74518 2 Running Title Page Running Title: DDI mechanisms and predictions of the HCV 3D regimen

Number of references: 34 Number of words in Abstract: 250 words Number of words in Introduction: 396 words Number of words in Discussion: 1,900 words Abbreviations: 3D, AbbVie's three direct acting antiviral regimen; AUCR, AUC ratio of substrate with perpetrator relative to control; CYP, cytochrome P450; DAA, direct acting antiviral; DDI, drug-drug interaction; HCV, hepatitis C virus DMD # 74518 3 Abstract To assess drug-drug interaction (DDI) potential for the 3 direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir and paritaprevir, in vitro studies profiled drug metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UGT1A1, OATP1B1/1B3, BCRP and P-gp. Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations but for drug transporters, additional PBPK modeling was necessary to achieve the same. When assessing perpetrator interactions, ritonavir is responsible for the strong increase in exposure of sensitive CYP3A substrates while paritaprevir (OATP1B1/1B3 inhibitor) increases greatly the exposure of sensitive OATP1B1/1B3 substrates. The 3D regimen drugs are UGT1A1 inhibitors and are predicted to increase moderately plasma exposure of sensitive UGT1A1 substrates. Paritaprevir, ritonavir and dasabuvir are BCRP inhibitors. Victim DDI predictions were qualitatively in line with the clinical observations. Plasma exposures of the 3D regimen were reduced by strong CYP3A inducers (paritaprevir and ritonavir; major CYP3A substrates), but not impacted by strong CYP3A4 inhibitors since ritonavir (CYP3A inhibitor) is already present in the regimen. Strong CYP2C8 inhibitors increase plasma exposure of dasabuvir (major CYP2C8 substrate), OATP1B1/1B3 inhibitors increase the plasma exposure of paritaprevir (OATP1B1/1B3 substrate), and Pgp or BCRP inhibitors (all compounds are substrates of P-gp and/or BCRP) increase plasma exposure of the 3D regimen. Overall, the comprehensive mechanistic assessment of compound disposition along with mechanistic and PBPK approaches to predict victim and perpetrator DDI liability, may enable better clinical management of non-studied drug combinations with the 3D regimen

Pharmacological actions of a novel, high-affinity, and selective human dopamine D3 receptor antagonist, SB277011-A.

ABSTRACT SB-277011-A {trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide}, is a brain-penetrant, high-affinity, and selective dopamine D 3 receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D 3 or D 2 long (hD 3 , hD 2 ) receptors showed SB-277011-A to have high affinity for the hD 3 receptor (pK i ϭ 7.95) with 100-fold selectivity over the hD 2 receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D 3 or D 2 . In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD 3 receptor (pK b ϭ 8.3) and was 80-fold selective over hD 2 receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2.8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D 3 receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine-or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78.8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D 3 receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D 3 receptors may benefit the treatment of schizophrenia