Hepatic transporter drug-drug interactions: an evaluation of approaches and methodologies

Introduction: Drug-drug interactions (DDIs) continue to account for 5% of hospital admissions and therefore remain a major regulatory concern. Effective, quantitative prediction of DDIs will reduce unexpected clinical findings and encourage projects to frontload DDI investigations rather than concentrating on risk management (‘manage the baggage’) later in drug development. A key challenge in DDI prediction is the discrepancies between reported models.

Areas covered: The current synopsis focuses on four recent influential publications on hepatic drug transporter DDIs using static models that tackle interactions with individual transporters and in combination with other drug transporters and metabolising enzymes. These models vary in their assumptions (including input parameters), transparency, reproducibility and complexity. In this review, these facets are compared and contrasted with recommendations made as to their application.

Expert opinion: Over the past decade, static models have evolved from simple [I]/k_i models to incorporate victim and perpetrator disposition mechanisms including the absorption rate constant, the fraction of the drug metabolised/eliminated and/or clearance concepts. Nonetheless, models that comprise additional parameters and complexity do not necessarily out-perform simpler models with fewer inputs. Further, consideration of the property space to exploit some drug target classes has also highlighted the fine balance required between frontloading and back-loading studies to design out or ‘manage the baggage’.     

Synthesis of S‐2‐((S)‐3‐(4‐chlorophenyl)‐N'‐((4‐chlorophenyl)sulfonyl)‐4‐phenyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carboximidamido)‐3‐(methyl‐d3)butanamide‐d5, octadeuterated JD5037

JD5037 ( 1 ) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB₁R) receptor. Peripheral CB₁ receptor antagonists/inverse agonists have great potential in the treatment of metabolic disorders like type 2 diabetes, obesity, and nonalcoholic steatohepatitis. We report the synthesis of octadeuterated [²H₈]‐JD5037 (S , S ) ( 8 ) along with its (S , R ) diastereomer ( 13 ) from commercially available L ‐valine‐d₈ starting material. The [²H₈]‐JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC‐MS/MS bioanalytical standard.     

Trametinib,a first-in-class oral MEK inhibitor mass balance study with limited enrollment of two male subjects with advanced cancers

Abstract

1.?This study assessed the mass balance, metabolism and disposition of [¹⁴C]trametinib, a first-in-class mitogen-activated extracellular signal-related kinase (MEK) inhibitor, as an open-label, single solution dose (2?mg, 2.9?MBq [79?µCi]) in two male subjects with advanced cancer.

2.?Trametinib absorption was rapid. Excretion was primarily via feces (～81% of excreted dose); minor route was urinary (～19% of excreted dose). The primary metabolic elimination route was deacetylation alone or in combination with hydroxylation. Circulating drug-related component profiles (composed of parent with metabolites) were similar to those found in elimination together with N-glucuronide of deacetylation product. Metabolite analysis was only possible from <50% of administered dose; therefore, percent of excreted dose (defined as fraction of percent of administered dose recovery over total dose recovered in excreta) was used to assess the relative importance of excretion and metabolite routes. The long elimination half-life (～10 days) favoring sustained targeted activity was important in permitting trametinib to be the first MEK inhibitor with clinical activity in late stage clinical studies.

3.?This study exemplifies the challenges and adaptability needed to understand the metabolism and disposition of an anticancer agent, like trametinib, with both low exposure and a long elimination half-life.     

Design, synthesis, antifungal activity, and ADME prediction of functional analogues of terbinafine

From the earlier quantitative structure–activity relationship (QSAR) and molecular modeling studies, a series of quinoline derivatives 5a–h mimicking terbinafine and containing different bulky aromatic rings in the side chain were designed using LeapFrog, a de novo drug design program. The designed compounds were synthesized and screened for antifungal activity in vitro against C. albicans. Of the ten compounds designed and synthesized, compounds 5c, d, f, h, and i exhibited minimum inhibitory concentration (MIC) in the range 4–25 μg/ml and were further evaluated for oral toxicity in animal model. The pharmacokinetic properties for these compounds were estimated in silico and compared with terbinafine. Compound 5h, N-methyl-N-[(2-naphthyl)methyl]-8-quinolinemethanamine, was found to be least toxic, possessing pharmacokinetic parameters close to those of terbinafine.     

Synthesis of a dual carbon-14-labeled calcitonin gene-related peptide receptor antagonist for use in a human absorption–distribution–metabolism–elimination study

Oral calcitonin gene-related peptide (CGRP) receptor antagonists have been shown to be effective in the acute and preventive treatment of migraine. CGRP receptor antagonists offer safety advantages over triptans because they are not active vasoconstrictors, which reduces cardiovascular risks. Bristol Myers Squibb discovered a high affinity CGRP receptor antagonist BMS-927711 for the treatment of migraine now FDA approved as Nurtec® ODT (rimegepant). Dual-labeled [¹⁴C]-BMS-927711 was prepared and used in a human absorption–distribution–metabolism–elimination (ADME) study. A dual-labeled analog of BMS-927711 was required to fully track the compound's metabolic transformation. The carbon-14-labeled synthesis of both right side and left side portions of [¹⁴C]-BMS-927711 is described.     

Optimization of ADME Properties for Sulfonamides Leading to the Discovery of a T-Type Calcium Channel Blocker,ABT-639

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