Mind the Gap: Model-Based Switching from Selatogrel to Maintenance Therapy with Oral P2Y12 Receptor Antagonists.

The P2Y receptor antagonist selatogrel is being developed for subcutaneous self-administration with a ready-to-use autoinjector at the onset of acute myocardial infarction (AMI) symptoms. The unique pharmacological profile of selatogrel (fast, potent, and short-acting) can bridge the time gap between the onset of AMI and first medical care. A clinical Phase 1 study showed a time-dependent pharmacodynamic interaction between selatogrel and loading doses of clopidogrel and prasugrel.

Pharmacokinetics, pharmacodynamics and safety of the novel C-X-C chemokine receptor 3 antagonist ACT-777991: Results from the first-in-human study in healthy adults.

Aims: The C-X-C chemokine receptor 3 (CXCR3) axis is highly upregulated in the tissue of patients with type 1 diabetes. Antagonizing CXCR3 may reduce the migration of CXCR3-expressing cells to the pancreas. The pharmacokinetics (PKs), target engagement (TE) (inhibition of CXCR3 internalization) and safety of single- and multiple-ascending doses (SADs and MADs) of ACT-777991, a novel orally available potent CXCR3 antagonist, were assessed in a double-blind, randomized, placebo-controlled phase 1 study.

Modeling time-delayed concentration-QT effects with ACT-1014-6470, a novel oral complement factor 5a receptor 1 (C5a receptor) antagonist.

The novel oral complement factor 5a receptor 1 antagonist ACT-1014-6470 was well tolerated in single- and multiple-ascending dose studies, including 24 h Holter electrocardiogram (ECG) recordings evaluating its cardiodynamics based on data from single doses of 30-200 mg and twice-daily (b.i.d.

In vitro validation of an in vivo phenotyping drug cocktail for major drug transporters in humans.

Purpose: Cocktails of transporter probe drugs are used in vivo to assess transporter activity and respective drug-drug interactions. An inhibitory effect of components on transporter activities should be ruled out. Here, for a clinically tested cocktail consisting of adefovir, digoxin, metformin, sitagliptin, and pitavastatin, inhibition of major transporters by individual probe substrates was investigated in vitro.

First-in-human study with ACT-1014-6470, a novel oral complement factor 5a receptor 1 (C5aR1) antagonist, supported by pharmacokinetic predictions from animals to patients.

Aberrantly controlled activation of the complement system contributes to inflammatory diseases. Safety, tolerability, and pharmacokinetics of single-ascending doses of ACT-1014-6470, a novel orally available complement factor 5a receptor 1 antagonist, were assessed in a randomized, double-blind, placebo-controlled Phase 1 study. Six ACT-1014-6470 doses (0.

Influence of hepatic impairment on the pharmacokinetics and pharmacodynamics of the P2Y12 receptor antagonist selatogrel.

Selatogrel is a potent and selective reversible P2Y12 receptor antagonist in development for early treatment of acute myocardial infarction via subcutaneous (s.c.) self-injection.

Transition from Syringe to Autoinjector Based on Bridging Pharmacokinetics and Pharmacodynamics of the P2Y Receptor Antagonist Selatogrel in Healthy Subjects.

Background And Objectives: Selatogrel is a potent, reversible, and selective antagonist of the platelet P2Y receptor currently developed for the treatment of acute myocardial infarction (AMI). In the completed Phase I/II studies, selatogrel was subcutaneously (s.c.

Combinations of common SNPs of the transporter gene ABCB1 influence apparent bioavailability, but not renal elimination of oral digoxin.

Effects of different genotypes on the pharmacokinetics of probe substrates may support their use as phenotyping agents for the activity of the respective enzyme or transporter. Digoxin is recommended as a probe substrate to assess the activity of the transporter P-glycoprotein (P-gp) in humans. Current studies on the individual effects of three commonly investigated single nucleotide polymorphisms (SNPs) of the ABCB1 gene encoding P-gp (C1236T, G2677T/A, and C3435T) on digoxin pharmacokinetics are inconclusive.

A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug-Drug Interactions.

Background: Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates.

Objective: This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail.

A Clinical Drug-Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin.

A new probe drug cocktail containing substrates of important drug transporters was tested for mutual interactions in a clinical trial. The cocktail consisted of (predominant transporter; primary phenotyping metric): 10 mg adefovir-dipivoxil (OAT1; renal clearance (CL )), 100 mg sitagliptin (OAT3; CL ), 500 mg metformin (several renal transporters; CL ), 2 mg pitavastatin (OATP1B1; clearance/F), and 0.5 mg digoxin (intestinal P-gp, renal P-gp, and OATP4C1; peak plasma concentration (C ) and CL ).

Assessment of Pharmacokinetic Drug-Drug Interactions in Humans: In Vivo Probe Substrates for Drug Metabolism and Drug Transport Revisited.

Pharmacokinetic parameters of selective probe substrates are used to quantify the activity of an individual pharmacokinetic process (PKP) and the effect of perpetrator drugs thereon in clinical drug-drug interaction (DDI) studies. For instance, oral caffeine is used to quantify hepatic CYP1A2 activity, and oral dagibatran etexilate for intestinal P-glycoprotein (P-gp) activity. However, no probe substrate depends exclusively on the PKP it is meant to quantify.

Drinking Ethanol Has Few Acute Effects on CYP2C9, CYP2C19, NAT2, and P-Glycoprotein Activities but Somewhat Inhibits CYP1A2, CYP2D6, and Intestinal CYP3A: So What?

We quantified the effect of acute ethanol exposure (initial blood concentrations 0.7 g/L) on major drug metabolizing enzymes and p-glycoprotein. Sixteen healthy Caucasians participated in a randomized crossover study with repeated administration of either vodka or water.

Reactive electrophilic oxylipins trigger a heat stress-like response through HSFA1 transcription factors.

Abiotic and biotic stresses are often characterized by an induction of reactive electrophile species (RES) such as the jasmonate 12-oxo-phytodienoic acid (OPDA) or the structurally related phytoprostanes. Previously, RES oxylipins have been shown massively to induce heat-shock-response (HSR) genes including HSP101 chaperones. Moreover, jasmonates have been reported to play a role in basal thermotolerance.