A human receptor occupancy assay to measure anti-PD-1 binding in patients with prior anti-PD-1.

Receptor occupancy (RO) assessment by flow cytometry is an important pharmacodynamic (PD) biomarker in the clinical development of large molecules such as monoclonal therapeutic antibodies (mAbs). The total-drug-bound RO assay format directly assesses mAb binding to cell surface targets using anti-drug detection antibodies. Here, we generated a flow cytometry detection antibody specifically binding to mAbs of the IgG P329GLALA backbone.

Ultra-sensitive and selective quantification of endothelin-1 in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry.

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor peptide and the plasma concentrations are commonly quantified by immunoassays such as enzyme-linked immuno-sorbent assays (ELISA) with the disadvantage of possible cross-reactivity with closely related endothelin derivatives. The aim of this study was to develop and validate an ultra-sensitive and selective assay for the quantification of ET-1 in human plasma, using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) after solid phase extraction. The assay fulfilled the requirements of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) guidelines for assay validation, with a lower limit of quantification of 1.

First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B.

Background & Aims: Myrcludex B is a first-in-class compound, which blocks entry of hepatitis B and D virus into hepatocytes in vitro and in animal models. Based on the required preclinical data we aimed to translate this compound into the first application in humans.

Methods: Single ascending doses of myrcludex B, a 47 amino acid peptide, were administered up to 20mg intravenously and 10mg subcutaneously in a prospective open first-in-human, phase I clinical trial to 36 healthy volunteers.

The effect of induction of CYP3A4 by St John's wort on ambrisentan plasma pharmacokinetics in volunteers of known CYP2C19 genotype.

To evaluate the impact of CYP2C19 polymorphisms on ambrisentan exposure and to assess its modification by St. John's wort (SJW), 20 healthy volunteers (10 CYP2C19 extensive, four poor and six ultrarapid metabolizers) received therapeutic doses of ambrisentan (5 mg qd po) for 20 days and concomitantly SJW (300 mg tid po) for the last 10 days. To quantify changes of CYP3A4 activity, midazolam (3 mg po) as a probe drug was used.

Pre-systemic elimination of tilidine: localization and consequences for the formation of the active metabolite nortilidine.

The therapeutic activity of tilidine, an opioid analgesic, is mainly related to its active metabolite nortilidine. Nortilidine formation mainly occurs during the high intestinal first-pass metabolism of tilidine by N-demethylation. Elimination of the active nortilidine to the inactive bisnortilidine is also mediated by N-demethylation and is supposed to take place in the liver, probably at a smaller rate.

Lack of a clinically significant interaction of grapefruit juice with ambrisentan and bosentan in healthy adults.

Objective: We assessed the effect of 1 x 300 mL/d and 3 x 300 mL/d grapefruit juice (GFJ) on ambrisentan and bosentan pharmacokinetics in healthy volunteers.

Methods: In the ambrisentan study, 12 healthy extensive metabolizers (EM) of CYP2C19 received therapeutic doses of ambrisentan (5 mg q.d.

Influence of St. John's wort on the steady-state pharmacokinetics and metabolism of bosentan.

Objective: We assessed the effect of St. John's wort (SJW) on bosentan pharmacokinetics at steady-state in different CYP2C9 genotypes in healthy volunteers.

Methods: Nine healthy extensive metabolizers of CYP2C9 and 4 poor metabolizers received therapeutic doses of bosentan (125 mg q.

Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1.

Purpose: We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1 15 haplotype in healthy volunteers.

Methods: In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n = 6), with CYP2C19 1/1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n = 4), with CYP2C19 EM and homozygous (n = 3) or heterozygous for SLCO1B1 15 (n = 1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3-14 and twice-daily oral doses of 500 mg clarithromycin on study days 11-14.

Clarithromycin substantially increases steady-state bosentan exposure in healthy volunteers.

Aims: The aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion-transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of CYP2C9 and SLCO1B1 (encoding for OATP1B1) genotypes and their combination.

Methods: We assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug.

Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity.

Purpose: The aim of this clinical study was to investigate a previously proposed mechanism of ketoconazole-mediated inhibition of cytochrome P450 3A (CYP3A) induction.

Methods: A two-phase, randomized, cross-over, open, mono-centre trial was carried out. Participants received ketoconazole and St John's wort for 8 days to study the proposed suppression of St John's wort-mediated induction of CYP3A at the transcriptional level.

Proposal of a new limited sampling strategy to predict CYP3A activity using a partial AUC of midazolam.

Purpose: Midazolam metabolic clearance to 1'-hydroxymidazolam is an accurate measure of CYP3A activity which requires extensive plasma and urine sampling. The objective of this study was to find a new limited sampling strategy (LSS) to predict midazolam metabolic clearance to 1'-hydroxymidazolam and subsequently CYP3A activity in an easy and reliable way, reducing costs and labour.

Methods: The development of this LSS is based on data from an in vivo drug-drug interaction study carried out in our clinical research unit.

Pharmacokinetics and pharmacodynamics of antimicrobial drugs.

Background: Antimicrobial drugs exhibit different characteristics in their correlation between antimicrobial drug concentrations and effects on microorganisms. These correlations have been studied using different approaches including in vitro analyses with constant and fluctuating concentrations and in vivo analyses involving animals and humans. Mathematical analysis includes correlation of pharmacokinetic-pharmacodynamic (PK-PD) indices to an outcome parameter.

Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation.

Variation in the tryptophan hydroxylase-2 gene (TPH2) coding for the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain modulates responses of limbic circuits to emotional stimuli and has been linked to a spectrum of clinical populations characterized by emotional dysregulation. Here, we tested a set of common single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of TPH2 for association with personality traits and with risk for personality disorders in two cohorts comprising of 336 healthy individuals and 420 patients with personality disorders. Personality dimensions were assessed by the Tridimensional Personality Questionnaire (TPQ) and the revised NEO Personality Inventory (NEO-PI-R).