Aberrantly controlled activation of the complement system contributes to inflammatory diseases. Safety, tolerability, and pharmacokinetics of singleascending 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 (0.5-200 mg) were selected after predictions from a Complex Dedrick plot. In each group, ACT-1014-6470 or matching placebo was administered to six and two healthy male individuals under fed conditions, respectively, including a cross-over part with 10 mg administered also under fasted conditions. Pharmacokinetic blood sampling and safety assessments (adverse events, clinical laboratory, vital signs, 12-lead electrocardiogram, and QT telemetry) were performed. ACT-1014-6470 was absorbed with a time to maximum plasma concentration (t max ) of 3 h across dose levels and eliminated with a terminal half-life of 30-46 h at doses ≥ 2.5 mg. Exposure increased approximately dose proportionally. Under fed compared to fasted conditions, ACT-1014-6470 exposure was 2.2-fold higher and t max delayed by 1.5 h. Pharmacokinetic modelling predicted that twicedaily oral administration is warranted in a subsequent multiple-dose study. No clinically relevant findings were observed in safety assessments. ACT-1014-6470 was well tolerated at all doses and could provide a novel therapy with more patient-friendly administration route compared to biologicals.
Background: Voriconazole, a first-line anti-fungal drug, exhibits nonlinear pharmacokinetics together with large inter-individual variability but a narrow therapeutic range, and it markedly inhibits CYP3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and of co-administered CYP3A4 substrates.Objective: This study aimed to investigate the metabolism of voriconazole in detail to better understand doseand time-dependent alterations in the pharmacokinetics 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. Methods:In vitro assays were carried out to describe mechanism-based inactivation (MBI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time curves of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically-based pharmacokinetic (PBPK) model in PK-Sim ® . The model was evaluated quantitatively with the predicted/observed ratio of AUC, Cmax, and Ctrough, the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time profiles over the full range of recommended intravenous and oral dosage regimens. Results:The result of the IC50 shift assay indicated that voriconazole causes MBI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregate Cmax ratios from 28 evaluation datasets being within a 0.5-to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregate Cmax ratios were inside a 0.5-to 2-fold range of 44 test profiles. The model suggests that the standard maintenance dose of 200 mg bid is sufficient for CYP2C19 IMs (intermediate metabolizers: *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of >1-2 mg/L to <5-6 mg/L for trough values, while 400 mg might be more suitable for RMs (rapid metabolizers: *1/*17, *17/*17) and NMs (normal metabolizers, *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model. Conclusions: Both the in vitro assay and model-based simulations confirmed MBI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's pharmacokinetics. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management.
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. Lack of selectivity for a given enzyme/transporter and expression of the respective enzyme/transporter at several sites in the human body are the main challenges. Thus, a detailed understanding of the role of individual PKPs for the pharmacokinetics of any probe substrate is essential to allocate the effect of a perpetrator drug to a specific PKP; this is a prerequisite for reliably informed pharmacokinetic models that will allow for the quantitative prediction of perpetrator effects on therapeutic drugs, also in respective patient populations not included in DDI studies. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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 adefovirdipivoxil (OAT1; renal clearance (CL R )), 100 mg sitagliptin (OAT3; CL R ), 500 mg metformin (several renal transporters; CL R ), 2 mg pitavastatin (OATP1B1; clearance/F), and 0.5 mg digoxin (intestinal P-gp, renal P-gp, and OATP4C1; peak plasma concentration (C max ) and CL R ). Using a randomized six-period, open change-over design, single oral doses were administrated either concomitantly or separately to 24 healthy male and female volunteers. Phenotyping metrics were evaluated by noncompartmental analysis and compared between periods by the standard average bioequivalence approach (boundaries for ratios 0.80-1.25). Primary metrics supported the absence of relevant interactions, whereas secondary metrics suggested that mainly adefovir was a victim of minor drug-drug interactions (DDIs). All drugs were well tolerated. This cocktail may be another useful tool to assess transporter-based DDIs in vivo.
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