Pharmacodynamics, pharmacokinetics and CYP3A4 interaction potential of the selective P2X3 receptor antagonist filapixant: A randomized multiple ascending-dose study in healthy young men.

AIMS: We report on investigations exploring the P2X3-receptor antagonist filapixant's effect on taste perception and cough-reflex sensitivity and describe its pharmacokinetics, including its CYP3A4-interaction potential. METHODS: In a randomized, placebo-controlled, double-blind study, 3 × 12 healthy men (18-45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2 weeks. A single dose of midazolam (1 mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste-strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments. RESULTS: Taste disturbances were observed mainly in the 250-mg group: six of nine participants (67%) in this group reported hypo- or dysgeusia in the questionnaire; eight participants (89%) reported taste-related adverse events. Five participants (56%) had a decrease in overall taste-strips-test scores ≥2 points (point estimate -1.1 points, 90% confidence interval [-3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co-administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration-time curve ratios and 90% confidence intervals were within 80-125%. No serious or severe adverse events were reported. CONCLUSIONS: Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor-selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough-challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential.

Proposal for defining the relevance of drug accumulation derived from single dose study data for modified release dosage forms.

Recently, the European Medicines Agency (EMA) published the new draft guideline on the pharmacokinetic and clinical evaluation of modified release (MR) formulations. The draft guideline contains the new requirement of performing multiple dose (MD) bioequivalence studies, in the case when the MR formulation is expected to show 'relevant' drug accumulation at steady state (SS). This new requirement reveals three fundamental issues, which are discussed in the current work: first, measurement for the extent of drug accumulation (MEDA) predicted from single dose (SD) study data; second, its relationship with the percentage residual area under the plasma concentration-time curve (AUC) outside the dosing interval (τ) after SD administration, %AUC(τ-∞)SD ; and third, the rationale for a threshold of %AUC(τ-∞)SD that predicts 'relevant' drug accumulation at SS. This work revealed that the accumulation ratio RA,AUC , derived from the ratio of the time-averaged plasma concentrations during τ at SS and after SD administration, respectively, is the 'preferred' MEDA for MR formulations. A causal relationship was derived between %AUC(τ-∞)SD and RA,AUC , which is valid for any drug (product) that shows (dose- and time-) linear pharmacokinetics regardless of the shape of the plasma concentration-time curve. Considering AUC thresholds from other guidelines together with the causal relationship between %AUC(τ-∞)SD and RA,AUC indicates that values of %AUC(τ-∞)SD ≤ 20%, resulting in RA,AUC ≤ 1.25, can be considered as leading to non-relevant drug accumulation. Hence, the authors suggest that 20% for %AUC(τ-∞)SD is a reasonable threshold and selection criterion between SD or MD study designs for bioequivalence studies of new MR formulations.

Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.

INTRODUCTION: BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa. OBJECTIVE: This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period. METHODS: Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated. RESULTS: Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed. CONCLUSIONS: The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required. CLINICAL TRIAL REGISTRATION: NCT03373422 (date registered: November 23, 2017).

Novel aldo-keto reductase 1C3 inhibitor affects androgen metabolism but not ovarian function in healthy women: a phase 1 study.

OBJECTIVE: Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been proposed for treatment of endometriosis and polycystic ovary syndrome. Clinical biomarkers of target engagement, which can greatly facilitate drug development, have not yet been described for AKR1C3 inhibitors. Here, we analyzed pharmacodynamic data from a phase 1 study with a new selective AKR1C3 inhibitor, BAY1128688, to identify response biomarkers and assess effects on ovarian function. DESIGN: In a multiple-ascending-dose placebo-controlled study, 33 postmenopausal women received BAY1128688 (3, 30, or 90 mg once daily or 60 mg twice daily) or placebo for 14 days. Eighteen premenopausal women received 60 mg BAY1128688 once or twice daily for 28 days. METHODS: We measured 17 serum steroids by liquid chromatography-tandem mass spectrometry, alongside analysis of pharmacokinetics, menstrual cyclicity, and safety parameters. RESULTS: In both study populations, we observed substantial, dose-dependent increases in circulating concentrations of the inactive androgen metabolite androsterone and minor increases in circulating etiocholanolone and dihydrotestosterone concentrations. In premenopausal women, androsterone concentrations increased 2.95-fold on average (95% confidence interval: 0.35-3.55) during once- or twice-daily treatment. Note, no concomitant changes in serum 17ß-estradiol and progesterone were observed, and menstrual cyclicity and ovarian function were not altered by the treatment. CONCLUSIONS: Serum androsterone was identified as a robust response biomarker for AKR1C3 inhibitor treatment in women. Aldo-keto reductase 1C3 inhibitor administration for 4 weeks did not affect ovarian function.ClinicalTrials.gov Identifier: NCT02434640; EudraCT Number: 2014-005298-36.

Safety, Pharmacodynamics, and Pharmacokinetics of P2X3 Receptor Antagonist Eliapixant (BAY 1817080) in Healthy Subjects: Double-Blind Randomized Study.

BACKGROUND AND OBJECTIVE: There is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers. METHODS: We conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant. RESULTS: Peak plasma concentrations of eliapixant were reached 3-4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak-trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events. CONCLUSIONS: Eliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017).

There are few effective treatments for patients with a long-term (chronic) cough. It is thought that chronic cough is caused by nerves becoming oversensitive, wrongly causing a cough when there is no need. We tested a new drug called eliapixant in 47 healthy men. Eliapixant reduces the excessive nerve signaling responsible for chronic cough. We looked for side effects of eliapixant and measured how it behaves in the body. In particular we looked for side effects relating to the sense of taste because gefapixant, a similar drug to eliapixant, can affect taste. Participants took one of four eliapixant doses or a placebo twice daily for 2 weeks. The highest levels of eliapixant in the blood were seen 3­4 h after taking the drug, and stable concentrations were seen after about 6 days. At the two highest doses, eliapixant reached concentrations in the body that should be high enough to work in patients with chronic cough. Side effects were generally similar between eliapixant and placebo. Taste-related side effects were mild and went away without needing treatment. The positive results of this study meant that eliapixant could be tested in patients with chronic cough.

Quantitative Systems Pharmacology Approaches for Immuno-Oncology: Adding Virtual Patients to the Development Paradigm.

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies. However, the current drug-development approach of exploiting a vast number of possible combination targets and dosing regimens has proven to be challenging and is arguably inefficient. In particular, the unprecedented number of clinical trials testing different combinations may no longer be sustainable by the population of available patients. Further development in IO requires a step change in selection and validation of candidate therapies to decrease development attrition rate and limit the number of clinical trials. Quantitative systems pharmacology (QSP) proposes to tackle this challenge through mechanistic modeling and simulation. Compounds' pharmacokinetics, target binding, and mechanisms of action as well as existing knowledge on the underlying tumor and immune system biology are described by quantitative, dynamic models aiming to predict clinical results for novel combinations. Here, we review the current QSP approaches, the legacy of mathematical models available to quantitative clinical pharmacologists describing interaction between tumor and immune system, and the recent development of IO QSP platform models. We argue that QSP and virtual patients can be integrated as a new tool in existing IO drug development approaches to increase the efficiency and effectiveness of the search for novel combination therapies.

In vitro pharmacodynamic models to determine the effect of antibacterial drugs.

In vitro pharmacodynamic (PD) models are used to obtain useful quantitative information on the effect of either single drugs or drug combinations against bacteria. This review provides an overview of in vitro PD models and their experimental implementation. Models are categorized on the basis of whether the drug concentration remains constant or changes and whether there is a loss of bacteria from the system. Further subdifferentiation is based on whether bacterial loss involves dilution of the medium or is associated with dialysis or diffusion. For comprehension of the underlying principles, experimental settings are simplified and schematically illustrated, including the simulations of various in vivo routes of administration. The different model types are categorized and their (dis)advantages discussed. The application of in vitro models to special organs, infections and pathogens is comprehensively presented. Finally, the relevance and perspectives of in vitro investigations in drug discovery and clinical research are elucidated and discussed.

Compliance assessment of ambulatory Alzheimer patients to aid therapeutic decisions by healthcare professionals.

BACKGROUND: Compliance represents a major determinant for the effectiveness of pharmacotherapy. Compliance reports summarising electronically compiled compliance data qualify healthcare needs and can be utilised as part of a compliance enhancing intervention. Nevertheless, evidence-based information on a sufficient level of compliance is scarce complicating the interpretation of compliance reports. The purpose of our pilot study was to determine the compliance of ambulatory Alzheimer patients to antidementia drugs under routine therapeutic use using electronic monitoring. In addition, the forgiveness of donepezil (i.e. its ability to sustain adequate pharmacological response despite suboptimal compliance) was characterised and evidence-based guidance for the interpretation of compliance reports was intended to be developed. METHODS: We determined the compliance of four different antidementia drugs by electronic monitoring in 31 patients over six months. All patients were recruited from the gerontopsychiatric clinic of a university hospital as part of a pilot study. The so called medication event monitoring system (MEMS) was employed, consisting of a vial with a microprocessor in the lid which records the time (date, hour, minute) of every opening. Daily compliance served as primary outcome measure, defined as percentage of days with correctly administered doses of medication. In addition, pharmacokinetics and pharmacodynamics of donepezil were simulated to systematically assess therapeutic undersupply also incorporating study compliance patterns. Statistical analyses were performed with SPSS and Microsoft Excel. RESULTS: Median daily compliance was 94% (range 48%-99%). Ten patients (32%) were non-compliant at least for one month. One-sixth of patients taking donepezil displayed periods of therapeutic undersupply. For 10 mg and 5 mg donepezil once-daily dosing, the estimated forgiveness of donepezil was 80% and 90% daily compliance or two and one dosage omissions at steady state, respectively. Based on the simulation findings we developed rules for the evidence-based interpretation of donepezil compliance reports. CONCLUSIONS: Compliance in ambulatory Alzheimer patients was for the first time assessed under routine conditions using electronic monitoring: On average compliance was relatively high but variable between patients. The approach of pharmacokinetic/pharmacodynamic in silico simulations was suitable to characterise the forgiveness of donepezil suggesting evidence-based recommendations for the interpretation of compliance reports.

Concentration-response studies and modelling of the pharmacodynamics of linezolid: Staphylococcus aureus versus Enterococcus faecium.

For assessing antibiotic effects, the minimum inhibitory concentration (MIC) neglects that most antibiotics display different rates of bacterial killing. Time-kill curves, on the other hand, provide details on these killing rates but their interpretation is more complex and hardly standardised. The aim of the present study was to develop an analysis method to easily compare the pharmacodynamics of linezolid (LZD) against Staphylococcus aureus and Enterococcus faecium via in vitro time-kill curve experiments and to describe it by mathematical modelling. The effect of LZD against both organisms was investigated in a static in vitro infection model using 0.5-32.0 µg/mL LZD over 24h. LZD concentrations were quantified by a validated HPLC assay. A modified sigmoidal maximum effect (Emax) pharmacokinetic/pharmacodynamic (PK/PD) model that accounts for time-dependent effects was developed in 'R'. As a continuous, growth-control-normalised pharmacodynamic measure, the relative bacterial reduction (RBR) was introduced and derived. LZD was more effective against S. aureus than against E. faecium (Emax 1.8-fold higher) at a comparable potency (EC50, 3.02 µg/mL vs. 1.80 µg/mL). The time delay of the maximum effect was predominantly observed within 6h of exposure. Model evaluation demonstrated its precision, robustness and predictive performance. In conclusion, the presented PK/PD analysis method provides quantitative measures (EC50, Emax) for the antibacterial drug effect as easy to interpret as point estimates, but more informative than the MIC since time- and concentration-dependent effects were considered. Application of the presented model developed as a flexible, robust tool in the free software 'R' appears promising.

Pharmacokinetics of the soluble guanylate cyclase activator cinaciguat in individuals with hepatic impairment.

Cinaciguat is intended for use in patients with acute decompensated heart failure. The drug is eliminated predominantly via the liver and, therefore, the potential impact of hepatic impairment on cinaciguat pharmacokinetics needs to be determined. This nonrandomized, open-label, observational study investigated the pharmacokinetics of cinaciguat in individuals with mild (Child-Pugh A; n = 8) or moderate (Child-Pugh B; n = 8) hepatic impairment and matched healthy volunteers (n = 16). An exploratory analysis of pharmacodynamic parameters was also conducted. Individuals with mild hepatic impairment and their controls received a single (4-hour) intravenous infusion of 100 µg/h cinaciguat, whereas individuals with moderate hepatic impairment and their controls received 50 µg/h. Cinaciguat was well tolerated and had a favorable safety profile. The most frequent treatment-emergent adverse events were headache (4 participants) and spontaneous penile erection (2 participants). In individuals with mild hepatic impairment, only minor increases in plasma cinaciguat concentrations and no significant differences in pharmacodynamic parameters were observed, compared with controls. Individuals with moderate hepatic impairment had a substantially higher cinaciguat exposure than controls. This higher exposure was associated with more pronounced vasodilatation. This study demonstrates that in individuals with mild hepatic impairment, individual dose adaptation may not be required.

Assessment of the effects of renal impairment on the pharmacokinetics of the soluble guanylate cyclase activator cinaciguat after a single intravenous dose.

This open-label, parallel-group, single-dose study assessed the safety and pharmacokinetics of cinaciguat, a novel soluble guanylate cyclase activator in clinical development for the treatment of acute decompensated heart failure, in individuals with mild, moderate, or severe renal impairment compared with individuals with normal renal function. Cinaciguat was administered as a 100 µg/h continuous infusion over 4 hours. Plasma concentrations were determined by high-performance liquid chromatography coupled with mass spectrometry. Renal function had only minor effects on the pharmacokinetics of cinaciguat. The apparent volume of distribution at steady state was slightly increased in individuals with renal impairment. The total body clearance from plasma showed a slight tendency to increase with progression of renal impairment, which can be explained by an increased hematocrit in individuals with renal impairment. No relevant influence was found on the terminal half-life. The fraction of cinaciguat unbound in plasma was very low (<1%) in all groups. Pharmacokinetic variability tended to be somewhat increased in individuals with renal impairment. Adverse events were mostly mild, and their incidence was similar in all groups. In conclusion, cinaciguat, a promising drug candidate for the treatment of acute decompensated heart failure, will not require dose adjustment based on renal function.

Proposal for a standardised identification of the mono-exponential terminal phase for orally administered drugs.

The area under the plasma concentration-time curve from time zero to infinity (AUC(0-inf)) is generally considered to be the most appropriate measure of total drug exposure for bioavailability/bioequivalence studies of orally administered drugs. However, the lack of a standardised method for identifying the mono-exponential terminal phase of the concentration-time curve causes variability for the estimated AUC(0-inf). The present investigation introduces a simple method, called the two times t(max) method (TTT method) to reliably identify the mono-exponential terminal phase in the case of oral administration. The new method was tested by Monte Carlo simulation in Excel and compared with the adjusted r squared algorithm (ARS algorithm) frequently used in pharmacokinetic software programs. Statistical diagnostics of three different scenarios, each with 10,000 hypothetical patients showed that the new method provided unbiased average AUC(0-inf) estimates for orally administered drugs with a monophasic concentration-time curve post maximum concentration. In addition, the TTT method generally provided more precise estimates for AUC(0-inf) compared with the ARS algorithm. It was concluded that the TTT method is a most reasonable tool to be used as a standardised method in pharmacokinetic analysis especially bioequivalence studies to reliably identify the mono-exponential terminal phase for orally administered drugs showing a monophasic concentration-time profile.