Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects.

AIMS: This investigation characterised tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 antibody TAK-079. METHODS: A randomised, double-blind, placebo-controlled trial of a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of TAK-079 at escalating doses in healthy subjects (n = 74), who were followed for 92 days postexposure. RESULTS: TAK-079 was well tolerated. All adverse events were mild or moderate. There were no withdrawals, infusion, or injection site reactions over the tested i.v. and s.c. doses up to 0.06 and 0.6 mg kg-1 , respectively. At higher doses, transient cytokine level increases, following i.v. administration, coincided with reduction in CD38-expressing cells; clinical symptoms included mild pyrexia, headache, and postural hypotension. Following an i.v. infusion of 0.06 mg kg-1 TAK-079, maximum observed serum concentration (Cmax ) was 100.4 (%CV: 52) ng mL-1 , time to Cmax was the end of infusion and natural killer (NK_ cells were reduced 93.8 (±8.5) % from baseline levels. Following a s.c. injection of 0.6 mg kg-1 TAK-079, Cmax was 23.0 (%CV: 67) ng mL-1 with time to Cmax of 24 (range 7.98-96.02) hours, and plasmablasts were subsequently reduced 93.4 (±8.8) % from predose levels. Serum immunoglobulin (Ig)M, IgA and IgG levels were reduced by 15-60% and had not returned to baseline levels within 78 days after administration at ≥0.3 mg kg-1 s.c. Reductions in NK cells at 0.6 mg kg-1 s.c. were approximately 2-3 times more durable than at 0.06 mg kg-1 i.v. CONCLUSIONS: TAK-079 was well tolerated and s.c. administration elicited more durable reductions in plasmablasts and NK cells. This plasmacytolytic profile could be useful for treating disorders caused by plasma or NK cells, malignant counterparts, and/or pathogenic antibodies.

Benchmarking renin suppression and blood pressure reduction of direct renin inhibitor imarikiren through quantitative systems pharmacology modeling.

Multiple classes of antihypertensive drugs inhibit components of the renin-angiotensin-aldosterone system (RAAS). The primary physiological effector of the RAAS is angiotensin II (AngII) bound to the AT1 receptor (AT1-bound AngII). There is a strong non-linear feedback from AT1-bound AngII on renin secretion. Since AT1-bound AngII is not readily measured experimentally, plasma renin concentration (PRC) and/or activity (PRA) are typically measured to indicate RAAS suppression. We investigated the RAAS suppression of imarikiren hydrochloride (TAK-272; SCO-272), a direct renin inhibitor currently under clinical development. We employed a previously developed quantitative system pharmacology (QSP) model to benchmark renin suppression and blood pressure regulation with imarikiren compared to other RAAS therapies. A pharmacokinetic (PK) model of imarikiren was linked with the existing QSP model, which consists of a mechanistic representation of the RAAS pathway coupled with a model of blood pressure regulation and volume homeostasis. The PK and pharmacodynamic effects of imarikiren were calibrated by fitting drug concentration, PRA, and PRC data, and trough AT1-bound AngII suppression was simulated. We also prospectively simulated expected mean arterial pressure reduction in a cohort of hypertensive virtual patients. These predictions were benchmarked against predictions for several other (previously calibrated) RAAS monotherapies and dual-RAAS therapies. Our analysis indicates that low doses (5-10 mg) of imarikiren are comparable to current RAAS therapies, and at higher doses (25-200 mg), RAAS suppression may be equivalent to existing dual-RAAS combinations (at registered doses). This study illustrates application of QSP modeling to predict phase II endpoints from phase I data.

Utility of a population pharmacokinetic meta analysis during the approval process of teduglutide for the treatment of short bowel syndrome.

OBJECTIVE: Teduglutide is a recombinant analogue of human glucagonlike peptide-2 (GLP-2) that was recently approved by the US and European regulatory agencies FDA and EMA for the treatment of short bowel syndrome (SBS). The objectives of this work were, firstly, to develop a population pharmacokinetic (popPK) model based on the available PK data of the entire clinical development program and, secondly, to utilize the model for the justification of the proposed dosing regimen. The exploratory analysis was based on a previously established structural PK model and focused primarily on the investigation of covariate effects. RESULTS: The plasma concentrationtime profiles of teduglutide after subcutaneous application were adequately described by a 1-compartment model with first order absorption and elimination. The area under the curve (AUC) was lower for male subjects, for subjects with higher creatinine clearance, for overweight subjects, and for SBS patients. However, except for subjects with severe renal impairment no clinically relevant effects on AUC were identified. CONCLUSION: Our model-based analysis supports the approved dose adjustment for SBS patients with and without renal impairments maintaining the exposure in a value range with acceptable variance for the target population.

Population pharmacokinetics, enzyme occupancy, and pharmacodynamic modeling of soticlestat in patients with developmental and epileptic encephalopathies.

Soticlestat (TAK-935) is a first-in-class, selective inhibitor of cholesterol 24-hydroxylase (CH24H) under phase III development for the treatment of the developmental and epileptic encephalopathies (DEEs), Dravet syndrome (DS), and Lennox-Gastaut syndrome (LGS). A previous model characterized the pharmacokinetics (PKs), CH24H enzyme occupancy (EO), and pharmacodynamics (PDs) of soticlestat in healthy volunteers. The present study extended this original model for patients with DEEs and investigated sources of variability. Model-based simulations were carried out to optimize dosing strategies for use in clinical trials. Data from eight phase I and II trials of healthy volunteers or patients with DEEs receiving oral soticlestat 15-1350 mg were included, encompassing 218 individuals for population PK (PopPK) analyses and 306 individuals for PK/PD analyses. Dosing strategies were identified through model-based simulations. The final mixed-effect PopPK/EO/PD model consisted of a two-compartment PK model and an effect-site compartment in the PK/EO model; soticlestat concentrations at the effect site were linked to 24S-hydroxycholesterol plasma concentrations using a semimechanistic inhibitory indirect response model. Covariates were included to account for sources of variability. Pediatric dosing strategies were developed for four body weight bands (10 to <15, 15 to <30, 30 to <45, and 45-100 kg) to account for covariate effects by body weight. The final PopPK and PK/EO/PD models accurately described PK, EO, and PD profiles of soticlestat in healthy volunteers and patients with DEEs. Covariate analyses and model-based simulations facilitated optimization of phase III trial dosing strategies for patients with DS or LGS.

Pharmacokinetics of teduglutide in subjects with renal impairment.

PURPOSE: Teduglutide is a recombinant analogue of human glucagon-like peptide-2 that has recently been approved for the treatment of short bowel syndrome in adults. This study was designed to study the influence of renal function and age on teduglutide pharmacokinetics. METHODS: This was an open-label study with six parallel groups (6 subjects each). Three groups with renal impairment (moderate, severe and end-stage renal disease) were compared to healthy subjects with normal renal function, which were matched to the renal-impaired subjects with respect to demographics. At least two elderly subjects (≥65 years) were enrolled per group. A single dose of 10 mg teduglutide was subcutaneously administered to each subject. Teduglutide plasma concentrations were measured using a validated liquid chromatography method with tandem mass spectrometric detection, and the primary pharmacokinetic variables (AUCinf and Cmax) were calculated. RESULTS: Area under the concentration versus time curve extrapolated to infinity (AUCinf) and maximum plasma concentration (Cmax) of teduglutide in subjects with end-stage renal disease were approximately 2.59- and 2.08-fold higher, respectively, than those of healthy subjects. The AUCinf and Cmax were also slightly higher in subjects with moderate and severe renal impairment. Comparison of healthy subjects aged <65 years with healthy elderly subjects revealed very similar pharmacokinetics in both subgroups. CONCLUSIONS: In our study population, the primary pharmacokinetic parameters of teduglutide increased with increased severity of renal impairment. These results suggest that the daily dose of teduglutide should be reduced by 50 % in patients with moderate and severe renal impairment and end-stage disease. We found no effect of age on the pharmacokinetics of teduglutide in healthy subjects. The treatment was well tolerated, and there were no safety concerns.

Application of population pharmacokinetic modeling to explore the impact of alternative roflumilast dosing regimens on tolerability.

OBJECTIVE: Roflumilast is the first phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and history of exacerbations. In clinical practice, side effects such as diarrhea appear to be somewhat more frequent in patients than that observed in clinical trials. We hypothesize that if patients could take a reduced dose for the first few weeks of therapy, the incidence of adverse events (AEs) could be reduced. METHODS: We used previously reported population pharmacokinetic/ pharmacodynamic modeling to simulate three dosing scenarios of roflumilast: 500 µ once daily (OD) (approved dose), 250 µ OD and 500 µ every other day (EoD). RESULTS: These models predicted that the 250 µ and EoD regimens were associated with lower plasma concentrations, lower total PDE4 inhibition, and lower incidence of diarrhea, nausea, and headache, versus the 500 µ OD dose. CONCLUSIONS: Reduction of roflumilast dose in the first few weeks of therapy may be able to reduce the incidence of treatment-related AEs. Clearly, modeling provides only the basis for hypothesis generation, and must be supported with clinical evidence from carefully designed trials.

A translational pharmacokinetic/pharmacodynamic approach supports optimal vonoprazan dosing for erosive oesophagitis and Helicobacter pylori infection.

BACKGROUND: Treatment of acid-related disorders relies on gastric acid suppression. The percentage of time intragastric pH is >4 (pH >4 holding time ratio [HTR]) is important for healing erosive oesophagitis; and the pH >6 HTR is critical for eradication of Helicobacter pylori infection, as bacterial replication is active and antibiotic effectiveness is optimised. Vonoprazan, a potassium-competitive acid blocker approved in the USA and other countries, suppresses gastric acid secretion in a predictable, rapid and consistent manner, extended over prolonged periods. AIM: To explore the relationship between vonoprazan exposure and pH HTR through a pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS: We pooled data from Phase 1 studies with intragastric pH measurements. Pharmacokinetic profiles were predicted for study participants using an existing population pharmacokinetic model. Pharmacokinetic and pharmacodynamic data were merged, and three direct-link PK/PD models were derived and used to simulate pH HTRs with between-participant variability for pH >4, >5 and >6, for vonoprazan doses of 20 mg once and twice daily. RESULTS: We used data from five Phase 1 studies to derive the PK/PD model. These included 245 participants (95.1% male, 50.6% Japanese and 49.4% non-Asian). Pre-dose, the mean pH >4 HTR was 6.4%, pH >5 3.2% and pH >6 1.2%. After 7 days of dosing, simulations predicted pH >4 HTRs of 89.7% and 98.1%, and pH >6 HTRs of 53.1% and 75.3%, for vonoprazan 20 mg once and twice daily, respectively. CONCLUSIONS: Vonoprazan 20 mg once- and twice-daily dosing demonstrated high, dose-dependent, 24-hour intragastric acid control in this PK/PD model, supporting clinical efficacy data in patients with acid-related disorders.

Population pharmacokinetics, enzyme occupancy, and 24S-hydroxycholesterol modeling of soticlestat, a novel cholesterol 24-hydroxylase inhibitor, in healthy adults.

Soticlestat is a first-in-class, selective inhibitor of cholesterol 24-hydroxylase (CH24H), which catabolizes cholesterol to 24S-hydroxycholesterol (24HC) in the brain, in phase III development for Dravet syndrome and Lennox-Gastaut syndrome treatment. This study aimed to develop a model of soticlestat pharmacokinetics (PKs) and pharmacodynamics (PDs) using 24HC plasma concentrations and CH24H enzyme occupancy (EO) time profiles. Subsequently, model-based simulations were conducted to identify dosing strategies for phase II trials in children and adults with developmental and epileptic encephalopathies (DEEs). Four phase I trials of healthy adults involving oral administration of soticlestat 15-1350 mg were used to develop the mixed-effect population PK/EO/PD model. The population PK analysis utilized 1727 observations (104 individuals), PK/EO analysis utilized 20 observations (11 individuals), and PK/PD analysis utilized 2270 observations (99 individuals). Optimal dosing strategies were identified from model-based PK, EO, and PD simulations. The PK/EO/PD model described the observed data well and comprised a two-compartment model with dose as a covariate on peripheral volume, linear elimination, and intercompartmental clearance. Transit and effect-site compartments were included to accommodate different dosage forms and the delay between plasma drug concentrations and EO. Model-based simulations indicated that soticlestat 100-300 mg twice daily may be an optimal adult dosing regimen with weight-adjusted pediatric dosing strategies identified for evaluation in phase II trials. The population PK/EO/PD model provided understanding of the soticlestat PK/PD relationship with partial delineation of sources of variability, and identified dosing strategies for phase II trials of children and adults with DEEs.

Single-dose and multi-dose delivery systems for intranasal fentanyl spray are bioequivalent as demonstrated in a replicate pharmacokinetic study.

BACKGROUND: Intranasal fentanyl spray (INFS, Instanyl®) was developed to treat cancer patients with Breakthrough Pain (BTP). INFS is delivered via a multi-dose delivery system (MDS) that is available in various dose strengths. The aim of this study was to demonstrate the pharmacokinetic bioequivalence of INFS single dose delivery system (SDS) in relation to the currently marketed MDS device. METHODS: In a randomized, single-center, single-dose, open label, comparative, four-period, two-sequence, replicate cross-over study, 48 healthy subjects (24 male and 24 female, mean age of 28.1 years, mean bodyweight 69.8 kg) received 200 µg/100 µl fentanyl administered via SDS and via MDS in one of two alternating treatment sequences. Naltrexone was given to all subjects to prevent potential fentanyl adverse drug reactions. Blood samples were frequently taken up to 72 hours post INFS administration and analyzed by liquid chromatography with tandem mass spectrometric detection. Primary pharmacokinetic parameters were area under the curve extrapolated to infinity (AUC0-∞) and peak plasma concentration (Cmax). Statistical analyses of the primary pharmacokinetic parameters were performed using a linear mixed effect model applied to the natural log-transformed data. RESULTS: Healthy subjects showed very similar plasma concentration over time profiles for both delivery systems. The mean fentanyl Cmax and AUC0-∞ values for SDS and MDS were 948 pg/ml, 949 pg/ml and 4,439 pg×h/ml, 4,489 pg×h/ml. respectively. Point estimates (and 90% confidence intervals) for AUC and Cmax were 0.97 (0.93 - 1.02) and 1.00 (0.92 - 1.09) and therefore in the bioequivalence range of 0.80 - 1.25. CONCLUSIONS: Results of this study show that SDS and MDS met the pre-defined regulatory criteria for bioequivalence. Safety profiles were consistent between both devices and no safety concerns were identified with INFS administered in combination with oral naltrexone.

Population pharmacokinetic meta-analysis of intranasal fentanyl spray as a means to enrich pharmacokinetic information for patients with cancer breakthrough pain.

BACKGROUND: The development of intranasal fentanyl (INFS) aimed for a rapid treatment of breakthrough pain (BTP) in cancer patients. The pharmacokinetics (PK) of INFS was well characterized in healthy subjects, while PK investigations in cancer patients are limited. OBJECTIVES: The objective was to develop a population PK model for fentanyl in volunteers and patients following INFS administration, to evaluate the influence of potential covariates and to simulate the exposure of fentanyl after repeated dosing in cancer patients. METHODS: PK data from ten clinical trials were used for model development. The final model was validated with nonparametric bootstrap and visual predictive check. In addition, the secondary PK parameters (AUC0-tlast, Cmax, tmax) of a separate validation data set of INFS were predicted and compared to noncompartmental analysis results. Afterwards, repeated dose PK profiles in cancer patients were simulated. RESULTS: Plasma profiles after INFS administration were best described by a three-compartment model. Significant covariate relationships were identified for naltrexone and oxymetazoline co-treatment. Influences of body weight, BMI, sex and cancer patient as subject type were considered not to be clinically relevant. PK parameters for subpopulations of cancer patients were derived. Steady state simulations revealed that an extension from the current SmPC scenario to 6 pain episodes per day would yield similar Cmax values. CONCLUSIONS: A robust population PK model for INFS was developed. The model enhances the understanding of fentanyl PK after INFS dosing in cancer patients with BTP, a population for whom real-life data would be very hard to obtain.

Multi-response model for rheumatoid arthritis based on delay differential equations in collagen-induced arthritic mice treated with an anti-GM-CSF antibody.

Collagen-induced arthritis (CIA) in mice is an experimental model for rheumatoid arthritis, a human chronic inflammatory destructive disease. The therapeutic effect of neutralizing the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) by an antibody was examined in the mouse disease in a view of deriving a pharmacokinetic/pharmacodynamic (PKPD) model. In CIA mice the development of disease is measured by a total arthritic score (TAS) and an ankylosis score (AKS). We present a multi-response PKPD model which describes the time course of the unperturbed and perturbed TAS and AKS. The antibody acts directly on GM-CSF by binding to it. Therefore, a compartment for the cytokine GM-CSF is an essential component of the mathematical model. This compartment drives the disease development in the PKPD model. Different known properties of arthritis development in the CIA model are included in the PKPD model. Firstly, the inflammation, driven by GM-CSF, dominates at the beginning of the disease and decreases after some time. Secondly, a destructive (ankylosis) part evolves in the TAS that is delayed in time. In order to model these two properties a delay differential equation was used. The PKPD model was applied to different experiments with doses ranging from 0.1 to 100 mg/kg. The influence of the drug was modeled by a non-linear approach. The final mathematical model consists of three differential equations representing the compartments for GM-CSF, inflammation and destruction. Our mathematical model described well all available dosing schedules by a simultaneous fit. We also present an equivalent and easy reformulation as ordinary differential equation which grants the use of standard PKPD software.

A Population Pharmacokinetic Model of Vonoprazan: Evaluating the Effects of Race, Disease Status, and Other Covariates on Exposure.

Vonoprazan, a potassium-competitive acid blocker, is under investigation in the United States and Europe for the treatment of erosive esophagitis and Helicobacter pylori infection. Population pharmacokinetic (popPK) analysis allows the identification of factors that could affect drug exposure in population subgroups. Here, we report a popPK model based on pooled data sets of available pharmacokinetic (PK) studies in healthy volunteers and patients with gastroesophageal reflux disease, including erosive esophagitis, from Asia and Europe. This model was used to evaluate the impact of different covariates, including race and disease status, on vonoprazan exposure. We analyzed PK data from 746 patients and 410 healthy volunteers from 15 clinical trials using a nonlinear mixed-effects approach to develop the popPK model. Model development focused on characterizing and quantifying the effects of clinical covariates of race (Asian vs non-Asian) and disease status (gastroesophageal reflux disease vs healthy volunteers) on vonoprazan exposure. Identified clinical covariates included fed/fasting status, race, sex, disease status, weight, serum creatinine, and age. The impact of variations in these clinical covariates on exposure to vonoprazan was smaller than the effect of halving or doubling the dose. PK parameters were similar in Asian and non-Asian populations. Variations in weight, age, and race are not predicted to have a clinically relevant impact on vonoprazan exposure or safety and require no changes in vonoprazan dosing. The limited impact of race on exposure suggests that efficacy and safety data for vonoprazan in Asian populations are translatable to non-Asian populations.

Application of a patient-centered reverse translational systems-based approach to understand mechanisms of an adverse drug reaction of immune checkpoint inhibitors.

Immunotherapy became a key pillar of cancer therapeutics with the approvals of ipilimumab, nivolumab, and pembrolizumab, which inhibit either cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1) that are negative regulators of T-cell activation. However, boosting T-cell activation is often accompanied by autoimmunity, leading to adverse drug reactions (ADRs), including high grade 3-4 colitis and its severe complications whose prevalence may reach 14% for combination checkpoint inhibitors. In this research, we investigated how mechanistic differences between anti-CTLA-4 (ipilimumab) and anti-PD-1 (nivolumab and pembrolizumab) affect colitis, a general class toxicity. The data analytical platform Molecular Health Effect was utilized to map population ADR data from the US Food and Drug Administration (FDA) Adverse Event Reporting System to chemical and biological databases for hypothesis generation regarding the underlying molecular mechanisms causing colitis. Disproportionality analysis was used to assess the statistical relevance between adverse events of interest and molecular causation. We verified that the anti-CTLA-4 drug is associated with an approximately three-fold higher proportional reporting ratio associated with colitis than those of the anti-PD-1 drugs. The signal of the molecular mechanisms, including signaling pathways of inflammatory cytokines, was statistically insignificant to test the hypothesis that the severer rate of colitis associated with ipilimumab would be due to a greater magnitude of T-cell activation as a result of earlier response of the anti-CTLA-4 drug in the immune response. This patient-centered systems-based approach provides an exploratory process to better understand drug pair adverse events at pathway and target levels through reverse translation from postmarket surveillance safety reports.

A case study of a patient-centered reverse translational systems-based approach to understand adverse event profiles in drug development.

Adverse drug reactions (ADRs) of targeted therapy drugs (TTDs) are frequently unexpected and long-term toxicities detract from exceptional efficacy of new TTDs. In this proof-of-concept study, we explored how molecular causation involved in trastuzumab-induced cardiotoxicity changes when trastuzumab was given in combination with doxorubicin, tamoxifen, paroxetine, or lapatinib. The data analytical platform Molecular Health Effect was utilized to map population ADR data from the US Food and Drug Administration (FDA) Adverse Event Reporting System to chemical and biological databases (such as UniProt and Reactome), for hypothesis generation regarding the underlying molecular mechanisms causing cardiotoxicity. Disproportionality analysis was used to assess the statistical relevance between adverse events of interest and molecular causation. Literature search was performed to compare the established hypotheses to published experimental findings. We found that the combination therapy of trastuzumab and doxorubicin may affect mitochondrial dysfunction in cardiomyocytes through different molecular pathways such as BCL-X and PGC-1α proteins, leading to a synergistic effect of cardiotoxicity. We found, on the other hand, that trastuzumab-induced cardiotoxicity would be diminished by concomitant use of tamoxifen, paroxetine, and/or lapatinib. Tamoxifen and paroxetine may cause less cardiotoxicity through an increase in antioxidant activities, such as glutathione conjugation. Lapatinib may decrease the apoptotic effects in cardiomyocytes by altering the effects of trastuzumab on BCL-X proteins. This patient-centered systems-based approach provides, based on the trastuzumab-induced ADR cardiotoxicity, an example of how to apply reverse translation to investigate ADRs at the molecular pathway and target level to understand the causality and prevalence during drug development of novel therapeutics.

No relevant cardiac, pharmacokinetic or safety interactions between roflumilast and inhaled formoterol in healthy subjects: an open-label, randomised, actively controlled study.

BACKGROUND: Roflumilast is an oral, selective phosphodiesterase 4 inhibitor with anti-inflammatory effects in chronic obstructive pulmonary disease (COPD). The addition of roflumilast to long-acting bronchodilators improves lung function in patients with moderate-to-severe COPD. The present study investigated drug-drug interaction effects between inhaled formoterol and oral roflumilast. METHODS: This was a single-centre (investigational clinic), open, randomised, multiple-dose, parallel-group study. In Regimen A, healthy men were treated with roflumilast (500 µg tablet once daily; Day 2-18) and concomitant formoterol (24 µg twice daily; Day 12-18). In Regimen B, healthy men were treated with formoterol (24 µg twice daily; Day 2-18) and concomitant roflumilast (500 µg once daily; Day 9-18). Steady-state plasma pharmacokinetics of roflumilast, roflumilast N-oxide and/or formoterol (Cmax and AUC0-τ) as well as pharmacodynamics - blood pressure, transthoracic impedance cardiography (ZCG), 12-lead digital electrocardiography, peripheral blood eosinophils, and serum glucose and potassium concentrations - were evaluated through Day 1 (baseline), Day 8 (Regimen B: formoterol alone) or Day 11 (Regimen A: roflumilast alone), and Day 18 (Regimen A and B: roflumilast plus formoterol). Blood and urine samples were taken for safety assessment at screening, pharmacokinetic profiling days and Day 19. Adverse events were monitored throughout the study. RESULTS: Of the 27 subjects enrolled, 24 were evaluable (12 in each regimen). No relevant pharmacokinetic interactions occurred. Neither roflumilast nor formoterol were associated with significant changes in cardiovascular parameters as measured by ZCG, and these parameters were not affected during concomitant administration. Formoterol was associated with a slight increase in heart rate and a corresponding shortening of the QT interval, without changes in the heart rate-corrected QTc interval. There were small effects on the other pharmacodynamic assessments when roflumilast and formoterol were administered individually, but no interactions or safety concerns were seen after concomitant administration. No severe or serious adverse events were reported, and no adverse events led to premature study discontinuation. CONCLUSIONS: No clinically relevant pharmacokinetic or pharmacodynamic interactions were found when oral roflumilast was administered concomitantly with inhaled formoterol, including no effect on cardiac repolarisation. Roflumilast was well tolerated.

Pharmacology, clinical efficacy, and tolerability of phosphodiesterase-4 inhibitors: impact of human pharmacokinetics.

Since more than two decades anti-inflammatory effects of inhibitors of phosphodiesterase-4 have been described in numerous cellular and animal studies and were finally confirmed in clinical trials. The path from an early, pioneering study with Ro20-1724 showing reduction of psoriatric plaque size in 1979 to modern PDE4 inhibitors such as oral apremilast in development for psoriasis, the inhaled PDE4 inhibitor GSK256066 in development for asthma and COPD and finally roflumilast, the first PDE4 inhibitor approved and currently marketed as an oral, once-daily remedy for severe COPD was marked by large progress in chemical optimization based on improved understanding of PDE4 biology and drug-like properties determining the appropriate pharmacokinetic profile. In this chapter aspects of the pharmacology and clinical efficacy of PDE4 inhibitors, which have been in clinical development over the years are summarized with specific emphasis on their clinical pharmacokinetic properties.

The targeted oral, once-daily phosphodiesterase 4 inhibitor roflumilast and the leukotriene receptor antagonist montelukast do not exhibit significant pharmacokinetic interactions.

This nonrandomized, fixed-sequence, 3-period study investigated potential pharmacokinetic interactions between the leukotriene receptor antagonist montelukast, approved for the treatment of asthma, and roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor in clinical development for asthma and chronic obstructive pulmonary disease. Pharmacokinetic interactions are of interest because both drugs may be coadministered and share a common metabolic pathway via cytochrome P450 3A. Single-dose montelukast (10 mg, po) was administered alone in period 1, followed by repeated once-daily roflumilast alone (500 microg, po) for 12 days (period 2). In period 3, 500 microg qd roflumilast was coadministered with 10 mg qd montelukast for 8 days. Different pharmacokinetic parameters were evaluated for montelukast alone, for steady-state roflumilast and its pharmacologically active metabolite roflumilast N-oxide alone, for single-dose montelukast when coadministered with steady-state roflumilast, and for steady-state roflumilast and its N-oxide metabolite when coadministered with steady-state montelukast. The AUC and Cmax of montelukast were modestly increased by 9% and 8%, respectively, when single-dose montelukast was coadministered with steady-state roflumilast. The pharmacokinetics of roflumilast and roflumilast N-oxide in steady state remained unchanged when repeat-dose montelukast was coadministered at steady-state. Concomitant administration of both drugs was well tolerated. These findings suggest that no dose adjustment is warranted for either drug when roflumilast and montelukast are coadministered.

Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects.

AIMS: To evaluate the effect of co-administration of rifampicin, an inducer of cytochrome P450 (CYP)3A4, on the pharmacokinetics of roflumilast and roflumilast N-oxide. Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor, being developed for the treatment of chronic obstructive pulmonary disease. Roflumilast is metabolized by CYP3A4 and CYP1A2, with further involvement of CYP2C19 and extrahepatic CYP1A1. In vivo, roflumilast N-oxide contributes >90% to the total PDE4 inhibitory activity. METHODS: Sixteen healthy male subjects were enrolled in an open-label, three-period, fixed-sequence study. They received a single oral dose of roflumilast 500 microg on days 1 and 12 and repeated oral doses of rifampicin 600 mg once daily on days 5-15. Plasma concentrations of roflumilast and roflumilast N-oxide were measured for up to 96 h. Test/Reference ratios and 90% confidence intervals (CIs) of geometric means for AUC and C(max) of roflumilast and roflumilast N-oxide and for oral apparent clearance (CL/F) of roflumilast were estimated. RESULTS: During the steady-state of rifampicin, the AUC(0-infinity) of roflumilast decreased by 80% (point estimate 0.21; 90% CI 0.16, 0.27); C(max) by 68% (0.32; CI 0.26, 0.39); for roflumilast N-oxide, the AUC(0-infinity) decreased by 56% (0.44; CI 0.36, 0.55); C(max) increased by 30% (1.30; 1.15, 1.48); total PDE4 inhibitory activity decreased by 58% (0.42; 0.38, 0.48). CONCLUSIONS: Co-administration of rifampicin and roflumilast led to a reduction in total PDE4 inhibitory activity of roflumilast by about 58%. The use of potent cytochrome P450 inducers may reduce the therapeutic effect of roflumilast.

Modeling of tumor growth and anticancer effects of combination therapy.

Combination therapies are widely used in the treatment of patients with cancer. Selecting synergistic combination strategies is a great challenge during early drug development. Here, we present a pharmacokinetic/pharmacodynamic (PK/PD) model with a smooth nonlinear growth function to characterize and quantify anticancer effect of combination therapies using time-dependent data. To describe the pharmacological effect of combination therapy, an interaction term was introduced into a semi-mechanistic anticancer PK/PD model. This approach enables testing of a pharmacological hypothesis with respect to an anticipated pharmacological synergy of drug combinations, such as an assumed pharmacological synergy of complementary inhibition of a particular signaling pathway. The model was applied to three real data sets derived from preclinical screening experiments using xenograft mice. The suggested model fitted well the observed data from mono- to combination-therapy and allowed physiologically meaningful interpretation of the experiments. The tested drug combinations were assessed for their ability to act as synergistic modulators of tumor growth inhibition by the interaction parameter psi. The presented approach has practical implications because it can be applied to standard xenograft experiments and may assist in the selection of both optimal drug combinations and administration schedules. The unique feature of the presented approach is the ability to characterize the nature of combined drug interaction as well as to quantify the intensity of such interactions by assessing the time course of combined drug effect.

What Can Be Learned From Crowdsourced Population Asparagus Urinary Odor Kinetics?

Asparagus consumption is associated with the production of malodorous urine. Interindividual variability was previously characterized by an American Society for Clinical Pharmacology and Therapeutics crowdsourced study. To further characterize urinary odor kinetics, we conducted a study with consenting participants from Takeda Pharmaceutical International Company. The participants were randomized to consume a specified number of asparagus spears and asked to record urine odor. A kinetic-pharmacodynamic model characterized the data from both the newly conducted Takeda study (N = 42) and the previously analyzed American Society for Clinical Pharmacology and Therapeutics studies (total N = 139). The updated model included the identification of an absorption process with a half-life of 25 minutes. We estimated the elimination half-life of the asparagus effect on malodorous urine to be 7.2 hours, which was 44% longer in our study. We built on previous experience using an improved R-Shiny app for conducting the crowdsourcing experiment, further demonstrating the utility of this population kinetics approach in organizational and educational settings.