How to Successfully Generate an Alternative Approach to a Thorough QT Study: GLPG1972 as an Example.

During development of a drug, the requirement of evaluating the proarrhythmic risk and delayed repolarization needs to be fulfilled. Would it be possible to create an alternative to a thorough QT (TQT) study or is there a need to perform a dedicated TQT study? How is an alternative approach generated, what information is available, and which instructions are considered missing today to generate such an approach? This tutorial describes the considerations and path followed to create an early and feasible alternative to a TQT study using experience-based insights from a successful application to the US Food and Drug Administration for GLPG1972, an ADAMTS-5 inhibitor, and discusses the approach used in light of the current guidelines and literature.

Phase 1 and 2 Randomized Clinical Studies Determine Lack of Efficacy for Anti-IL-17C Antibody MOR106 in Moderate-Severe Atopic Dermatitis.

Interleukin 17C (IL-17C) modulates epithelial inflammation and has a possible role in atopic dermatitis (AD) pathology. Four randomized clinical studies (Phase 1 and 2) investigated the safety, tolerability, efficacy, and pharmacokinetic profile of the anti-IL-17C monoclonal antibody MOR106 for up to 12 weeks (NCT03568071: n = 207 adults with moderate-severe AD; NCT03689829 Part 1: n = 32 healthy males; NCT03689829 Part 2: n = 44 adults with moderate-severe AD; and NCT03864627: n = 76 adults with moderate-severe AD). In these studies, MOR106 was either administered intravenously (i.v.) every 2 or 4 weeks at doses between 1-10 mg/kg, or subcutaneously (s.c.), either as a single dose or doses every 2 weeks at 320 mg. Overall, MOR106 was well-tolerated, and the safety profile was consistent with monoclonal antibodies approved for AD. Bioavailability following s.c. dosing was 55%, and steady-state drug levels were reached at 2-4 weeks. Ongoing studies were terminated following a futility analysis of the Phase 2 placebo-controlled dose-finding study (NCT03568071) due to a low probability for achieving the primary efficacy endpoint. Cumulatively, MOR106 demonstrated ineffectiveness for the treatment of AD, but its safety and pharmacokinetic characteristics warrant further drug development in other indications. Funding: sponsored by Galapagos NV; funded by Novartis AG.

Safety, Pharmacokinetics, and Pharmacodynamics of the ADAMTS-5 Inhibitor GLPG1972/S201086 in Healthy Volunteers and Participants With Osteoarthritis of the Knee or Hip.

GLPG1972/S201086 is a disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5) inhibitor in development as an osteoarthritis disease-modifying therapy. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics (turnover of plasma/serum ARGS-aggrecan neoepitope fragments [ARGS]) of GLPG1972 in 3 randomized, double-blind, placebo-controlled phase 1 trials. Study A, a first-in-human trial of single (≤2100 mg [fasted] and 300 mg [fed]) and multiple (≤1050 mg once daily [fed]; 14 days) ascending oral (solution) doses, investigated GLPG1972 in healthy men (N = 41; NCT02612246). Study B investigated multiple ascending oral (tablet) doses of GLPG1972 (≤300 mg once daily [fed]; 4 weeks) in male and female participants with osteoarthritis (N = 30; NCT03311009). Study C investigated single (Japanese: ≤1500 mg; White: 300 mg [fasted]) and multiple (Japanese, ≤1050 mg once daily; White, 300 mg once daily [fed]; 14 days) ascending oral (tablet) doses of GLPG1972 in healthy Japanese and White men (N = 88). The pharmacokinetic profile of GLPG1972 was similar between healthy participants and participants with osteoarthritis, with low to moderate interindividual variability. GLPG1972 was rapidly absorbed (median time to maximum concentration, 4 hours), and eliminated with a mean apparent terminal elimination half-life of ≈10 hours. Steady state was achieved within 2 days of dosing, with minimal accumulation. Steady-state plasma exposure after 300 mg of GLPG1972 showed no or minor differences between populations. Area under the plasma concentration-time curve (56.8-67.6 µg · h/mL) and time to maximum concentration (4 hours) were similar between studies. Urinary excretion of GLPG1972 (24 hours) was low (<11%). Multiple dosing significantly reduced ARGS levels vs baseline at all time points for all doses vs placebo. GLPG1972 was generally well tolerated at all doses.

The pharmacokinetics, safety, and tolerability of mirabegron in children and adolescents with neurogenic detrusor overactivity or idiopathic overactive bladder and development of a population pharmacokinetic model-based pediatric dose estimation.

INTRODUCTION: Mirabegron, a selective ß3-adrenoreceptor agonist, is a well-established alternative to antimuscarinics in adults with overactive bladder (OAB) symptoms and is under development for use in pediatric patients. Understanding drug pharmacokinetics (PK) in pediatric patients is needed to determine appropriate dosing. Conducting these studies is ethically complex, particularly as regulatory guidance requires that PK is assessed in pediatric patients with a therapeutic need for the drug. It is also vital to evaluate the safety/tolerability and palatability/acceptability of pediatric formulations. PURPOSE: The purpose of the study was to characterize the PK of mirabegron in pediatric patients with neurogenic detrusor overactivity or idiopathic OAB, to provide a basis for a weight-based dosing algorithm, and to evaluate the safety, tolerability, and palatability/acceptability of the formulations. MATERIALS AND METHODS: A preliminary population PK model constructed from adult data with allometric scaling was used to predict single weight-adjusted mirabegron doses. This was developed to achieve exposures in pediatric patients in two phase 1 studies that were consistent with steady state in adults following once-daily 25 mg ('low dose') and 50 mg ('high dose') dosing. In study 1, adolescents (12-<18 years) and children (5-<12 years) received a single tablet under fed or fasted conditions. In study 2, children (3-<12 years) received a single oral suspension dose under fed conditions. The PK data were used to assess the predictive value of the preliminary PK model and to update it to analyze mirabegron PK in pediatric patients. The safety/tolerability and palatability/acceptability of the formulations were evaluated. RESULTS: Forty-three patients comprised six study cohorts: adolescents, low-dose tablets, fed (n = 7); children, low-dose tablets, fed (n = 7); adolescents, high-dose tablets, fed (n = 8); children, high-dose tablets, fed (n = 6); children, high-dose tablets, fasted (n = 6); and children, high-dose oral suspension, fed (n = 9). The population PK model-based doses for tablets and oral suspension achieved exposures that were typically consistent with steady state in adults. The final population PK model was used to describe the PK for mirabegron in pediatric patients (Table). Both formulations were well tolerated, and there were no reports of bad taste or swallowing difficulties for the tablets, although some found the oral suspension unpleasant. CONCLUSIONS: The single, weight-adjusted pediatric mirabegron doses were successfully predicted by population PK modeling to achieve drug exposures comparable with steady state in adults. The finalized PK model used to characterize the pediatric PK of mirabegron will be utilized to develop a weight-based dosing algorithm. The single mirabegron doses were well tolerated.

A Cocktail Interaction Study Evaluating the Drug-Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels.

ASP8477 (molecular weight 325.36 g/mol) is a fatty acid amide hydrolase inhibitor intended for the treatment of neuropathic pain. Results from in vitro studies indicated that ASP8477 is a direct inhibitor of cytochrome P450 (CYP) 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes at expected efficacious concentrations, with the strongest effect on CYP2C19; a phase 1 study confirmed ASP8477 to be a CYP2C19 inhibitor. To further evaluate the interaction potential of ASP8477, a cocktail interaction study was performed using the probe substrates of the validated Inje cocktail containing losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). Because ASP8477 shows nonlinear pharmacokinetics, 3 doses (20, 60, and 100 mg) were evaluated. This study revealed changes in exposure (area under the concentration-time curve) of the probe substrates after treatment with 20, 60, and 100 mg ASP8477, respectively, compared with substrates alone with geometric mean ratios of: midazolam, 119%, 151%, and 158%; losartan, 107%, 144%, and 190%; omeprazole, 213%, 456%, and 610%; and dextromethorphan, 138%, 340%, and 555% (with increasing doses, respectively). Overall, ASP8477 was a weak inhibitor for CYP3A4 and CYP2C9, a moderate to strong inhibitor for CYP2C19, and a weak to strong inhibitor for CYP2D6, with doses from 20 to 100 mg. This study confirmed that the Inje cocktail approach was able to detect relevant drug-drug interactions impacting further development of ASP8477 and future therapeutic use. With the approach used here, the inhibiting effect of a perpetrator drug on different CYP enzymes can be evaluated, and at different doses, thereby supporting dose recommendations for potential interactions.

Extrapolation of praziquantel pharmacokinetics to a pediatric population: a cautionary tale.

L-praziquantel (PZQ) pharmacokinetic data were analyzed from two relative bioavailability Phase 1 studies in adult, healthy subjects with two new oral dispersion tablet (ODT) formulations of L-PZQ administered under various combinations of co-administration with food, water, and/or crushing. Linear mixed effects models adequately characterized the noncompartmental estimates of the pharmacokinetic profiles in both studies. Dose, food, and formulation were found to significantly affect L-PZQ exposure in both studies. The model for AUC was then extrapolated to children 2-5 years old accounting for enzyme maturation and weight. The predicted exposures were compared to an external Phase 1 study conducted by the Swiss Tropical and Public Health Institute using a currently marketed formulation (Cesol 600 mg immediate-release tablets) and found to be substantially lower than observed. A root cause analysis was completed to identify the reason for failure of the models. Various scenarios were proposed and tested. Two possible reasons for the failure were identified. One reason was that the model did not account for the reduced hepatic clearance seen in patients compared to the healthy volunteer population used to build the model. The second possible reason was that PZQ absorption appears sensitive to meal composition and the model did not account for differences in meals between a standardized Phase 1 unit and clinical sites in Africa. Further studies are needed to confirm our hypotheses.

A Phase I, Randomized, Double-Blind, Laser-Evoked Potential Study to Evaluate the Analgesic/Antihyperalgesic Effect of ASP9226, a State-Dependent N-Type Voltage-Gated Calcium Channel Inhibitor, in Healthy Male Subjects.

Objective: Evaluate the analgesic/antihyperalgesic effects of ASP9226, a state-dependent N-type voltage-gated calcium channel inhibitor, in healthy male subjects. Design: Randomized, double-blind, double-dummy, placebo- and active comparator-controlled crossover study. Setting: HPR Dr. Schaffler GmbH, Munich, Germany. Subject: Healthy male subjects aged 18-55 years. Methods: Twenty-four eligible subjects were randomly assigned to one of four treatment sequences and received single doses of ASP9226 (30 mg or 50 mg), pregabalin (150 mg), or placebo during four treatment periods. Laser-evoked potentials (LEP) and postlaser pain visual analog scales (VAS) on capsaicin-treated skin were assessed during main assessment days (the first day of each study period). Primary and secondary end points were the differences in LEP N2-P2 peak-to-peak (PtP) amplitudes and VAS score, respectively, in all subjects. Results: Overall, treatment with pregabalin resulted in a significantly lower LEP N2-P2 PtP amplitude vs placebo (-3.30 µV, P < 0.0001). There were no clinically relevant differences in N2-P2 PtP amplitudes between placebo and either ASP9226 dose (-0.31 µV and -0.27 µV). Furthermore, subjects reported significantly lower VAS pain scores with pregabalin vs placebo (-9.90%, P < 0.0001) in contrast to ASP9226 30 mg (-2.1%) and ASP9226 50 mg (1.2%) vs placebo. Subgroup analysis of LEP and VAS pain in participants with positive prestudy capsaicin response (n = 13) were in keeping with results in all subjects. Conclusions: ASP9226 was well tolerated; however, there was no improvement in LEP and VAS pain scores with ASP9226 at either dose vs placebo.

A Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Phase I Study of Analgesic/Antihyperalgesic Properties of ASP8477, a Fatty Acid Amide Hydrolase Inhibitor, in Healthy Female Subjects.

Objectives: To evaluate the analgesic/antihyperalgesic effect of ASP8477. Design: Randomized, double-blind, double-dummy, cross-over, placebo- and active comparator-controlled study. Setting: HPR Dr. Schaffler GmbH, Munich, Germany. Subjects: Healthy female subjects aged 18-65 years. Methods: Eligible subjects were randomly assigned to one of six treatment sequences and received multiple ascending doses of ASP8477, duloxetine, and placebo over three treatment periods (each consisting of 21-day dosing separated by 14-day washout periods). On the last day of each dose level, laser evoked potentials (LEPs) and visual analog scales (VAS pain) on capsaicin-treated skin at baseline and at multiple postdose time points were assessed. The primary end point was the difference in LEP N2-P2 peak-to-peak (PtP) amplitudes for ASP8477 100 mg vs placebo. Results: Twenty-five subjects were randomized. In all subjects, LEP N2-P2 PtP amplitudes were numerically lower for ASP8477 100 mg vs placebo (P = 0.0721); in subjects who demonstrated positive capsaicin skin effects, a greater mean difference of -2.24 µV (P = 0.0146) was observed. Across all doses, LEP N2-P2 PtP amplitudes were lower for duloxetine compared with ASP8477 (mean difference -3.80 µV; P < 0.0001) or placebo (mean difference -5.21 µV; P < 0.0001). The effect of ASP8477 (all doses) on down-scoring the VAS pain score was significant compared with placebo (mean difference -2.55%; P < 0.0007). Conclusions: ASP8477 was well tolerated in this study. Analysis of all subjects did not demonstrate a significant difference in LEP for ASP8477 100 mg over placebo but did in subjects who demonstrated positive capsaicin skin effects.

Translational PK-PD modeling in pain.

The current gap between animal research and clinical development of analgesic drugs presents a challenge for the application of translational PK-PD modeling and simulation. First, animal pain models lack predictive and construct validity to accurately reflect human pain etiologies and, secondly, clinical pain is a multidimensional sensory experience that can't always be captured by objective and robust measures. These challenges complicate the use of translational PK-PD modeling to project PK-PD data generated in preclinical species to a plausible range of clinical doses. To date only a few drug targets identified in animal studies have shown to be successful in the clinic. PK-PD modeling of biomarkers collected during the early phase of clinical development can bridge animal and clinical pain research. For drugs with novel mechanism of actions understanding of the target pharmacology is essential in order to increase the success of clinical development. There is a specific interest in the application of human pain models that can mimic different aspects of acute/chronic pain symptoms and serves as link between animal and clinical pain research. In early clinical development the main objective of PK-PD modeling is to characterize the relationship between target site binding and downstream biomarkers that have a potential link to the clinical endpoint (e.g. readouts from the human pain models) so as to facilitate the selection of doses for proof of concept studies. In patient studies, the role of PK-PD modeling and simulation is to characterize and confirm patient populations in terms of responder profiles with the aim to find the right dose for the right patient.

Pharmacodynamic analysis of the analgesic effect of capsaicin 8% patch (Qutenza™) in diabetic neuropathic pain patients: detection of distinct response groups.

Treatment of chronic pain is associated with high variability in the response to pharmacological interventions. A mathematical pharmacodynamic model was developed to quantify the magnitude and onset/offset times of effect of a single capsaicin 8% patch application in the treatment of painful diabetic peripheral neuropathy in 91 patients. In addition, a mixture model was applied to objectively match patterns in pain-associated behavior. The model identified four distinct subgroups that responded differently to treatment: 3.3% of patients (subgroup 1) showed worsening of pain; 31% (subgroup 2) showed no change; 32% (subgroup 3) showed a quick reduction in pain that reached a nadir in week 3, followed by a slow return towards baseline (16% ± 6% pain reduction in week 12); 34% (subgroup 4) showed a quick reduction in pain that persisted (70% ± 5% reduction in week 12). The estimate of the response-onset rate constant, obtained for subgroups 1, 3, and 4, was 0.76 ± 0.12 week(-1) (median ± SE), indicating that every 0.91 weeks the pain score reduces or increases by 50% relative to the score of the previous week (= t½). The response-offset rate constant could be determined for subgroup 3 only and was 0.09 ± 0.04 week(-1) (t½ 7.8 weeks). The analysis allowed separation of a heterogeneous neuropathic pain population into four homogenous subgroups with distinct behaviors in response to treatment with capsaicin. It is argued that this model-based approach may have added value in analyzing longitudinal chronic pain data and allows optimization of treatment algorithms for patients suffering from chronic pain conditions.

Sugammadex is cleared rapidly and primarily unchanged via renal excretion.

Sugammadex is a modified γ-cyclodextrin which rapidly reverses rocuronium-and vecuronium-induced neuromuscular blockade. Previous studies suggest that sugammadex is mostly excreted unchanged via the kidneys. This single-center, open-label, non-randomized study used (14)C-labeled sugammadex to further investigate the excretion, metabolic and pharmacokinetic (PK) profiles of sugammadex in six healthy male volunteers. (14)C-labeled sugammadex 4 mg/kg (0.025 MBq/kg of (14)C-radioactivity) was administered as a single intravenous bolus. Blood, urine, feces and exhaled air samples were collected at pre-defined intervals for assessment of sugammadex by liquid chromatography-mass spectrometry (LC-MS) and for radioactivity measurements. Adverse events were also assessed. Excretion of sugammadex was rapid with ∼70% of the dose excreted within 6 h and ∼90% within 24 h. Less than 0.02% of radioactivity was excreted in feces or exhaled air. Ninety-five percent of the radioactivity detected in urine could be attributed to sugammadex, as determined by LC-MS, suggesting very limited metabolism of sugammadex. LC-MS analysis of plasma samples found that sugammadex accounted for 100% of total (14)C-radioactivity in the plasma. In general, PK parameters determined from radioactivity and sugammadex plasma concentrations were very similar. Any adverse events were of mild-to-moderate intensity, and judged unrelated to sugammadex. These findings demonstrate that sugammadex is cleared rapidly, almost exclusively via the kidney, with minimal or no metabolism.

Design, synthesis and structure-activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate.

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.

Safety, tolerability and pharmacokinetics of sugammadex using single high doses (up to 96 mg/kg) in healthy adult subjects: a randomized, double-blind, crossover, placebo-controlled, single-centre study.

BACKGROUND AND OBJECTIVE: Sugammadex facilitates rapid reversal of rocuronium- and vecuronium-induced neuromuscular blockade. This study aimed to evaluate the safety, tolerability and pharmacokinetics of high doses of sugammadex (up to 96 mg/kg) in healthy subjects. METHODS: In this randomized, double-blind, crossover, placebo-controlled, single-centre study, 13 healthy adults were scheduled to receive three single intravenous doses of sugammadex in ascending order (32, 64 and 96 mg/kg) and placebo (interspersed between sugammadex doses), each separated by a 1-week washout period. Subjects were randomized to one of four treatment sequences, receiving doses as constant rate infusions over 5 minutes. Safety was assessed by adverse events, 12-lead ECGs, vital signs, and blood and urine laboratory parameters; pharmacokinetics were evaluated from blood and urine sugammadex concentrations. RESULTS: Sugammadex was well tolerated in 12 of the 13 subjects, with adverse events being generally mild, of limited duration and more frequent at higher doses. The most common adverse event was dysgeusia; there were no serious adverse events. One subject was withdrawn from the study after experiencing several adverse events following first exposure to sugammadex, related to a probable hypersensitivity reaction to sugammadex. Pharmacokinetics were dose linear over the dose range studied (32-96 mg/kg), and 90-93% of the sugammadex dose was excreted unchanged in urine within 48 hours. CONCLUSION: High doses of sugammadex (up to 96 mg/kg) were well tolerated in 12 of the 13 subjects. One male subject experienced several adverse events associated with a probable hypersensitivity reaction to sugammadex. Pharmacokinetics were dose linear over the range 32-96 mg/kg, with elimination predominantly via the renal route.

Pharmacodynamic and pharmacokinetic effects of the intravenous CB1 receptor agonist Org 26828 in healthy male volunteers.

An ideal drug for outpatient treatments under conscious sedation would have both sedative and analgesic properties. CB1/CB2 agonists are expected to have sedative, amnestic, analgesic and anti-emetic properties. The main objective of this first study in humans was to assess the sedative properties of intravenous Org 26828. In addition, pharmacokinetics, amnestic properties, postural stability, and behavioural and cardiovascular effects were studied. Midazolam intravenous 0.1 mg/kg and placebo were used as controls. The pharmacokinetic parameters (Cmax and AUC0-inf) of the main metabolite Org 26761 were proportional to dose. No effects were observed after doses up to 0.3 µg/kg of Org 26828. Dose-related effects were observed at higher doses. Although subjects reported subjective sedation after administration of Org 26828 at 3 and 6 µg/kg, the observed sedation was considerably less than after midazolam. Doses higher than the maximum tolerated dose of 1 µg/kg of Org 26828 caused unpleasant central nervous system effects (anxiety, paranoia, hallucinations). Therefore, Org 26828 is not suitable for providing sedation for outpatient surgical procedures.