A combined physiologically-based pharmacokinetic and quantitative systems pharmacology model for modeling amyloid aggregation in Alzheimer's disease.

Antibody-mediated removal of aggregated ß-amyloid (Aß) is the current, most clinically advanced potential disease-modifying treatment approach for Alzheimer's disease. We describe a quantitative systems pharmacology (QSP) approach of the dynamics of Aß monomers, oligomers, protofibrils, and plaque using a detailed microscopic model of Aß40 and Aß42 aggregation and clearance of aggregated Aß by activated microglia cells, which is enhanced by the interaction of antibody-bound Aß. The model allows for the prediction of Aß positron emission tomography (PET) imaging load as measured by a standardized uptake value ratio. A physiology-based pharmacokinetic model is seamlessly integrated to describe target exposure of monoclonal antibodies and simulate dynamics of cerebrospinal fluid (CSF) and plasma biomarkers, including CSF Aß42 and plasma Aß42 /Aß40 ratio biomarkers. Apolipoprotein E genotype is implemented as a difference in microglia clearance. By incorporating antibody-bound, plaque-mediated macrophage activation in the perivascular compartment, the model also predicts the incidence of amyloid-related imaging abnormalities with edema (ARIA-E). The QSP platform is calibrated with pharmacological and clinical information on aducanumab, bapineuzumab, crenezumab, gantenerumab, lecanemab, and solanezumab, predicting adequately the change in PET imaging measured amyloid load and the changes in the plasma Aß42 /Aß40 ratio while slightly overestimating the change in CSF Aß42 . ARIA-E is well predicted for all antibodies except bapineuzumab. This QSP model could support the clinical trial design of different amyloid-modulating interventions, define optimal titration and maintenance schedules, and provide a first step to understand the variability of biomarker response in clinical practice.

Phase 1 Single Ascending and Multiple Ascending Dose Studies of Phosphodiesterase-9 Inhibitor E2027: Confirmation of Target Engagement and Selection of Phase 2 Dose in Dementia With Lewy Bodies Trial.

BACKGROUND: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase9 (PDE9) being evaluated as a treatment for dementia with Lewy bodies. METHODS: Phase 1, randomized, double-blind, single ascending dose (SAD, n=96) and multiple ascending dose (MAD, n=68) studies evaluated E2027 doses (5 to 1200 mg) in healthy subjects. The impact of age, race (Japanese/non-Japanese), and food on pharmacokinetics (PK)/pharmacodynamics were evaluated. Serial cerebrospinal fluid (CSF) samples were collected to assess the target engagement. RESULTS: E2027 PK profiles were biphasic (elimination half-life: ~30 hours. Approximately 3-fold accumulation was observed following multiple once-daily dosing. E2027 single doses of 50 to 400 mg resulted in mean maximum increases in CSF cyclic guanosine monophosphate ranging from 293% to 461% within 5.37 to 12.9 hours after dose administration to assess target engagement. Dose-response modelling of steady-state predose CSF cyclic guanosine monophosphate concentrations showed ≥200% increase from baseline is maintained with doses of ≥50 mg QD. The most common adverse events with E2027 were post-LP syndrome and back pain. PK profiles were similar between Japanese and non-Japanese. Higher exposure observed in fed versus fasted state was not considered clinically significant. PK exposure was higher in elderly subjects. CONCLUSIONS: S.E2027 was well-tolerated following single and multiple administration. E2027 achieved maximal and sustained target engagement at 50 mg QD, the dose selected for the phase 2 clinical trial.

Perampanel and pregnancy.

OBJECTIVE: The objective was to summarize pregnancy and fetal/postnatal outcomes following maternal perampanel exposure using preclinical and clinical data, and to use physiologically based pharmacokinetic (PBPK) modeling to improve understanding of perampanel pharmacokinetics (PK) during pregnancy. METHODS: Preclinical developmental studies with perampanel were conducted in pregnant rats and rabbits. Clinical data were collated from the Eisai global perampanel safety database, comprising reports of perampanel exposure during pregnancy from routine clinical settings, interventional studies, and non-interventional post-marketing studies, searched for events coded to Medical Dictionary for Regulatory Activities (MedDRA) high-level group terms of Pregnancy, Labor, Delivery, and Postpartum Conditions and/or the Standardized MedDRA Query terms of Congenital, Familiar, and Genetic Disorders. A PBPK model was used to predict clinical perampanel PK throughout pregnancy. RESULTS: Preclinical studies indicated that perampanel may be linked with post-implantation loss and/or some specific physical development delays but not fertility and early embryonic development. As of August 31, 2018, 96 pregnancies in 90 women receiving perampanel had been reported. No concomitant medications were reported in 26 (28.9%) women taking perampanel. Overall, 43 pregnancies reached full term (all normal live births), 28 did not reach term (induced abortion, n = 18; spontaneous miscarriage, n = 6; incomplete spontaneous miscarriage, n = 2; premature delivery, n = 1; stillbirth [Fallot's tetralogy], n = 1), 18 were lost to follow-up, and seven were ongoing at data cut-off. Adverse events were reported in five full-term neonates (low Apgar score, n = 2; fatal neonatal aspiration, n = 1; cystic fibrosis and congenital deafness, n = 1; poor sucking reflex and shallow breathing, n = 1). PK simulations predicted perampanel exposure decreases throughout pregnancy and is up to four- and three-fold lower towards the end of pregnancy compared with non-pregnant women for total and unbound perampanel, respectively. SIGNIFICANCE: These data provide preliminary information on perampanel use during pregnancy and should be interpreted with caution. Further outcome data are required to estimate the prevalence of adverse pregnancy outcomes with perampanel exposure.

Physiologically-based pharmacokinetic modeling to predict drug interactions of lemborexant with CYP3A inhibitors.

Lemborexant, a recently approved dual orexin receptor antagonist for treatment of adults with insomnia, is eliminated primarily by cytochrome P450 (CYP)3A metabolism. The recommended dose of lemborexant is 5 mg once per night, with a maximum recommended dose of 10 mg once daily. A physiologically-based pharmacokinetic (PBPK) model for lemborexant was developed and applied to integrate data obtained from in vivo drug-drug interaction (DDI) assessments, and to further explore lemborexant interaction with CYP3A inhibitors and inducers. The model predictions were in good agreement with observed pharmacokinetic data and with DDI results from clinical studies with CYP3A inhibitors, itraconazole and fluconazole. The model further predicted that DDI effects of weak CYP3A inhibitors (fluoxetine and ranitidine) are weak, and effects of moderate inhibitors (erythromycin and verapamil) are moderate. Based on the PBPK simulations and clinical efficacy and safety data, the maximum daily recommended lemborexant dose when administered with weak CYP3A inhibitors is 5 mg; co-administration of moderate and strong inhibitors should be avoided except in countries where 2.5 mg has been approved.

Drug-Drug Interaction Study of Benznidazole and E1224 in Healthy Male Volunteers.

E1224 is a prodrug of ravuconazole (RVZ), an antifungal drug with promising anti-Trypanosoma cruzi activity, the causative organism of Chagas disease (CD). This study was designed to assess the pharmacokinetics (PK) and safety interactions of benznidazole (BNZ), the drug of choice for treatment of CD, and E1224 in healthy volunteers. This open-label, single-center, sequential, single- and multiple-oral-dose study enrolled 28 healthy male subjects. These subjects received BNZ (2.5 mg/kg) once daily on days 1 and 9 and twice daily from day 12 to day 15 and E1224 once daily from day 4 to day 15 (loading dose of 400 mg for 3 days and maintenance dose of 100 mg for 9 days). The maximum concentration (Cmax) and area under the concentration curve from zero to infinity for BNZ were comparable, whether BNZ was given alone or with E1224 at steady state, with ratios of geometric means for BNZ-RVZ to BNZ of 0.96 and 0.83 and corresponding 90% confidence intervals (CIs) of 0.91 to 1.10 and 0.80 to 0.87, respectively. However, RVZ Cmax and area under the concentration curve from zero to 24 h increased by about 35% when concomitantly administered with BNZ at steady state (ratio of geometric means for RVZ-BNZ/RVZ of 1.31 and 1.36 and corresponding 90% CIs of 1.23 to 1.39 and 1.31 to 1.41, respectively). Both compounds were well tolerated. There were no clinically relevant safety interactions between E1224 and BZN. Given these results, coadministration of RVZ and BNZ should not require any adaptation of E1224 dosing.

Changes in perampanel levels during de-induction: Simulations following carbamazepine discontinuation.

OBJECTIVE: To evaluate the time course of changes in perampanel levels when co-administered with carbamazepine, and following carbamazepine discontinuation, using a physiologically based pharmacokinetic (PBPK) model. METHODS: The PBPK model was developed, verified using clinical PK data, and used to simulate the effect of abrupt discontinuation and down-titration (75 mg twice daily [bid]/wk) of co-administered carbamazepine 300 mg bid on the PK of perampanel once daily (qd). Perampanel dose tapering (8-4 mg) and up-titration (2-6 mg) were simulated during abrupt carbamazepine 300 mg bid discontinuation to identify a titration schedule that minimizes changes in perampanel plasma concentrations. RESULTS: The PBPK model accurately reproduced perampanel plasma concentration-time profiles from clinical studies in single- and multiple-dose regimen simulations, including multiple-dose carbamazepine co-administration. The time course of return to pre-induced perampanel levels occurred more slowly following carbamazepine down-titration (~48 days after first down-titration) vs abrupt discontinuation (~25 days). Perampanel dose tapering (8-4 mg) at abrupt carbamazepine discontinuation produced minimal changes in steady-state concentrations, which returned to the levels observed during carbamazepine co-administration in ~15 days from the time of carbamazepine discontinuation. When perampanel was up-titrated in the presence of carbamazepine, return to steady state occurred more slowly when carbamazepine was down-titrated weekly (~45 days) vs abrupt discontinuation (~24 days). CONCLUSION: This PBPK model simulated and predicted optimal perampanel dose tapering and up-titration schedules for maintaining perampanel levels during conversion to monotherapy. These results may guide physicians when managing conversion from perampanel polytherapy with concomitant enzyme-inducing anti-seizure medications to monotherapy.

Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges.

The substantial progress made in the basic sciences of the brain has yet to be adequately translated to successful clinical therapeutics to treat central nervous system (CNS) diseases. Possible explanations include the lack of quantitative and validated biomarkers, the subjective nature of many clinical endpoints, and complex pharmacokinetic/pharmacodynamic relationships, but also the possibility that highly selective drugs in the CNS do not reflect the complex interactions of different brain circuits. Although computational systems pharmacology modeling designed to capture essential components of complex biological systems has been increasingly accepted in pharmaceutical research and development for oncology, inflammation, and metabolic disorders, the uptake in the CNS field has been very modest. In this article, a cross-disciplinary group with representatives from academia, pharma, regulatory, and funding agencies make the case that the identification and exploitation of CNS therapeutic targets for drug discovery and development can benefit greatly from a system and network approach that can span the gap between molecular pathways and the neuronal circuits that ultimately regulate brain activity and behavior. The National Institute of Neurological Disorders and Stroke (NINDS), in collaboration with the National Institute on Aging (NIA), National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), and National Center for Advancing Translational Sciences (NCATS), convened a workshop to explore and evaluate the potential of a quantitative systems pharmacology (QSP) approach to CNS drug discovery and development. The objective of the workshop was to identify the challenges and opportunities of QSP as an approach to accelerate drug discovery and development in the field of CNS disorders. In particular, the workshop examined the potential for computational neuroscience to perform QSP-based interrogation of the mechanism of action for CNS diseases, along with a more accurate and comprehensive method for evaluating drug effects and optimizing the design of clinical trials. Following up on an earlier white paper on the use of QSP in general disease mechanism of action and drug discovery, this report focuses on new applications, opportunities, and the accompanying limitations of QSP as an approach to drug development in the CNS therapeutic area based on the discussions in the workshop with various stakeholders.

Applications of Quantitative Systems Pharmacology in Model-Informed Drug Discovery: Perspective on Impact and Opportunities.

Quantitative systems pharmacology (QSP) approaches have been increasingly applied in the pharmaceutical since the landmark white paper published in 2011 by a National Institutes of Health working group brought attention to the discipline. In this perspective, we discuss QSP in the context of other modeling approaches and highlight the impact of QSP across various stages of drug development and therapeutic areas. We discuss challenges to the field as well as future opportunities.

Recommendations for the Design of Clinical Drug-Drug Interaction Studies With Itraconazole Using a Mechanistic Physiologically-Based Pharmacokinetic Model.

Regulatory agencies currently recommend itraconazole (ITZ) as a strong cytochrome P450 3A (CYP3A) inhibitor for clinical drug-drug interaction (DDI) studies. This work by an International Consortium for Innovation and Quality in Pharmaceutical Development working group (WG) is to develop and verify a mechanistic ITZ physiologically-based pharmacokinetic model and provide recommendations for optimal DDI study design based on model simulations. To support model development and verification, in vitro and clinical PK data for ITZ and its metabolites were collected from WG member companies. The model predictions of ITZ DDIs with seven different CYP3A substrates were within the guest criteria for 92% of area under the concentration-time curve ratios and 95% of maximum plasma concentration ratios, thus verifying the model for DDI predictions. The verified model was used to simulate various clinical DDI study scenarios considering formulation, duration of dosing, dose regimen, and food status to recommend the optimal design for maximal inhibitory effect by ITZ.

Clinical Drug-Drug Interaction Potential of BFE1224, Prodrug of Antifungal Ravuconazole, Using Two Types of Cocktails in Healthy Subjects.

BFE1224, prodrug of ravuconazole, is a novel, once-daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug-drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2. In addition, repaglinide was separately administered to the same subjects in study 2. There were no major effects on the pharmacokinetics of CYP and transporter substrates, except for an approximate threefold increase in midazolam exposure after oral administration of BFE1224. The clinical DDIs of BFE1224 were mild for CYP3A and minor for other major CYPs (CYP1A2/2C8/2C9/2C19/2D6) as well as those of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3.

Pharmacokinetic/pharmacodynamic drug-drug interactions of avatrombopag when coadministered with dual or selective CYP2C9 and CYP3A interacting drugs.

AIMS: Avatrombopag, a thrombopoietin receptor agonist, is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A. We assessed three drug-drug interactions of avatrombopag as a victim with dual or selective CYP2C9/3A inhibitors and inducers. METHODS: This was a three-part, open-label study. Forty-eight healthy subjects received single 20 mg doses of avatrombopag alone or with one of 3 CYP2C9/3A inhibitors or inducers: fluconazole 400 mg once daily for 16 days, itraconazole 200 mg twice daily on Day 1 and 200 mg once daily on Days 2-16, or rifampicin 600 mg once daily for 16 days. Pharmacokinetics, pharmacodynamics (platelet count) and safety of avatrombopag were evaluated. RESULTS: Coadministration of a single 20-mg dose of avatrombopag with fluconazole at steady-state resulted in 2.16-fold increase of AUC of avatrombopag, prolonged terminal elimination phase half-life (from 19.7 h to 39.9 h) and led to a clinically significant increase in maximum platelet count (1.66-fold). Itraconazole had a mild increase on both avatrombopag pharmacokinetics and pharmacodynamics compared to fluconazole. Coadministration of rifampicin caused a 0.5-fold decrease in AUC and shortened terminal elimination phase half-life (from 20.3 h to 9.84 h), but has no impact on maximum platelet count. Coadministration with interacting drugs was found to be generally safe and well-tolerated. CONCLUSIONS: The results from coadministration of fluconazole or itraconazole suggest that CYP2C9 plays a more predominant role in metabolic clearance of avatrombopag than CYP3A. To achieve comparable platelet count increases when avatrombopag is coadministered with CYP3A and CYP2C9 inhibitors, an adjustment in the dose or duration of treatment is recommended, while coadministration with strong inducers is not currently recommended.

Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective.

This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.

Preclinical QSP Modeling in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape.

A cross-industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering.

Eribulin shows high concentration and long retention in xenograft tumor tissues.

PURPOSE: Eribulin, a synthetic analog of the natural product halichondrin B, is a microtubule dynamics inhibitor. In this study, we report the pharmacokinetic profiles of eribulin in mice, rats, and dogs following intravenous administrations with optimized and validated bio-analytical methods. METHODS: Eribulin was administered at 0.5 and 2 mg/kg in mice, 0.5 and 1 mg/kg in rats, and 0.08 mg/kg in dogs. Tumor and brain penetration of eribulin was also evaluated in LOX human melanoma xenograft models. Concentrations in plasma, tumor, and brain were measured by the LC-MS/MS method. RESULTS: The profiles of eribulin were characterized by extensive distribution, moderate clearance, and slow elimination in the three species. The pharmacokinetics are linear in mice and rats. In xenograft mice, the penetration into the brain was low, as expected, since eribulin is a P-glycoprotein substrate. In contrast to disposition in brain, the exposure of eribulin was approximately 20-30 times higher in tumor than that in plasma and half-lives were 17.8-35.9 h after both single and multiple dose regimens. CONCLUSIONS: Eribulin was distributed rapidly and eliminated slowly in mice, rats, and dogs. The exposure of eribulin was approximately 20-30 times higher in tumor than in plasma in xenograft mice. These results might be caused by eribulin's mechanism of action including increased perfusion in tumor by vascular remodeling effect.

Effect of enzyme inhibition on perampanel pharmacokinetics: Why study design matters.

OBJECTIVES: Perampanel, a selective, noncompetitive AMPA receptor antagonist, is indicated as adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 12years and older. In vitro studies and Phase I trials indicate that perampanel is metabolized almost exclusively by CYP3A, with an elimination half-life (t1/2) averaging approximately 105h. Understanding of pharmacokinetic (PK) interactions-enzyme inhibition or induction-and anticipating their occurrence are important for management of patients with epilepsy. Here we report PK results from a Phase I drug-drug interaction (DDI) study (Study 005) combining perampanel with the CYP3A inhibitor ketoconazole, as well as supplementary in silico predictions further exploring this interaction. METHODS: A Phase I, randomized, open-label, two-period, two-treatment, two-way crossover study was conducted in 26 healthy adult male volunteers. Subjects were randomized to 1 of 2 treatment sequences. In one period, subjects received a single 1-mg fasting dose of perampanel (Day1); in the other period, subjects received ketoconazole 400mg once daily for 10days with a single 1-mg perampanel dose while fasting (Day3). Blood samples were drawn at multiple time points up to 288h after the perampanel dose. Pharmacokinetic parameters of perampanel were calculated by noncompartmental analysis, and safety was recorded. An integrated, physiologically based PK model built in Simcyp® provided additional insight into this interaction. Drug-drug interaction intensity was measured by the ratio of systemic exposure (area under plasma concentration-time curve [AUC]) of perampanel in the presence or absence of concomitant ketoconazole. RESULTS: Single oral doses of 1mg perampanel and once-daily oral doses of ketoconazole 400mg were safe and well tolerated. Maximum perampanel plasma concentration (Cmax) and time to Cmax showed no apparent differences when perampanel was administered alone versus with ketoconazole. Ketoconazole co-administration resulted in an approximate 20% increase in perampanel AUC (P<0.001). This increase, although statistically significant, was a<2.0-fold AUC change and alone would suggest a modest effect of ketoconazole. To further explore these results, DDI simulations were performed to query the findings and test additional study conditions. Using the actual trial conditions of Study 005, the simulations also predicted an AUC ratio increase <2-fold, providing verification of the simulation assumptions and the modest effect of ketoconazole for 10days. Simulations further suggested that an interaction effect of ketoconazole on perampanel exposure (>2-fold) of potential clinical significance could be predicted when using larger doses of ketoconazole (e.g., 200mg every 6h) coadministered for a greater time period (e.g., 30days), with AUC ratio as high as 3.36. Additionally, simulations suggested that a significant interaction with co-administration of perampanel and an inhibitor more potent than ketoconazole (such as itraconazole) could not be ruled out. CONCLUSIONS: Selecting an appropriate study design is critical to fully characterize the PK interaction for drugs such as perampanel that have a long t1/2. Although a negligible effect on perampanel PK was observed following co-administration of ketoconazole 400mg/day for 10days, this is likely due in part to the relatively brief co-administration period of ketoconazole and perampanel (<3 times the t1/2 of perampanel). While short-term administration of a CYP3A inhibitor may not significantly increase perampanel exposure, such increases may be expected following chronic and larger dosing or with a more potent inhibitor.

Translational pharmacokinetic-pharmacodynamic analysis in the pharmaceutical industry: an IQ Consortium PK-PD Discussion Group perspective.

With inadequate efficacy being the primary cause for the attrition of drug candidates in clinical development, the need to better predict clinical efficacy earlier in the drug development process has increased in importance in the pharmaceutical industry. Here, we review current applications of translational pharmacokinetic-pharmacodynamic (PK-PD) modeling of preclinical data in the pharmaceutical industry, including best practices. Preclinical translational PK-PD modeling has been used in many therapeutic areas and has been impactful to drug development. The role of preclinical translational PK-PD modeling in drug discovery and development will continue to evolve and broaden, given that its broad implementation in the pharmaceutical industry is relatively recent and many opportunities still exist for its further application.

Safety and pharmacokinetic profile of rufinamide in pediatric patients aged less than 4 years with Lennox-Gastaut syndrome: An interim analysis from a multicenter, randomized, active-controlled, open-label study.

OBJECTIVE: A good knowledge of safety and age group-specific pharmacokinetics (PK) of antiepileptic drugs (AEDs) in young pediatric patients is of great importance in clinical practice. This paper presents 6-month interim safety and PK from an ongoing 2-year open-label study (Study 303) of adjunctive rufinamide treatment in pediatric subjects ≥ 1 to < 4 years with inadequately controlled epilepsies of the Lennox-Gastaut syndrome (LGS) spectrum. METHODS: Subjects (N = 37) were randomized to either rufinamide or any other approved AED chosen by the investigator as adjunctive therapy to the subject's existing regimen of 1-3 AEDs. RESULTS: Interim safety results showed that treatment-emergent adverse events (TEAEs) were similar between the rufinamide (22 [88.0%]) and any-other-AED group (9 [81.8%]), with most events considered mild or moderate. A population PK analysis was conducted including plasma rufinamide concentrations from Study 303 and two other study populations of LGS subjects ≥ 4 years. The rufinamide PK profile was dose independent. The apparent clearance (CL/F) estimated from the PK model was 2.19 L/h; it was found to increase significantly as a function of body weight. Coadministration of valproic acid significantly decreased rufinamide CL/F. CL/F was not significantly affected by other concomitant AEDs, age, gender, race, hepatic function, or renal function. No adjustments to body weight-based rufinamide dosing in subjects ≥ 1 to < 4 years are necessary. SIGNIFICANCE: Rufinamide was safe and well tolerated in these pediatric subjects. Results from the interim analysis demonstrate that rufinamide's safety and PK profile is comparable in subjects ≥ 1 to < 4 and ≥ 4 years with LGS. CLINICAL TRIAL REGISTRATION: Study 303 (clinicaltrials.gov: NCT01405053).

Preclinical pharmacokinetic/pharmacodynamic modeling and simulation in the pharmaceutical industry: an IQ consortium survey examining the current landscape.

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.

Design, synthesis, and pharmacological evaluation of fluorinated tetrahydrouridine derivatives as inhibitors of cytidine deaminase.

Several 2'-fluorinated tetrahydrouridine derivatives were synthesized as inhibitors of cytidine deaminase (CDA). (4R)-2'-Deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine (7a) showed enhanced acid stability over tetrahydrouridine (THU) 5 at its N-glycosyl bond. As a result, compound 7a showed an improved oral pharmacokinetic profile with a higher and more reproducible plasma exposure in rhesus monkeys compared to 5. Co-administration of 7a with decitabine, a CDA substrate, boosted the plasma levels of decitabine in rhesus monkeys. These results demonstrate that compound 7a can serve as an acid-stable alternative to 5 as a pharmacoenhancer of drugs subject to CDA-mediated metabolism.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel γ-secretase modulator, E2212, in healthy human subjects.

E2212, a novel γ-secretase modulator, is under development for the treatment of Alzheimer's disease. The safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses (10-250 mg, double-blind, placebo-controlled, randomized) of E2212 were evaluated. In this phase I clinical trial, E2212 was found to be well tolerated in single doses. Maximum tolerated dose was not achieved up to 250 mg. Most AEs were mild to moderate in severity with no identifiable dose related pattern. There were no clinically significant findings on physical and ophthalmologic examinations as well as vital signs, laboratory, ECG and C-SSRS assessments. E2212 was rapidly absorbed, with median tmax values ranging from 0.5 to 1.0 h. E2212 exhibited biphasic disposition with the terminal t1/2 of 12.5-19.0 h. Renal excretion was the minor pathway for E2212 elimination. Increased PD response (reduction in plasma concentrations of Aß(x-42)) was observed with increasing doses. The maximum PD response was observed in the highest dose 250 mg cohort, with ΔAUAC(0-24 h) of 44.1% and Amax of 53.6%. These results support further clinical development of E2212.