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The objective of this study was to investigate the pharmacokinetics and ex vivo pharmacodynamics of increasing doses of RWJ 67657, along with the effect of food at one dose level in a first-in-human (FIH) study. This was a placebo-controlled, double-blind, randomized trial in healthy male subjects. Subjects received increasing doses of RWJ 67657 or placebo as a single oral dose (0.25-30 mg/kg) under fasting conditions. The effect of food was investigated for the 10-mg/kg dose. Plasma concentrations of RWJ 67657 were measured over a period of 48 hours using a validated LC-MS/MS method. To evaluate the pharmacodynamics of RWJ 67657, inhibition of cytokine production was monitored from exvivo-stimulated polymorphonuclear blood cells (PBMCs). Pharmacokinetic/pharmacodynamic modeling was used to characterize the inhibitory activity of RWJ 67657. RWJ 67657 was rapidly absorbed (mean tmax = 0.6-2.5 h). The pharmacokinetics of RWJ 67657 appear to be nonlinear with respect to single-dose administration of the investigative formulation. Coadministration of food did not have a significant effect on half-life or time to peak concentration (tmax) but decreased the exposure. Mean Cmax values in the presence of food were almost 50% lower than during fasting (542 vs. 1283 ng/mL), and the AUC decreased from 2832 to 1904 ng.h/mL with food. RWJ 67657 inhibited TNF-alpha, IL-8, and IL-6 in a concentration-dependent manner with mean IC50 values of 0.18 microM, 0.04 microM, and 0.43 microM, respectively. At 20 mg/kg, the median inhibition was greater than 85%. There were no significant adverse effects associated with single doses of this drug. This study demonstrates that RWJ 67657 has acceptable safety and pharmacokinetics to warrant further investigation in a repeat-dose setting. In addition, the early determination of effect on biomarkers suggests potential efficacy in diseases mediated by proinflammatory and inflammatory cytokines. [ABSTRACT FROM AUTHOR]

The 2022 United States Food and Drug Administration (US FDA) draft guidance on diversity plan (DP), which will be implemented through the Diversity Action Plans by December 2025, under the 21st Century Cures Act, marks a pivotal effort by the FDA to ensure that registrational studies adequately reflect the target patient populations based on diversity in demographics and baseline characteristics. This white paper represents the culminated efforts of the International Consortium of Quality and Innovation (IQ) Diversity and Inclusion (D&I) Working Group (WG) to assess the implementation of the draft FDA guidance by members of the IQ consortium in the discipline of clinical pharmacology (CP). This article describes current practices in the industry and emphasizes the tools and techniques of quantitative pharmacology that can be applied to support the inclusion of a diverse population during global drug development, to support diversity and inclusion of underrepresented patient populations, in multiregional clinical trials (MRCTs). It outlines strategic and technical recommendations to integrate demographics, including age, sex/gender, race/ethnicity, and comorbidities, in multiregional phase III registrational studies, through the application of quantitative pharmacology. Finally, this article discusses the challenges faced during global drug development, which may otherwise limit the enrollment of a broader, potentially diverse population in registrational trials. Based on the outcomes of the IQ survey that provided the current awareness of diversity planning, it is envisioned that in the future, industry efforts in the inclusion of previously underrepresented populations during global drug development will culminate in drug labels that apply to the intended patient populations at the time of new drug application or biologics license application rather than through post-marketing requirements., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Pediatric data for phenylephrine, a decongestant used in cold medicines, are limited. This study characterized the pharmacokinetics and metabolism of phenylephrine HCl in children aged 2-17 years., Methods: Forty-one children experiencing nasal congestion were dosed orally with phenylephrine HCl from 2.5 to 10 mg using a modified weight-age schedule. Plasma from blood samples collected up to 4.5 h after dosing was analyzed for phenylephrine. Urine collected over 24 h was analyzed for phenylephrine and metabolites. Blood pressure and pulse were measured after each blood sampling, and electrocardiograms were recorded before and after dosing. Pharmacokinetic parameters were estimated using noncompartmental methods., Results: Mean phenylephrine total exposure (AUC ∞ ) for children aged 2-5, 6-11, and 12-17 years was 672, 830, and 1020 pg∙h/mL, and mean maximum concentration (C max ) was 477, 589, and 673 pg/mL, respectively. Times to peak concentration (T max ) ranged from 0.17 to 1.5 h, and elimination half-life (t ½,β ) was short from 1.2 to 1.6 h. Oral clearance (CL/F) increased with age, but with allometric scaling for body size, this trend reversed as scaled clearance (CL/F, scaled ) was modestly higher in youngest children. No clinically relevant changes in vital signs or electrocardiograms were observed., Conclusion: A dosing schedule with additional weight-age increments would provide more consistent systemic concentrations as children age and receive the next higher dose. No developmental delays in clearance mechanisms were apparent when oral clearance was scaled for body size. Phenylephrine pharmacokinetics and metabolism were consistent with adult data, although AUC∞ for the youngest group and C max for all pediatric groups were lower. Single doses of phenylephrine HCl were well tolerated. TRIAL REGISTRATION: Clintrials.gov NCT00762567, registered 30 September 2008., (© 2022. The Author(s).)

Background: The safety and immunogenicity of JNJ-64041809 (JNJ-809), a live-attenuated, double-deleted Listeria monocytogenes (LADD Lm)-based immunotherapy targeting 4 relevant prostate cancer antigens, was evaluated in a phase 1 study in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: Men with progressive mCRPC who had received ≥2 prior approved therapies were enrolled. Primary study objectives were to determine the recommended phase 2 dose (RP2D) and to evaluate the safety and immunogenicity of JNJ-809., Results: A total of 26 patients received JNJ-809 (1 × 10 8 CFU (n = 6); 1 × 10 9 CFU (n = 20)). No dose-limiting toxicities were reported, and 1 × 10 9 CFU was selected as the RP2D. The most common adverse events (AEs) reported were chills (92%), pyrexia (81%), and fatigue (62%). The most frequent grade ≥3 AEs were lymphopenia (27%) and hypertension (23%). Serious AEs were reported in 27% of patients including 1 patient with grade 3 intestinal obstruction. JNJ-809 transiently induced peripheral cytokines, including interferon-γ, interleukin-10, and tumor necrosis factor-α. Of the 7 patients evaluable for T cell responses at the 1 × 10 9 CFU dose, evidence of post-treatment antigenic responses were observed in 6 to the Listeria antigen listeriolysin O and in 5 to ≥1 of the 4 encoded tumor antigens. Best overall response was stable disease in 13/25 response-evaluable patients. The study was terminated early as data collected were considered sufficient to evaluate safety and immunogenicity., Conclusions: JNJ-809 has manageable safety consistent with other LADD Lm-based therapies. Limited antigen-specific immune responses were observed, which did not translate into objective clinical responses., (© 2021. The Author(s).)

We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.6 kg). Subcutaneous and intravenous DARA monotherapies were administered once every week for cycles 1-2, once every 2 weeks for cycles 3-6, and once every 4 weeks thereafter (1 cycle is 28 days). The subcutaneous DARA combination therapy was administered with the adaptation of corresponding standard-of-care regimens. PK samples were collected between cycle 1 and cycle 12. Among monotherapy studies, throughout the treatment period, subcutaneous DARA provided similar/slightly higher trough concentrations (C trough ) versus intravenous DARA, with lower maximum concentrations and smaller peak-to-trough fluctuations. The PK profile was consistent between subcutaneous DARA monotherapy and combination therapies. The exposure-response relationship between daratumumab PK and efficacy or safety end points was similar for subcutaneous and intravenous DARA. Although the ≤65-kg subgroup reported a higher incidence of neutropenia, no relationship was found between the incidence of neutropenia and exposure, which was attributed, in part, to the preexisting imbalance in neutropenia between subcutaneous DARA (45.5%) and intravenous DARA (19%) in patients ≤50 kg. A flat relationship was observed between body weight and any grade and at least grade 3 infections. The results support the DARA 1800-mg subcutaneous flat dose as an alternative to the approved intravenous DARA 16 mg/kg., (© 2020 Janssen Pharmaceuticals. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

The phase 3 COLUMBA study demonstrated noninferiority of subcutaneous daratumumab (DARA SC) to intravenous daratumumab (DARA IV) in relapsed or refractory multiple myeloma. We present a subgroup analysis of Asian patients from COLUMBA. Eligible patients had ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were double refractory. Co-primary endpoints were overall response rate (ORR) and maximum trough concentration (C trough ). Secondary endpoints included rates of infusion-related reactions, progression-free survival, and patient-reported satisfaction with therapy. Sixty-seven Asian patients (DARA SC, n = 30; DARA IV, n = 37) were randomized, including 42 Japanese patients (DARA SC, n = 18; DARA IV, n = 24). Comparable ORRs for DARA SC versus DARA IV were seen in the Asian cohort (66.7% vs 43.2%) and Japanese-only cohort (61.1% vs 54.2%), including patients weighing ≤ 65 kg. Similarity of C trough was seen in both Asian and Japanese-only cohorts; the ratio of the geometric mean of the C trough concentrations for DARA SC/DARA IV was 143.96% (90% confidence interval (CI), 112.03-185.00%) and 148.02% (90% CI, 113.32-193.34%), respectively. The Asian cohort (both treatment groups) and Japanese-only cohort (DARA SC group) experienced higher rates of grade 3/4 cytopenias compared with the global COLUMBA population, occurring predominantly in patients of low bodyweight; no patients discontinued treatment due to cytopenias. The Cancer Therapy Satisfaction Questionnaire results generally favored DARA SC. In the Asian and Japanese-only cohorts, DARA SC was comparable to DARA IV. The efficacy, pharmacokinetic, safety, and satisfaction results were generally consistent with the global COLUMBA population regardless of patient bodyweight. ClinicalTrials.gov Identifier: NCT03277105.

Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd, n = 67; D-VMP, n = 67; D-Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71·6% [90% confidence interval (CI) 61·2-80·6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88·1% (90% CI 79·5-93·9%) and 90·8% (90% CI 82·6-95·9%). With longer median follow-up for D-VMP and D-Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease-negativity (10 -5 ) rates were 16·4% and 15·4%. Infusion-related reactions across all cohorts were infrequent (≤9·0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard-of-care regimens demonstrated comparable clinical activity to DARA IV-containing regimens, with low infusion-related reaction rates and reduced administration time., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Increasingly, new drug development by major pharmaceutical companies relies on in-licensing of innovative therapies. Often there are limited data accompanying these novel entities. By focusing on scientific principles and generating key preclinical and clinical data, discovery companies can improve their valuations. From the lens of a large pharmaceutical company, we highlight key scientific aspects that are assessed to mitigate risk in valuations and deal terms. Our focus is on clinical development aspects for oncology drugs by stage of development. However, these lessons apply equally to other therapeutic areas., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Bortezomib is a first-in-class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib's benefit-risk profile. Here, we performed exposure-response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6-week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42·2 vs. 38·5 mg/m 2 ) and ALCYONE patients stayed on treatment longer (mean: 7·2 vs. 5·8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with ≥ 39·0 versus < 39·0 mg/m 2 cumulative dose (hazard ratio, 0·119; P < 0·0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab., Methods: In this ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomised, phase 3 trial, we recruited adult patients (age ≥18 years) if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66-85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration (C trough ; cycle 3, day 1 pre-dose). The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose. This trial is registered with ClinicalTrials.gov, NCT03277105., Findings: Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5-9·3), overall response and C trough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89-1·37). The geometric means ratio for C trough was 107·93% (90% CI 95·74-121·67), and the maximum C trough was 593 μg/mL (SD 306) in the subcutaneous group and 522 μg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 [13%] of 260 patients evaluable for safety in the subcutaneous group and 36 [14%] of 258 patients in the intravenous group), neutropenia (34 [13%] and 20 [8%]), and thrombocytopenia (36 [14%] and 35 [14%]). Pneumonia was the only serious adverse event in more than 2% of patients (seven [3%] in the subcutaneous group and 11 [4%] in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1])., Interpretation: Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. These data could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies., Funding: Janssen Research & Development., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the bioequivalence of norelgestromin and ethinyl estradiol (NGMN-EE) and adhesion of a transdermal contraceptive patch containing a newly sourced adhesive component (test) compared with the marketed (reference) patch., Study Design: In this randomized, double-blind, 2-way crossover study, healthy women received single 7-day application of both test and reference patches. Treatment phase included two treatment periods of 11 days each separated by a 21-day washout period starting from day of patch removal (day 8) of treatment period 1. Assessments included NGMN and EE pharmacokinetics (PK), adhesion using European Medicines Agency (EMA) 5-point scale, irritation potential and application-site reactions, and safety. Patches were bioequivalent if 90% CIs of ratios of means of test/reference for AUC 168h , AUC inf , and C ss fell within 80-125%. Patch adhesion was comparable if ratios of mean cumulative adhesion percentage values of test/reference were ≥90.0%., Results: Seventy women were randomized; 57 completed both treatments with ≥80% adhesion (score 0-1). Bioequivalence of test and reference patches was demonstrated as 90% CI of ratio of geometric means for AUC 168h , AUC inf , and C ss for NGMN and EE fell within 80-125%. Both patches had similar adhesion properties (geometric mean ratio was 100.3% [90% CI, 93.2-107.9]). Similar rates of mild-to-moderate itching (11% vs 10%) and erythema events (79% vs 74%) were reported for test and reference patches, respectively, on day 8., Conclusions: The test patch with the newly sourced adhesive component is bioequivalent to the currently marketed NGMN-EE transdermal patch and has similar adhesion and irritation potential., Implications Statement: The norelgestromin and ethinyl estradiol transdermal patch containing a newly sourced adhesive component is bioequivalent to the currently marketed patch for both active moieties. Both patches had similar adhesion, irritation potential, and safety profiles., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Dacogen, the formulated product of the pharmaceutically active agent decitabine (5 aza-2'-deoxycytidine), is approved for treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). The current analysis was performed to characterize the pharmacokinetics of decitabine in pediatric patients with AML and evaluate their consistency with the PK in adult patients. A population pharmacokinetic model was developed by pooling decitabine concentration-time data from 5 adult (AML and MDS) and 2 pediatric (AML) studies. A total of 840 concentration-time data points obtained from 71 adults and 28 pediatric subjects (1 to 16 years old) were available for analysis. A 2-compartment linear pharmacokinetic (PK) model with allometric scaling using body surface area accounting for body size adequately described the PK of decitabine. After accounting for body size, decitabine pharmacokinetics were not affected by age, sex, race, dosing regimen, renal function (creatinine clearance), bilirubin, or disease type (AML or MDS) and all PK parameters (including clearance, steady-state volume of distribution, maximum concentration, time to reach maximal concentration, and terminal half-life) were comparable between adult and pediatric patients. Simulated concentration-time profiles using the final population PK model suggested that decitabine exposure at steady state was similar in adults and pediatrics for a 20 mg/m 2 decitabine dose administered as a 1-hour infusion once daily. The current analysis suggests that decitabine PK is similar in pediatric AML patients and a combined adult AML and MDS population., (© 2018, The American College of Clinical Pharmacology.)

New drug development is both resource and time intensive, where later clinical stages result in significant costs. We analyze recent late-stage failures to identify drugs where failures result from inadequate scientific advances as well as drugs where we believe pitfalls could have been avoided. These can be broadly classified into two categories: 1) where science is mature and the failures can be avoided through rigorous and prospectively determined decision-making criteria, scientific curiosity, and discipline to follow up on emerging findings; and 2) where problems encountered in Phase 3 failures cannot be explained at this time, as the science is not sufficiently advanced and companies/investigators need to recognize the possibility of deficiency of our knowledge. Through these case studies, key themes critical for successful drug development emerge-understanding the therapeutic pathway including receptor and signaling biology, pharmacological responses related to safety and efficacy, pharmacokinetics of the drug and exposure at target site, optimum dose, and dosing regimen; and identification of patient sub-populations likely to respond and will have a favorable benefit-risk profile, design of clinical trials, and a quantitative framework that can guide data-driven decision making. It is essential that the right studies are conducted early in the development process to answer the key questions, with the emphasis on learning in the early stages of development, whereas Phase 3 should be reserved for confirming the safety and efficacy. Utilization of innovative technology in identifying patients based on molecular signature of their disease, rapid assessment of pharmacological response, mechanistic modeling of emerging data, seamless operational processes to reduce start-up and wind-down time for clinical trials through use of electronic health records and data mining, and development of novel and objective clinical efficacy endpoints are some concepts for improving the success rate.

Aims: Edoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P-glycoprotein (P-gp). Three edoxaban drug-drug interaction studies examined the effects of P-gp inhibitors with varying degrees of CYP3A4 inhibition., Methods: In each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P-gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study., Results: Coadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half-life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9-fold and peak exposure by 8.7-fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed., Conclusions: Administration of dual inhibitors of P-gp and CYP3A4 increased edoxaban exposure by less than two-fold. This effect appears to be primarily due to inhibition of P-gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects., (© 2016 Daiichi Sankyo. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Edoxaban, a once daily non-vitamin K antagonist oral anticoagulant, is a direct, selective, reversible inhibitor of factor Xa (FXa). In healthy subjects, single oral doses of edoxaban result in peak plasma concentrations within 1.0-2.0 h of administration, followed by a biphasic decline. Exposure is approximately dose proportional for once daily doses of 15-150 mg. Edoxaban is predominantly absorbed from the upper gastrointestinal tract, and oral bioavailability is approximately 62 %. Food does not affect total exposure to edoxaban. The terminal elimination half-life in healthy subjects ranges from 10 to 14 h, with minimal accumulation upon repeat once daily dosing up to doses of 120 mg. The steady-state volume of distribution is approximately 107 L, and total clearance is approximately 22 L/h; renal clearance accounts for approximately 50 % of total clearance, while metabolism and biliary secretion account for the remaining 50 %. Intrinsic factors, such as age, sex and race, do not affect edoxaban pharmacokinetics after renal function is taken into account. Oral administration of edoxaban results in rapid changes in anticoagulatory biomarkers, with peak effects on anticoagulation markers (such as anti-FXa), the prothrombin time and the activated partial thromboplastin time occurring within 1-2 h of dosing.

Background and Objectives: Edoxaban is an oral, once-daily direct factor Xa inhibitor. To support the possibility that patients may choose to switch treatment from another nonvitamin K antagonist oral anticoagulant to edoxaban, this clinical study was conducted to evaluate the pharmacokinetic and pharmacodynamic effects of edoxaban after switching from rivaroxaban or dabigatran etexilate to edoxaban., Methods: In this open-label, three-period, crossover study, healthy subjects received 3 days of edoxaban 60 mg daily, rivaroxaban 20 mg daily, or dabigatran etexilate 150 mg twice daily, followed by edoxaban 60 mg on day 4., Results: Day 4 edoxaban pharmacokinetic parameters were similar for all treatments. The peak effect of edoxaban on prothrombin time (PT) after 4 days of edoxaban only was 21.8 ± 2.46 s; after switching from rivaroxaban to edoxaban, peak effect on PT was similar at 21.8 ± 2.88 s. After switching from dabigatran etexilate to edoxaban, least squares mean activated partial thromboplastin time (aPTT) at 2 h after administration was 47.6 vs 35.0 s for edoxaban alone. The treatment difference was 12.8 s (95% confidence interval 10.5-15.1; p < 0.0001). Post hoc analysis revealed that predose aPTT was elevated on day 3 of dabigatran etexilate administration, and on day 4, indicating a carryover effect from dabigatran. All treatments were well tolerated and there were no safety concerns upon switching, with no increased risk of bleeding., Conclusions: The study results suggest that switching to edoxaban from either rivaroxaban or dabigatran etexilate at the time of the next dose is well tolerated and maintains coagulation status.

Two studies in healthy subjects assessed the absorption of edoxaban when delivered to specific locations within the gastrointestinal tract using Enterion capsules. In study 1 (single-dose, 4-way crossover), 8 participants received edoxaban 60 mg as immediate-release (IR) tablets (treatment A), as powder formulation delivered to the distal small bowel (treatment B) or ascending colon (treatment C), or as an aqueous suspension delivered to the ascending colon (treatment D). In study 2 (single-dose, 2-way crossover), 10 participants received edoxaban 30 mg as IR tablets (treatment E) or in granulate formulation with fumaric acid 50 mg, added to acidify the local gastrointestinal tract and enhance solubility, delivered to the ascending colon (treatment F). Peak and total exposure following targeted drug delivery to the distal gastrointestinal tract were significantly lower than with IR tablet delivery. In study 1, total exposure ratios of treatments B, C, and D compared with A were 14.9%, 7.9%, and 6.1%, respectively. In study 2, relative total exposure was 12.6% for treatment F despite the fumaric acid. Time to peak concentration was longer with higher variability for edoxaban delivered to the distal gastrointestinal tract compared with the IR tablet. These data indicate that edoxaban absorption occurs predominantly in the proximal small intestine., (© 2015, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Background: Edoxaban, a direct factor Xa inhibitor, is a once-daily, non-vitamin K antagonist oral anticoagulant. There is no established method to reverse the activity of non-vitamin K oral anticoagulants in cases of hemorrhage or urgent surgery. This study evaluated the ability of a 3-factor prothrombin complex concentrate (3F-PCC) to reverse the anticoagulatory effects of edoxaban., Methods: In this phase 1 study, 24 healthy subjects were randomly assigned to receive a single dose of 60 or 180mg edoxaban, followed by placebo, 25IU/kg 3F-PCC, or 50IU/kg 3F-PCC. Edoxaban pharmacokinetics and pharmacodynamics, including the primary endpoint of prothrombin time (PT) and endogenous thrombin potential (ETP), were assessed. D-dimer and prothrombin fragment 1 and 2 (F1+2) were also measured., Results: Overall, there were no apparent consistent effects of 3F-PCC on edoxaban pharmacokinetics. Administration of 3F-PCC 25 or 50IU/kg with edoxaban 60 or 180mg did not substantially accelerate the return of PT to baseline levels. However, infusion of 3F-PCC 25 and 50IU/kg did substantially accelerate return to baseline of ETP compared with placebo. D-dimer and F1+2 data did not indicate any lasting procoagulant effects of 3F-PCC infusion, although a transient increase in F1+2 was noted during and after 3F-PCC infusion. Edoxaban and 3F-PCC co-administration was well tolerated in normal healthy subjects., Conclusions: There was no apparent reversal of PT prolongation with 3F-PCC following edoxaban infusion, but ETP was completely reversed. Co-administration of 3F-PCC was well tolerated, but a dose-dependent increase in F1+2 may reflect a procoagulant risk., (Copyright © 2015. Published by Elsevier Ltd.)

Today, the majority of phase 1 dose-escalation first-in-human studies are designed as blinded, placebo-controlled protocols. First-in-human phase 1 studies are a critical component of the drug development process, but in our opinion, the additions of blinding and placebo control to these study protocols are a matter of faith without scientific support to show that the increased complexity, time, burdensome nature and expense of such additions, plus the increase in human subjects studied, are justified and useful in the drug development process. Here, we document the prevalence of such studies, review and respond to the rationalizations for such protocols and propose that the addition of blinding and placebo control to first-in-human and many other underpowered phase 1 studies is unnecessary because these additions provide little documented benefit to the drug development process., (© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Edoxaban is an oral, direct, once-daily, factor Xa inhibitor developed for stroke prevention in patients with atrial fibrillation and for the treatment and secondary prevention of recurrent thromboembolism in patients with acute symptomatic venous thromboembolism. Among elderly patients who require anticoagulation therapies, some may have end-stage renal disease (ESRD). This open-label, phase 1, randomised, two-way crossover study was conducted to evaluate the pharmacokinetics of edoxaban in 10 subjects on haemodialysis. Eligible subjects with ESRD on chronic haemodialysis received a single, oral dose of edoxaban 15 mg 2 hours (h) prior to (on-dialysis) or in between (off-dialysis) haemodialysis sessions. Haemodialysis resulted in a minor decrease in mean total exposure (AUC0-∞; 676.2 ng·h/ml) as compared with that observed in subjects off-dialysis (691.7 ng·h/ml). Mean maximum observed plasma concentration (Cmax) values were comparable between on-dialysis and off-dialysis treatments (53.3 vs 56.3 ng/ml, respectively). Mean apparent total body clearance (CL/F) values were 24.1 and 22.5 l/h during the on-dialysis and off-dialysis treatment periods, respectively. Dialyser clearance was 5.7 l/h and haemodialysis clearance was 6.1 l/h. Haemodialysis clearance was only 6.1 l/h, suggesting that it only accounts for one-fourth of the total clearance in these subjects. A single, oral dose of 15 mg of edoxaban was well tolerated by subjects with ESRD. In conclusion, based on these single-dose PK data, a supplementary dose of edoxaban may not be required following a haemodialysis session. Importantly, haemodialysis is not an effective mechanism for removal of edoxaban from the blood.

This was a double-blind, placebo-controlled, randomized, 5-period crossover study in 49 healthy subjects with a history of light (occasional) recreational stimulant use, to evaluate the abuse-related subjective effects of oral osmotic-controlled extended-release methylphenidate with comparable doses of immediate-release methylphenidate. Healthy subjects with a history of light recreational stimulant use were enrolled in the study if they demonstrated a positive response to a 20-mg dose of d-amphetamine and a negative placebo response. Enrolled subjects received single doses of placebo, 54 and 108 mg osmotic-controlled extended-release methylphenidate, and 50 and 90 mg immediate-release methylphenidate. For each treatment, pharmacokinetics, pharmacodynamics, and safety were assessed for 24 hours. Subjective data were collected through standard questionnaires and visual analog scales for positive, stimulant, negative, and other effects. Immediate-release and osmotic-controlled extended-release methylphenidate produced expected plasma concentration-time profiles of d-methylphenidate. Both doses of immediate-release methylphenidate (50 and 90 mg) produced statistically significantly higher subjective effects (eg, positive, stimulant) with respect to placebo for all measures. The higher osmotic-controlled extended-release methylphenidate dose of 108 mg also produced statistically significant differences from placebo for most measures. However, the most commonly prescribed therapeutic dose of osmotic-controlled extended-release methylphenidate (54 mg) did not produce significant differences from placebo for most measures. In addition, for comparable dose levels, osmotic-controlled extended-release methylphenidate produced lower positive and stimulant subjective effects than immediate-release methylphenidate, and low-dose immediate-release methylphenidate (50 mg) produced greater subjective effects than high-dose osmotic-controlled extended-release methylphenidate, with many effects demonstrating statistically significant differences. These data support the hypothesis that a formulation can modulate abuse potential by controlling the rate and extent of drug delivery.

The primary objective of this study was to determine if the abuse liability of methylphenidate is governed by formulation differences that affect rates of drug delivery. In this double-blind, placebo-controlled, randomized, crossover study, subjects with a history of recreational drug use received single oral doses of placebo, 60 mg of immediate-release methylphenidate (IR) and 108 mg of extended-release methylphenidate (osmotic release oral system [OROS]). Over 24 hours after dosing, blood was collected to determine plasma concentrations of methylphenidate, and subjects completed subjective assessments of abuse liability (Addiction Research Center Inventory, Drug Rating Questionnaire-Subject, and Subjective Drug Value). The abuse-related subjective effects of IR and OROS methylphenidate were statistically significantly different from placebo, confirming the overall validity of the study. Although a higher dose of OROS methylphenidate was used compared with IR methylphenidate (108 mg vs 60 mg), subjective effects were consistently lower for OROS compared with IR methylphenidate (statistically significant for 3 of 6 measures of positive effects), particularly at early time points. In general, pharmacokinetic-pharmacodynamic parameters were correlated from a poor to modest degree, with greater correlations observed for IR methylphenidate. In addition, a post hoc "qualification" method was developed, which demonstrated that pharmacological qualification might improve the assessment of subjective effects. Although requiring epidemiological confirmation, the results suggest that OROS methylphenidate, with its characteristic slow ascending plasma concentration profile, may have lower abuse potential. This conclusion is reflected by lower subjective responses during early hours as compared with the IR formulation with its rapid drug delivery and accompanying greater subjective effects.

Objective: The abuse potential of methylphenidate has been related to the drug's capacity to produce a rapid onset of blockade of the presynaptic dopamine transporter in the brain. An oral once-a-day osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would also produce a slower onset of blockade of the presynaptic dopamine transporter and would be associated with a lower risk for detection and likeability, compared to immediate-release methylphenidate., Method: Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Doses predicted to produce equivalent maximum concentration (C(max)) values were selected (40 mg of immediate-release methylphenidate and 90 mg of osmotic-release methylphenidate). Plasma d-methylphenidate levels and responses to detection/likeability questionnaire items were obtained hourly for 10 hours after administration of methylphenidate on two separate occasions for each subject. Dopamine transporter receptor occupancies were measured at hours 1, 3, 5, and 7 by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography., Results: Despite similar C(max) values for both formulations, osmotic-release methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS dopamine transporter occupancy, and no detection/likeability, compared with immediate-release methylphenidate., Conclusions: The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.

Cyclosporine and tacrolimus are substrates and potent inhibitors of the multidrug transporter, P-glycoprotein, in vitro. The authors have investigated the effect of chronic therapy with these and other immunosuppressive drugs on the expression and function of P-glycoprotein in T lymphocytes. Using a P-gp antibody, the authors studied the level of expression of P-gp in CD4 and CD8 T cells over a period of time in renal transplant patients. For comparison, a group of healthy volunteers and patients who did not receive any calcineurin inhibitors but were maintained on mycophenolate mofetil was included. The P-gp expression on lymphocytes from these two groups remained constant (over several months' time). However, patients who were started on tacrolimus or cyclosporine had an initial decline in expression of P-gp on CD4 T cells. Patients who were initiated on calcineurin therapy on day 1 posttransplant also had a decrease in expression of P-gp on CD4 T lymphocytes. This preliminary analysis suggests that the calcineurin inhibitors might be modulating the expression and function of transporters in lymphocytes, thus changing not only the drug concentration but also the apparent efficacy of these drugs. Further understanding and elucidation of such effects would be important in understanding the relationship between pharmacokinetics and pharmacodynamics of these and other drugs, especially for immunosuppressive and anti-AIDS therapy.

Purpose: The effect of drugs on P-glycoprotein (P-gp) is normally studied in transfected or overexpressing cell lines derived from tumor cells or animal tissue. We wanted to develop an assay using normal healthy human tissue to study and characterize the drug-transporter interaction., Methods: Lymphocytes were isolated from healthy human blood. The effect of inhibitors of P-gp (cyclosporine, tacrolimus, verapamil, quinidine, vinblastine) and of other transporters (indomethacin, probenecid, sulfinpyrazone) on intracellular accumulation of rhodamine 123 was evaluated by flow cytometry., Results: The efflux of rhodamine 123 was inhibited by P-gp inhibitors in a saturable, concentration-dependent manner. The potency of inhibition of P-gp was cyclosporine > tacrolimus > quinidine > verapamil > vinblastine. Vinblastine inhibited P-gp at lower concentrations, whereas at high concentrations, there was an activation of rhodamine 123 efflux from lymphocytes. The multidrug resistance associated protein (MRP) inhibitors, sulfinpyrazone and probenecid, did not have any significant effect on intracellular accumulation of rhodamine 123, but indomethacin caused a concentration-dependent increase in retention of rhodamine 123, indicating the involvement of other uncharacterized transporters., Conclusions: Lymphocytes can serve as a model tissue for studying modulation of P-gp activity by drugs. Both inhibitors and inducers of P-gp activity can be evaluated.