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Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase II study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1-14 of a 3-week cycle. To confirm 200 mg/day as the recommended phase III dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure-response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100-200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure-response analyses of data from 62 patients in the phase II study showed exposure-related increases in probabilities of locoregional control at 18 months (primary end point), overall response, complete response, and the radiosensitization mechanism-related composite safety end point "mucositis and/or dysphagia" (P < 0.05). Exposure-response relationships were not discernible for 12 of 13 evaluated safety end points, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model-derived target inhibition profiles, positive exposure-efficacy relationships, and lack of discernible exposure-safety relationships for most safety end points, supports selection of xevinapant 200 mg/day on days 1-14 of a 3-week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events., (© 2023 EMD Serono and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Belzutifan (Welireg, Merck & Co., Inc., Rahway, NJ, USA) is an oral, potent inhibitor of hypoxia-inducible factor 2α, approved for the treatment of certain patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors. It is primarily metabolized by the polymorphic uridine 5'-diphospho-glucuronosyltransferase (UGT) 2B17 and cytochrome (CYP) 2C19. A population pharmacokinetic (PK) model was built, using NONMEM version 7.3, based on demographics/PK data from three clinical pharmacology (food effect, formulation bridging, and genotype/race effect) and two clinical studies (phase I dose escalation/expansion in patients with RCC and other solid tumors; phase II in patients with VHL). Median (range) age for the combined studies was 55 years (19-84) and body weight was 73.6 kg (42.1-165.8). Belzutifan plasma PK was well-characterized by a linear two-compartment model with first-order absorption and elimination. For patients with VHL, the predicted geometric mean (% coefficient of variation) apparent clearance was 7.3 L/h (51%), apparent total volume of distribution was 130 L (35%), and half-life was 12.39 h (42%). There were no clinically relevant differences in belzutifan PK based on the individual covariates of age, sex, ethnicity, race, body weight, mild/moderate renal impairment, or mild hepatic impairment. In this model, dual UGT2B17 and CYP2C19 poor metabolizers (PMs) were estimated to have a 3.2-fold higher area under the plasma concentration-time curve compared to UGT2B17 extensive metabolizer and CYP2C19 non-PM patients. This population PK analysis enabled an integrated assessment of PK characteristics with covariate effects in the overall population and subpopulations for belzutifan labeling., (© 2023 Merck Sharp & Dohme LLC. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and co-medications as covariates on sparsentan PKs. Blood samples were collected from 236 healthy volunteers, 16 subjects with hepatic impairment, and 194 primary and genetic FSGS patients enrolled in nine studies ranging from phase I to phase III. Sparsentan plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry with a lower limit of quantitation of 2 ng/mL. Modeling was conducted with the first-order conditional estimation with η-ϵ interaction (FOCE-1) method in NONMEM. A total of 20 covariates were tested using a univariate forward addition and stepwise backward elimination analysis with significance level of p < 0.01 and p < 0.001, respectively. A two-compartment model with first-order absorption and an absorption lag time with proportional plus additive residual error (2 ng/mL) described sparsentan PKs. A 32% increase of clearance due to CYP3A auto-induction occurred at steady-state. Covariates retained in the final model included formulation, cytochrome P450 (CYP) 3A4 inhibitor co-administration, sex, race, creatinine clearance, and serum alkaline phosphatase. Moderate and strong CYP3A4 inhibitors comedications increased area under the concentration-time curve by 31.4% and 191.3%, respectively. This population PK model of sparsentan suggests that dose adjustments may be warranted for patients taking moderate and strong CYP3A4 inhibitors concomitantly, but other covariates analyzed may not require dose adjustments., (© 2023 Travere Therapeutics. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Bezlotoxumab is approved for prevention of recurrent Clostridioides (Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI who are at high risk for recurrent CDI. Previous studies have shown that although serum albumin levels are an important predictor for bezlotoxumab exposure, this has no clinically meaningful impact on efficacy. This pharmacokinetic modeling study assessed whether hematopoietic stem cell transplant (HSCT) recipients, at increased risk of CDI and exhibiting decreased albumin levels within the first month posttransplant, are at risk of clinically relevant reductions in bezlotoxumab exposure., Methods: Observed bezlotoxumab concentration-time data pooled from participants in Phase III trials MODIFY I and II (ClinicalTrials.gov identifiers NCT01241552/NCT01513239) and three Phase I studies (PN004, PN005, and PN006) were used to predict bezlotoxumab exposures in two adult post-HSCT populations: A Phase Ib study of posaconazole including allogeneic HSCT recipients (ClinicalTrials.gov identifier NCT01777763; posaconazole-HSCT population); and a Phase III study of fidaxomicin for CDI prophylaxis (ClinicalTrials.gov identifier NCT01691248; fidaxomicin-HSCT population). The bezlotoxumab PK model used the minimum albumin level for each individual in post-HSCT populations to mimic a "worst-case scenario.", Findings: Predicted worst-case bezlotoxumab exposures for the posaconazole-HSCT population (N = 87) were decreased by 10.8% versus bezlotoxumab exposures observed in the pooled Phase III/Phase I data set (N = 1587). No further decrease was predicted for the fidaxomicin-HSCT population (N = 350)., Implications: Based on published population pharmacokinetic data, the predicted decrease in bezlotoxumab exposure in the post-HSCT populations is not expected to have a clinically meaningful effect on bezlotoxumab efficacy at the recommended 10 mg/kg dose. Dose modification is therefore not required in the hypoalbuminemia setting expected post-HSCT., Competing Interests: Declaration of Interest Drs Wong and Wrishko are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc., Rahway, NJ, USA, who may own stock and/or hold stock options in in Merck & Co., Inc., Rahway, NJ, USA. Dr de Almeida was an employee of Certara Strategic Consulting Services at the time of this research. Mr Kleijn is an employee of Certara Strategic Consulting Services. Although the sponsors formally reviewed a penultimate draft, the opinions expressed are those of the authors and may not necessarily reflect those of the sponsors. All co-authors approved the final version of the manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The ALK in Lung Cancer Trial of brigAtinib in First Line (ALTA-1L) compared brigatinib versus crizotinib in anaplastic lymphoma kinase (ALK) inhibitor-naive patients with ALK+ non-small cell lung cancer (NSCLC). A population pharmacokinetic (PK) model was used to estimate brigatinib exposures for exposure-efficacy and exposure-safety analyses in ALTA-1L. A previously developed population PK model for brigatinib was applied to estimate brigatinib PK parameters. Relationships between static (time-independent) and dynamic (time-varying) exposure metrics and efficacy (progression-free survival [PFS], objective response rate [ORR], and intracranial ORR [iORR]) and safety outcomes (selected grade ≥2 and grade ≥3 adverse events [AEs]) were evaluated using logistic regression and time-to-event analyses. There were no meaningful differences in brigatinib PK in the first-line and second-line settings, supporting use of the previous population PK model for the first-line population. Exposure-response analyses showed no significant effect of time-varying brigatinib exposure on PFS. Brigatinib exposure was not significantly related to ORR, but higher exposure was associated with higher iORR (odds ratio: 1.13, 95% confidence interval: 1.01-1.28, p = 0.049). Across the observed median exposure (5th-95th percentile) at steady state for 180 mg once daily, the predicted probability of iORR was 0.83 (0.58-0.99). AEs significantly associated with higher exposure were elevated lipase (grade ≥3) and amylase (grade ≥2). Time to first brigatinib dose reduction was not related to exposure. These results support the benefit-risk profile of first-line brigatinib 180 mg once daily (7-day lead-in dose at 90 mg once daily) in patients with ALK+ NSCLC., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Objective: To investigate the pharmacokinetics and pharmacodynamics of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with neuromyelitis optica spectrum disorder (NMOSD). Methods: Data were analyzed from 95 patients with aquaporin-4-IgG-positive NMOSD who received eculizumab during the PREVENT study (ClinicalTrials.gov: NCT01892345). Relationships were explored between eculizumab exposure and free complement C5 concentrations, terminal complement activity, and clinical outcomes. Results: Pharmacokinetic data were well-described by a two-compartment model with first-order elimination, and time-variant body-weight and plasmapheresis/plasma exchange effects. Steady-state serum eculizumab concentrations were achieved by Week 4 and were sustained, with serum trough eculizumab concentrations maintained above the 116 μg/ml threshold for complete complement inhibition throughout 168 weeks of treatment in all post-baseline samples from 89% of patients. Complete inhibition of terminal complement was achieved at Day 1 peak and pre-dosing trough eculizumab concentration in nearly all post-baseline samples assessed (free C5 <0.5 μg/ml in all post-baseline samples from 96% of patients; in vitro hemolysis <20% in all post-baseline samples from 93% of patients). Kaplan-Meier survival analysis of time to first relapse showed separation of eculizumab-treated patients from those receiving placebo, but no separation based on eculizumab exposure quartile, indicating an optimized dose regimen with maximized efficacy. Conclusions: The approved eculizumab dosing regimen (900/1,200 mg) for adults with aquaporin-4-IgG-positive NMOSD is confirmed by rigorous quantitative model-based analysis of exposure-response. The data demonstrate that eculizumab's mechanism of action translates into clinical effect by achieving rapid, complete, and sustained terminal complement inhibition., Competing Interests: PS and XG were employees of Alexion Pharmaceuticals, Inc. at the time the work described in this paper was undertaken; RP is an employee of Alexion Pharmaceuticals, Inc.; HJK and FB are employees of Certara Strategic Consulting, which received funding from Alexion Pharmaceuticals. The authors declare that this study received funding from Alexion Pharmaceuticals Inc. The funder had the following involvement with the study as sponsor: study design; collection, analysis, interpretation of data, the writing of this article, and the decision to submit it for publication. Editorial assistance was provided by Piper Medical Communications, funded by Alexion Pharmaceuticals Inc., (Copyright © 2021 Singh, Gao, Kleijn, Bellanti and Pelto.)

Objective: To investigate the pharmacokinetics, pharmacodynamics, and exposure-response of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with generalized myasthenia gravis (gMG). Methods: The analysis used data from 62 patients aged ≥ 18 years with anti-acetylcholine receptor (AChR) antibody-positive refractory gMG who received eculizumab during the REGAIN study (ClinicalTrials.gov: NCT01997229). One- and two-compartment population-pharmacokinetic models were evaluated, and the impact of covariates on pharmacokinetic parameters was assessed. Relationships between eculizumab exposure and free C5 concentration, in vitro hemolytic activity, clinical response, and tolerability were characterized. Results: Steady-state serum eculizumab concentrations were achieved by Week 4 and were sustained throughout the 26-week treatment period. The eculizumab pharmacokinetic data were well-described by a two-compartment model with first-order elimination, including effects of body weight on pharmacokinetic parameters and plasma-exchange events on clearance. Complete inhibition of terminal complement was achieved in nearly all patients at the time of trough and peak eculizumab concentrations at all post-dose timepoints assessed (free C5 < 0.5 μg/ml in 92% of patients; in vitro hemolysis < 20% in 87% of patients). Serum eculizumab concentrations of ≥116 μg/ml achieved free C5 concentrations of < 0.5 μg/ml. Clinical efficacy and tolerability were consistent across the eculizumab exposure range. Conclusions: Rigorous, quantitative, model-based exposure-response analysis of serum eculizumab concentration and response data demonstrated that the approved eculizumab dosing (900/1,200 mg) for adults with anti-AChR antibody-positive refractory gMG rapidly achieved complete inhibition of terminal complement activation and provided sustained clinical efficacy across the eculizumab exposure range., Competing Interests: JM and RP are employed by Alexion Pharmaceuticals, Inc.; XG was employed by Alexion Pharmaceuticals, Inc. at the time the work described in this paper was undertaken; HJK and FB are employed by Certara Strategic Consulting, which received funding from Alexion Pharmaceuticals, Inc., (Copyright © 2021 Monteleone, Gao, Kleijn, Bellanti and Pelto.)

Ivosidenib is a once daily (q.d.), orally available, potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for treatment of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and intensive chemotherapy ineligible AML with a susceptible IDH1 mutation. Population pharmacokinetics (PKs; N = 253), exposure-response (efficacy [n = 201] and safety [n = 253]), and concentration-corrected electrocardiogram QT interval (QTc; n = 171) analyses were performed using phase I data (100 mg twice daily and 300-1200 mg q.d.). Ivosidenib disposition was well-described by a two-compartment PK model with first-order absorption and elimination. Between-subject variability was moderate for PK parameters. Intrinsic factors did not affect ivosidenib PKs. Moderate/strong CYP3A4 inhibitors increased the area under the plasma ivosidenib concentration-time curve at steady state (AUC ss ) by 60%. Efficacy responders and nonresponders had similar ivosidenib exposures. Based on AUC ss , there was no apparent relationship between ivosidenib exposure and efficacy or adverse events. The plasma ivosidenib concentration-QT analysis showed a mean change in QTc using Fridericia's method (ΔQTcF) of 17.2 msec at the approved 500 mg q.d. dose. Because of the direct association between ivosidenib exposure and QTcF, patients should have their electrocardiograms and electrolytes monitored, and comedications that increase ivosidenib exposure or prolong the QT interval should be avoided. These model-based analyses quantitatively provide a framework to describe the relationship among ivosidenib dose, exposure, and clinical end points. With precautions for QTc prolongation, the exposure-response analyses support the 500 mg q.d. dose in patients with AML with a susceptible IDH1 mutation., (© 2020 Agios Pharmaceuticals, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: We present study designs, dose selection and preliminary patient characteristics from two phase 3 clinical trials of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough (RCC) or unexplained chronic cough (UCC)., Methods: COUGH-1 (NCT03449134) and COUGH-2 (NCT03449147) are randomised, placebo-controlled, double-blind, parallel-group trials in subjects with RCC or UCC (age ≥18 years; cough duration ≥1 year; Cough Severity Visual Analogue Scale score ≥40 mm). The primary efficacy study periods are 12 weeks (40-week extension; COUGH-1) and 24 weeks (28-week extension; COUGH-2). Interventions include placebo, gefapixant 15 mg and gefapixant 45 mg (1:1:1 ratio). The primary efficacy endpoints are average 24-h cough frequency at Week 12 (COUGH-1) and Week 24 (COUGH-2). Awake cough frequency, patient-reported outcomes and responder analyses are secondary endpoints., Results: The doses of 45 mg (to provide maximal efficacy and acceptable tolerability) and 15 mg (to provide acceptable efficacy and improved tolerability) were selected based on phase 1 and 2 studies. In COUGH-1, 730 participants have been randomised and treated; 74% are female with mean age of 59 years (39% over 65 years), and mean baseline duration of cough of 11.5 years. In COUGH-2, 1314 participants have been randomised and treated; 75% are female with mean age of 58 years (33% over 65 years), and mean baseline duration of cough of 11.1 years., Conclusions: These global studies include participants with baseline characteristics consistent with previous RCC and UCC studies and will inform the efficacy and safety profile of gefapixant in the treatment of patients with RCC and UCC., Competing Interests: Conflict of interest: D.R. Muccino is an employee of Merck & Co., Inc., Kenilworth, NJ, USA. Conflict of interest: A.H. Morice reports grants and personal fees from Merck during the conduct of the study. Conflict of interest: S.S. Birring reports clinical trial fees to his institution by Merck during the conduct of the study; a grant for an investigator-led study from Merck, personal fees for scientific advisory work from Merck, Bayer, Sanofi, Pfizer, Patara and Menlo, and speaker fees from Roche, outside the submitted work. Conflict of interest: P.V. Dicpinigaitis reports consulting fees from Merck during the conduct of the study. Conflict of interest: I.D. Pavord reports speaker fees, advisory board honoraria, sponsorship to attend scientific meetings and payments for organising educational events from AstraZeneca; speaker fees, advisory board honoraria and sponsorship to attend scientific meetings from Boehringer Ingelheim; a speaker fee from Aerocrine; speaker fees and advisory board honoraria from Almirall and Novartis; speaker fees, advisory board honoraria and sponsorship to attend scientific meetings from GlaxoSmithKline; advisory board honoraria from Genentech and Regeneron; speaker honoraria, payments for organising educational events and sponsorship to attend scientific meetings from Teva; speaker honoraria and a research grant from Chiesi; advisory board honoraria, speaker fees and grant support from Sanofi; advisory board honoraria from Circassia and Knopp; and funding as a Senior Investigator from NIHR, outside the submitted work. Conflict of interest: C. Assaid is an employee of Merck & Co., Inc., Kenilworth, NJ, USA. Conflict of interest: H.J. Kleijn reports that the contributions to the paper were performed as a paid consultant (employee of Certara) for Merck. Conflict of interest: A. Hussain is an employee of Merck & Co., Inc., Kenilworth, NJ, USA. Conflict of interest: C. La Rosa is an employee of Merck & Co., Inc., Kenilworth, NJ, USA. Conflict of interest: L. McGarvey reports personal fees from Afferent Pharmaceuticals and Merck & Co., Inc., grants, personal fees and nonfinancial support from Chiesi, personal fees and nonfinancial support from Boehringer Ingelheim, grants and nonfinancial support from Glaxo Smith Kline, grants and personal fees from Almirall, personal fees from AstraZeneca, and grants from NC3R, during the conduct of the study; and grants from the European Union Interreg VA Health & Life Science Programme outside the submitted work;. Conflict of interest: J.A. Smith reports funding for a commercial study paid to Manchester University NHS Foundation Trust, and personal fees for advisory boards and consultancy work from Merck Inc., during the conduct of the study; funding for a commercial study paid to Manchester University NHS Foundation Trust, and personal fees for advisory boards and consultancy work from GlaxoSmithKline, a grant to Christie Hospital and commercial funding for a clinical trial, and consultancy fees from NeRRe Pharmaceuticals, commercial funding for clinical trials and consultancy fees from Menlo and Bayer, consultancy fees from Boehringer Ingelheim, Genentech and Neomed, provision of cough monitoring equipment by Vitalograph, consultancy fees from Chiesi, a grant paid to Manchester University NHS Foundation Trust and personal fees from Afferent, consultancy fees from Bellus, and funding for a commercial study paid to Manchester University NHS Foundation Trust by and consultancy work for Axalbion, outside the submitted work. In addition, J.A. Smith has a patent, “A method for generating output data”, licenced., (Copyright ©ERS 2020.)

Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor antagonist in clinical development with positive phase III outcomes for acute treatment of migraine. This paper describes the population exposure-response (E-R) modeling and simulations, which were used to inform the phase III dose-selection rationale, based on ~ 800 participants pooled across two phase IIb randomized dose-finding clinical trials. The E-R model describes the placebo and ubrogepant treatment effects based on migraine pain end points (2-hour pain relief and 2-hour pain freedom) at various dose levels. Sensitivity analyses were conducted to evaluate various assumptions of placebo response in light of the high placebo response observed in one phase II trial. A population pharmacokinetic model describing the effect of formulations was included in the E-R simulation framework to assess potential dose implications of a formulation switch from phase II to phase III. Model-based simulations predict that a dose of 25 mg or higher is likely to achieve significantly better efficacy than placebo with desirable efficacy levels. The understanding of E-R helped support the dose selection for the phase III clinical trials., (© 2019 Merck Sharp & Dohme Corp. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society of Clinical Pharmacology & Therapeutics.)

Bezlotoxumab is a monoclonal antibody approved for the prevention of recurrent Clostridium difficile infection (rCDI). In a previous exposure-response (E-R) analysis of bezlotoxumab exposure and rCDI, based on data from two phase 3 trials in participants who received placebo or bezlotoxumab 10 mg/kg, rCDI was treated as a binary endpoint and discontinued subjects were imputed as not having rCDI, resulting in an apparent positive E-R trend between rCDI rates and bezlotoxumab exposure. Therefore, a time-to-event (TTE) analysis was applied to investigate the E-R relationship, accounting for the time to rCDI occurrence and participant discontinuation. A TTE model, applying a time-dependent hazard function and right-censoring of data based on rCDI, discontinuation, or study end was developed. Exposure effects and covariates effects were evaluated as predictors affecting the hazard. The TTE model consisted of a Gompertz function with age, endogenous immunoglobulin G to C. difficile toxin B (IgG-B), history of CDI, hospitalization, sex, Charlson Comorbidity Index, and concomitant use of systemic antibiotics affecting the hazard. Exposure effects were characterized with a maximum effect (E max ) E-R relationship on the baseline parameter, and bezlotoxumab exposures achieved at the 10 mg/kg dose were found to be on the plateau of the E-R curve. Endogenous IgG-B significantly impacted the E max , indicating that low-titer participants derive a greater benefit from bezlotoxumab treatment compared with high-titer participants. The results support the conclusions of the previous E-R analysis, where exposures achieved at the 10 mg/kg dose are on the plateau of the E-R curve.

β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ) peptides and is considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical development program, we characterized the safety, pharmacokinetics (PKs), and pharmacodynamics of the BACE1 inhibitor verubecestat (MK-8931) in 24 healthy Japanese adults in a two-part, single-center, randomized, placebo-controlled phase I trial (protocol MK-8931-007) and compared the results with historical data from non-Japanese subjects. Both single (20, 100, and 450 mg) and multiple (80 and 150 mg once daily for 14 days) doses of verubecestat were well tolerated. Verubecestat's PK profile was similar in Japanese and non-Japanese subjects. Verubecestat also reduced mean cerebrospinal fluid concentrations of the Aβ proteins Aβ40, Aβ42, and soluble β fragment of amyloid precursor protein; the level of reduction was comparable between Japanese and non-Japanese subjects. These results support the continued global development of verubecestat as a potential disease-modifying agent for Japanese and non-Japanese subjects who are at risk for developing AD., (© 2019 Merck Sharp & Dohme Corp. Clinical Phamacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

The fully human monoclonal antibody bezlotoxumab is indicated for preventing the recurrence of Clostridioides difficile (formerly Clostridium difficile ) infection (CDI) in adults who receive antibacterial treatment for CDI and who are at high risk for a CDI recurrence. The efficacy and safety of 10-mg/kg of body weight bezlotoxumab were demonstrated in two phase 3 trials: the MODIFY I (ClinicalTrials.gov registration number NCT01241552) and MODIFY II (ClinicalTrials.gov registration number NCT01513239) trials. Here, a population pharmacokinetic (popPK) analysis, performed using data from the MODIFY I and II trials ( n = 1,515) and from three phase 1 trials ( n = 72) to characterize bezlotoxumab pharmacokinetics (PK) in phase 3 clinical trial participants and in healthy subjects, is reported. A stepwise covariate search was conducted to identify factors influencing PK. Post hoc -estimated bezlotoxumab exposures from the popPK model were used to conduct an exposure-response analysis for CDI recurrence. Bezlotoxumab PK were described by a two-compartment model with linear elimination and allometric scaling for clearance and the volume of distribution by body weight. Although the final popPK model included gender, ethnicity (Japanese descent), race (black versus nonblack), and albumin level as significant covariates, the impact of these factors was not clinically meaningful, based on the totality of the PK and clinical experience. Exposure-response analysis of CDI recurrence demonstrated a similar low rate of CDI recurrence over the entire range of exposures achieved in the phase 3 trials, indicating that exposures were on the maximal response plateau of the exposure-response curve. Overall, the analyses confirmed the appropriateness of the 10-mg/kg dose across the phase 3 trial population with no dose adjustments necessary over a broad demographic background., (Copyright © 2019 American Society for Microbiology.)

The abnormal accumulation of amyloid- β (A β ) in the brain parenchyma has been posited as a central event in the pathophysiology of Alzheimer's disease. Recently, we have proposed a systems pharmacology model of the amyloid precursor protein (APP) pathway, describing the A β APP metabolite responses (A β 40, A β 42, sAPP α , and sAPP β ) to β -secretase 1 (BACE1) inhibition. In this investigation this model was challenged to describe A β dynamics following γ -secretase (GS) inhibition. This led an extended systems pharmacology model, with separate descriptions to characterize the sequential cleavage steps of APP by BACE1 and GS, to describe the differences in A β response to their respective inhibition. Following GS inhibition, a lower A β 40 formation rate constant was observed, compared with BACE1 inhibition. Both BACE1 and GS inhibition were predicted to lower A β oligomer levels. Further model refinement and new data may be helpful to fully understand the difference in A β dynamics following BACE1 versus GS inhibition., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

Merck & Co., Inc. (Kenilworth, New Jersey) has recently published an integrated strategy for implementation of dried blood spots (DBS) in late-stage trials for population pharmacokinetic (PK) modeling. We applied this strategy for another late-stage clinical program: ubrogepant (MK-1602), a novel oral calcitonin gene-related peptide receptor antagonist for acute treatment of migraine. At the time of implementation, ubrogepant was entering phase 2 development. DBS was implemented to acquire PK information proximal to an acute migraine event to enable exposure-response modeling. The clinical endpoint was a spontaneous event, which generally occurs outside a clinic visit. Thus, an innovative feature of this trial was facilitating DBS in an outpatient setting. In vitro and bioanalytical tests established initial method feasibility and suitability for further evaluations in the clinic. A quantitative relationship was developed between blood and plasma concentrations from concurrently collected samples in a phase 1 (healthy subjects) and phase 2 (target patient population) study using graphical and population PK approaches. This integrated information was presented to the Food and Drug Administration for regulatory input. Following regulatory concurrence, DBS was poised for use in further clinical studies. Population PK modeling was used to dissect sources of variability contributing to DBS collection in the outpatient setting. What has been learned from this program has informed the broader integrated strategy of Merck & Co., Inc. (Kenilworth, NJ) for DBS implementation in clinical trials and research to improve the precision of PK data collected in an outpatient setting., (© 2017, The American College of Clinical Pharmacology.)

β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aβ40, Aβ42, and sAPPβ in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials., (Copyright © 2016, American Association for the Advancement of Science.)

The deposition of amyloid-β (Aβ) oligomers in brain parenchyma has been implicated in the pathophysiology of Alzheimer's disease. Here we present a systems pharmacology model describing the changes in the amyloid precursor protein (APP) pathway after administration of three different doses (10, 30, and 125 mg/kg) of the β-secretase 1 (BACE1) inhibitor MBi-5 in cisterna magna ported rhesus monkeys. The time course of the MBi-5 concentration in plasma and cerebrospinal fluid (CSF) was analyzed in conjunction with the effect on the concentrations of the APP metabolites Aβ42, Aβ40, soluble β-amyloid precursor protein (sAPP) α, and sAPPβ in CSF. The systems pharmacology model contained expressions to describe the production, elimination, and brain-to-CSF transport for the APP metabolites. Upon administration of MBi-5, a dose-dependent increase of the metabolite sAPPα and dose-dependent decreases of sAPPβ and Aβ were observed. Maximal inhibition of BACE1 was close to 100% and the IC50 value was 0.0256 μM (95% confidence interval, 0.0137-0.0375). A differential effect of BACE1 inhibition on Aβ40 and Aβ42 was observed, with the Aβ40 response being larger than the Aβ42 response. This enabled the identification of an Aβ42 oligomer pool in the systems pharmacology model. These findings indicate that decreases in monomeric Aβ responses resulting from BACE1 inhibition are partially compensated by dissociation of Aβ oligomers and suggest that BACE1 inhibition may also reduce the putatively neurotoxic oligomer pool., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Exposure-response analyses of sugammadex on activated partial thromboplastin time (APTT) and prothrombin time international normalized ratio (PT(INR)) were performed using data from two clinical trials in which subjects were co-treated with anti-coagulants, providing a framework to predict these responses in surgical patients on thromboprophylactic doses of low molecular weight or unfractionated heparin. Sugammadex-mediated increases in APTT and PT(INR) were described with a direct effect model, and this relationship was similar in the presence or absence of anti-coagulant therapy in either healthy volunteers or surgical patients. In surgical patients on thromboprophylactic therapy, model-based predictions showed 13.1% and 22.3% increases in respectively APTT and PT(INR) within 30min after administration of 16mg/kg sugammadex. These increases remain below thresholds seen following treatment with standard anti-coagulant therapy and were predicted to be short-lived paralleling the rapid decline in sugammadex plasma concentrations., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: To report the first three studies with SCH 900435, a selective glycine-1 re-uptake inhibitor in development for treating schizophrenia, using systematic evaluations of pharmacodynamics to understand the observed effects., Methods: Three double-blind, placebo-controlled studies (single, visual effect and multiple dose) were performed. In the single and multiple dose study SCH 900435 (0.5-30 mg) was given to healthy males and frequent pharmacokinetic and pharmacodynamic measurements were performed. The visual effects study incorporated visual electrophysiological measures of macular, retinal and intracranial visual pathway function., Results: In the single dose study (highest difference, 95% CI, P) increases in smooth pursuit eye movements (8, 12 mg (-6.09, 10.14, -2.04, 0.013), 30 mg), pupil : iris ratio (20 and 30 mg (-0.065, 0.09, -0.04, <0.0001)), VAS colour perception (30 mg (-9.48, 13.05, -5.91, <0.0001)) and changes in spontaneous reports of visual disturbance were found, while FSH (8 mg (0.42, 0.18, 0.66, 0.0015), 12, 20 mg), LH (8-30 mg (1.35, 0.65, 2.05, 0.0003)) and EEG alpha2 activity decreased (12, 20, 30 mg (0.27, 0.14, 0.41, 0.0002)). A subsequent dedicated visual effects study demonstrated that visual effects were transient without underlying electrophysiological changes. This provided enough safety information for starting a multiple ascending dose study, showing less visual symptoms after twice daily dosing and titration, possibly due to tolerance., Conclusions: Several central nervous system (CNS) effects and gonadotropic changes resulted from administration of 8 mg and higher, providing evidence for CNS penetration and pharmacological activity of SCH 900435. Antipsychotic activity in patients, specificity of the reported effects for this drug class and possible tolerance to visual symptoms remain to be established., (© 2012 Centre for Human Drug Research. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Aims: An integrated population pharmacokinetic-pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic-pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time., Methods: Data (n= 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects., Results: Sugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg(-1) 3 min after rocuronium, sugammadex 4 mg kg(-1) during deep neuromuscular blockade and sugammadex 2 mg kg(-1) during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time., Conclusions: Simulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min., (© 2011 N.V. Organon, a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

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.

CB1/CB2 agonists are reported to have sedative, amnestic, analgesic and anti-emetic properties, which would make them ideal drugs for outpatient treatments under conscious sedation. The main objective of this in human study was to assess the sedative properties of Org 28611, a potent water-soluble CB1 agonist. Single ascending doses were administered during a slow 25 min infusion and after a 1 min bolus administration to healthy male volunteers. In addition, the pharmacokinetics, amnestic properties, postural stability, electro-encephalography, behavioural and cardiovascular effects were studied. Midazolam 0.1 mg/kg was used as a positive control. The pharmacokinetic parameters were proportional to dose. No effects were observed after intravenous administration of doses up to Org 28611 1 microg/kg. Dose-related effects were observed at higher doses. Although subjects reported subjective sedation after administration of Org 28611 3-10 microg/kg, the observed sedation was considerably less than after midazolam. Org 28611 is, therefore, not suitable for providing sedation for outpatient surgical procedures and doses above the maximum tolerated dose of 3 microg/kg (either administered as a slow infusion or a bolus dose) can cause untoward psychotropic effects.

Paroxetine inhibits cytochrome P(450) 2D6, which is involved in the metabolism of mirtazapine. The possible drug-drug interaction between two pharmacologically distinct antidepressants, mirtazapine and paroxetine, has been investigated in a randomized, three-way crossover study in 24 healthy male and female subjects. After a titration phase of 3 days, each subject received single daily doses of 30 mg mirtazapine, 40 mg paroxetine or the combination for 6 days. Assessments included serial blood sampling for pharmacokinetics at steady state, cognitive testing using the test battery of CDR Ltd, a visual analogue mood rating scale (Bond and Lader) and the Leeds Sleep Evaluation Questionnaire. Paroxetine inhibits the metabolism of mirtazapine, as shown by increases of approximately 17% and 25% of the 24 h AUC's of mirtazapine and its demethyl metabolite, respectively. Mirtazapine did not alter the pharmacokinetics of paroxetine. The combined administration of mirtazapine and paroxetine probably does not alter cognitive functioning or result in major changes on the visual analogue mood rating scale and Sleep Evaluation Questionnaire, compared with the administration of either drug alone. The incidence of adverse events was lower during combined administration of mirtazapine and paroxetine than during administration of either drug alone. Fatigue, dizziness, headache, nausea, anxiety and somnolence were the most common adverse events during combined administration. These data suggest that the combination of mirtazapine and paroxetine is unlikely to lead to clinically relevant drug-drug interactions and can be used without dose adjustment of either drug. The combination may even be better tolerated than either drug alone. Copyright 2001 John Wiley & Sons, Ltd.

Objective: To assess the absolute bioavailability of ganirelix (Antagon/Orgalutran; NV Organon, Oss, the Netherlands) after a single SC injection., Design: Randomized, crossover, pharmacokinetic study., Setting: Phase I clinical research unit., Patient(s): Nineteen healthy female volunteers of reproductive age., Intervention(s): Two separate injections of 0.25 mg of ganirelix were given, one subcutaneously and one intravenously, with a washout period of 1 week between injections. Blood samples were taken for assessment of serum ganirelix concentrations, and blood pressure, heart rate, and adverse events were monitored., Main Outcome Measure(s): Pharmacokinetic parameters., Result(s): Fifteen subjects were evaluated. The mean concentration-time profile after SC administration was comparable to that after IV administration. The mean (+/- SD) peak concentration and time of occurrence after SC administration were 14.8+/-3.2 ng/mL and 1.1+/-0.3 hours, respectively. The mean (+/- SD) half-lives after IV administration and SC administration were highly similar (12.7+/-3.7 hours and 12.8+/-4.3 hours, respectively). Mean (+/- SD) AUC0-infinity (area under the concentration-time curve) values of 105+/-11 ng/mL x hours and 96+/-12 ng/mL x hours were calculated for IV administration and SC administration, respectively, resulting in an absolute mean (+/- SD) bioavailability of 91.3%+/-6.7%. Both treatments were well tolerated., Conclusion(s): Ganirelix is absorbed rapidly and extensively after SC administration, resulting in a high absolute bioavailability of >90%.