Initial characterization of the toxicity and efficacy of elacytarabine (CP-4055), a novel antileukemic agent, using a multidimensional exposure-response relationship model.

6619^ Background: Elacytarabine (CP-4055), an elaidic acid ester of ara-C, is a novel antineoplastic agent developed to treat hematologic malignancies (HM). It is metabolized to active ara-CTP and inactive ara-U. In 3 studies, diverse elacytarabine monotherapy doses and regimens were given to patients with advanced HM and solid tumours. This analysis aimed to 1) describe the pharmacokinetics (PK) of elacytarabine in these patients and 2) investigate the relationship between PK and toxicity and efficacy in HM. Methods: Population PK analyses were run with ADAPT 5 (ITS) and included 146 patients given a 2h, 4h or 120h continuous infusion (CIV) of elacytarabine. Elacytarabine, ara-C and ara-U plasma concentrations (Cp) were simultaneously modeled and explained. Standard model discrimination criteria were used to select the best model. With the model, different dosing regimens were simulated to find average exposure and % of patients with efficacious or toxic exposure. A multi-dimensional exposure-response relationship (MDERR) was developed with pre-clinical and clinical data. Results: The best model was a 2-compartment (CPT) model with linear elimination and formation rates for the metabolism of elacytarabine to ara-C. Mean PK parameters were Vc = 4.12 L/m2, CL= 5.27 L/h/m2 and T1/2 = 7.57 h. Elacytarabine PK included a peripheral CPT with a non-linear distribution process to reflect saturable binding to red blood cells, otherwise its PK was linear. Ara-C and ara-U PK were described by 2- and 1-CPT linear models, respectively. The MDERR model related efficacy and toxicity thresholds to elacytarabine dosing regimens, and indicated that a 120 h CIV dosing regimen is preferable, allowing elacytarabine to exceed efficacious Cp for longer than the other investigated regimens. A minimum dose of 1000 mg/m2/day is needed for most patients to receive efficacious exposure. Conclusions: Elacytarabine is a promising anti-leukemic agent for patients with advanced HM. Its PK, toxicity and efficacy were characterized in patients given diverse dosing regimens. An MDERR model, which will be further refined or confirmed in upcoming clinical trials, was proposed.

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Understanding the drug exposure–response relationship of bedaquiline to predict efficacy for novel dosing regimens in the treatment of multidrug‐resistant tuberculosis

British Journal of Clinical Pharmacology ◽

10.1111/bcp.14199 ◽

2020 ◽

Vol 86 (5) ◽

pp. 913-922

Author(s):

Lénaïg Tanneau ◽

Mats O. Karlsson ◽

Elin M. Svensson

Keyword(s):

Drug Exposure ◽

Multidrug Resistant ◽

Response Relationship ◽

Resistant Tuberculosis ◽

Exposure Response ◽

Multidrug Resistant Tuberculosis ◽

Dosing Regimens ◽

Relationship Of

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Pharmacokinetics (PK) and efficacy of sunitinib in patients with metastatic renal cell carcinoma (mRCC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4531 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4531-4531 ◽

Cited By ~ 2

Author(s):

B. E. Houk ◽

M. Amantea ◽

R. J. Motzer ◽

M. D. Michaelson ◽

B. I. Rini ◽

...

Keyword(s):

Clinical Response ◽

Tumor Volume ◽

Kinase Inhibitor ◽

Plasma Concentrations ◽

Response To Treatment ◽

Response Relationship ◽

Multiple Tumor ◽

Exposure Response ◽

Phase Ii Studies ◽

Population Pk

4531 Background: Sunitinib malate (SU11248) is an oral, multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, FLT3, and RET. Clinical studies have demonstrated efficacy of sunitinib in patients with multiple tumor types including two phase II studies in mRCC, where second-line monotherapy with sunitinib showed a response rate of greater than 40% by RECIST, with an additional ≥25% of pts exhibiting prolonged stable disease. A population PK analysis was performed to assess the exposure-response relationship between PK and tumor volume changes, clinical response, and time to tumor progression (TTP) in these two mRCC studies. Methods: In these two studies, 169 patients with mRCC were treated with sunitinib 50 mg/day for 4 weeks, followed by a 2-week off period (Schedule 4/2). Response to treatment was assessed by measuring tumor volume. Clinical response was assessed using RECIST and TTP using logistic regression and Kaplan-Meier survival analysis. A previously described population PK model of sunitinib and its primary active metabolite SU12662 was updated using additional data from three trials, including the two RCC trials. Using the model and trough plasma concentrations, steady-state AUCs of sunitinib plus SU12662 were estimated for each mRCC patient and tested as a predictor of response. Results: PK profiles were evaluable for 149 patients in the two mRCC trials. Plasma clearance (CL) decreased by an average of 28% in mRCC patients relative to healthy volunteers. Covariates, such as gender, age, and ECOG score also affected CL, however all of these changes were less than the estimated inter-individual variability in CL of 43%. Improved clinical response and longer TTPs were associated with greater AUCs. Within 12 weeks of treatment, mean tumor volume decreased by 24–32% in each trial. Conclusions: Individual patient exposures to sunitinib and SU12662 can be predicted with sparse concentration measurements using population PK analysis, and an exposure-response relationship is evident in mRCC. Dose adjustment is not warranted based upon any evaluated covariate. Over the first 12 weeks of treatment at 50 mg daily on Schedule 4/2, increased exposure was associated with improved clinical response and decreased tumor volumes. [Table: see text]

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Posaconazole Exposure-Response Relationship: Evaluating the Utility of Therapeutic Drug Monitoring

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05900-11 ◽

2012 ◽

Vol 56 (6) ◽

pp. 2806-2813 ◽

Cited By ~ 90

Author(s):

Michael J. Dolton ◽

John E. Ray ◽

Deborah Marriott ◽

Andrew J. McLachlan

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Fungal Infections ◽

Gastrointestinal Disease ◽

Plasma Concentrations ◽

Response To Therapy ◽

Common Finding ◽

Therapeutic Drug ◽

Response Relationship ◽

Exposure Response

ABSTRACTPosaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.

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Model-Based Exposure-Response Assessment for Spectinamide 1810 in a Mouse Model of Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01744-20 ◽

2021 ◽

Cited By ~ 1

Author(s):

Santosh Wagh ◽

Chetan Rathi ◽

Pradeep B. Lukka ◽

Keyur Parmar ◽

Zaid Temrikar ◽

...

Keyword(s):

Mouse Model ◽

Plasma Concentrations ◽

Dose Fractionation ◽

Population Pharmacokinetic ◽

Response Relationship ◽

Postantibiotic Effect ◽

Bacterial Killing ◽

Exposure Response

Despite decades of research, tuberculosis remains a leading cause of death from a single infectious agent. Spectinamides are a promising novel class of anti-tuberculosis agents, and lead spectinamide 1810 has demonstrated excellent efficacy, safety and drug-like properties in numerous in vitro and in vivo assessments in mouse models of tuberculosis. In the current dose ranging and dose fractionation study, we used 29 different combinations of dose level and dosing frequency to characterize the exposure-response relationship for spectinamide 1810 in a mouse model of M. tuberculosis infection and in healthy animals. The obtained data on 1810 plasma concentrations and counts of colony-forming units in lungs were analyzed using a population pharmacokinetic/pharmacodynamic (PK/PD) approach as well as classical anti-infective PK/PD indices. The analysis results indicate that there was no difference in the PK of 1810 in infected compared to healthy, uninfected animals. The PK/PD index analysis showed that bacterial killing of 1810 in mice was best predicted by fC max /MIC and fAUC/MIC rather than f%T MIC . A novel PK/PD model with consideration of postantibiotic effect could adequately describe the exposure-response relationship for 1810 and supports the notion that the in vitro observed postantibiotic effect of this spectinamide also translates to the in vivo situation in mice. The obtained results and pharmacometric model for the exposure-response relationship of 1810 provide a rational basis for dose selection in future efficacy studies of this compound against M. tuberculosis .

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Effect of recombinant bovine somatotropin on pregnancy rates of Nellore cows resynchronized with the use of new DIB and third use, and inseminated at fixed-time

JOURNAL OF ADVANCES IN AGRICULTURE ◽

10.24297/jaa.v4i1.4304 ◽

2015 ◽

Vol 4 (1) ◽

pp. 356-362

Author(s):

Josemara Silva Santos ◽

Tania Cavalcante ◽

Francisca Elda Ferreira Dias ◽

Domenica Palomaris Mariano de Souza ◽

Alencariano J.S. Falcão ◽

...

Keyword(s):

Artificial Insemination ◽

Linear Models ◽

Plasma Concentrations ◽

Fixed Time ◽

Estradiol Benzoate ◽

Pregnancy Rates ◽

Recombinant Bovine Somatotropin ◽

Equine Chorionic Gonadotropin ◽

Rectal Palpation ◽

Intravaginal Device

The objective of the experiment was to evaluate the effects of recombinant bovine somatropin (rbST), and the reuse of the progesterone (P4) releasing devices in resynchronization, on the pregnancy rates of Nellore cows submitted to fixed-time artificial insemination. A group of 123 multiparae Nellore cows, was submitted to a resynchronization protocol: on day 0 a Bovine Intravaginal Device (DIB® ) with 1,0g of P4 was implanted, associated with intramuscular administration of 2,0mg of estradiol benzoate (IM); on day 8 DIB was removed; and 1,0mg of estradiol cypionate, 0,15mg of prostaglandin F2? and 300 UI of equine chorionic gonadotropin were administered; on day 10, fixed-time artificial insemination was conducted (FTAI). The cows were randomized into G1 (n=12) – without rbST / with used Bovine Intravaginal Device, G2 (n=50) – without rbST / with new DIB, G3 (n=11) - with rbST / with used DIB and G4 (n=50) – with rbST/ with new DIB. rbST was introduced on the eighth day of the protocol. Sixty days after TAI, pregnancy diagnoses were conducted, via rectal palpation. Blood samples were taken on day 0, 8 and 10 of the protocol, in order to assess P4 plasma concentrations. Pregnancy rates were statistically evaluated through Generalized Linear Models Theory and their significance was tested with Analysis of Deviance. Pregnancy rates were 58%, 40%, 81% and 48% for G1, G2, G3 and G4, respectively, with significant statistical difference for G3. Plasma concentrations of P4 were not statistically different among groups, or collections. In view of the results obtained, we concluded that the administration of rbST in association with P4 DIB, used for the third time, improves pregnancy rates. Estrus resynchronization and re-insemination positively impacted pregnancy rates.

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The Effect of an Alternative Definition of “Percent Highly Annoyed” on the Exposure–Response Relationship: Comparison of Noise Annoyance Responses Measured by ICBEN 5-Point Verbal and 11-Point Numerical Scales

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18126258 ◽

2021 ◽

Vol 18 (12) ◽

pp. 6258

Author(s):

Makoto Morinaga ◽

Thu Lan Nguyen ◽

Shigenori Yokoshima ◽

Koji Shimoyama ◽

Takashi Morihara ◽

...

Keyword(s):

Sound Pressure ◽

Response Relationship ◽

Alternative Definition ◽

Exposure Response ◽

Noise Annoyance ◽

Numerical Scale ◽

Verbal Scale ◽

Sound Pressure Levels ◽

Acoustic Surveys ◽

Definition Of

Since the development of the 5-point verbal and 11-point numerical scales for measuring noise annoyance by the ICBEN Team 6, these scales have been widely used in socio-acoustic surveys worldwide, and annoyance responses have been easily compared internationally. However, both the top two categories of the 5–point verbal scale and the top three ones of the 11-point numerical scale are correspond to high annoyance, so it is difficult to precisely compare annoyance responses. Therefore, we calculated differences in day–evening–night-weighted sound pressure levels (Lden) by comparing values corresponding to 10% highly annoyed (HA) on Lden_%HA curves obtained from measurements in 40 datasets regarding surveys conducted in Japan and Vietnam. The results showed that the Lden value corresponding to 10% HA using the 5-point verbal scale was approximately 5 dB lower than that of the 11-point numerical scale. Thus, some correction is required to compare annoyance responses measured by the 5-point verbal and the 11-point numerical scales. The results of this study were also compared with those of a survey in Switzerland.

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Exposure–Response Analysis for Selection of Optimal Dosage Regimen of Anifrolumab in Patients With Systemic Lupus Erythematosus

Rheumatology ◽

10.1093/rheumatology/keab176 ◽

2021 ◽

Author(s):

Yen Lin Chia ◽

Linda Santiago ◽

Bing Wang ◽

Denison Kuruvilla ◽

Shiliang Wang ◽

...

Keyword(s):

Type I Interferon ◽

Drug Clearance ◽

Optimal Dosage ◽

Type I ◽

Efficacy And Safety ◽

Response Relationship ◽

Phase 3 ◽

Optimal Dosage Regimen ◽

Exposure Response ◽

Selection Of

Abstract Objectives The randomized, double-blind, phase 2 b MUSE study evaluated the efficacy and safety of the type I interferon receptor antibody anifrolumab (300 mg or 1000 mg every 4 weeks) compared with placebo for 52 weeks in patients with chronic, moderate to severe SLE. Characterizing the exposure–response relationship of anifrolumab in MUSE will enable selection of its optimal dosage regimen in two phase 3 studies in patients with SLE. Methods The exposure–response relationship, pharmacokinetics (PK), and SLE Responder Index (SRI[4]) efficacy data were analysed using a population approach. A dropout hazard function was also incorporated into the SRI(4) model to describe the voluntary patient withdrawals during the 1-year treatment period. Results The population PK model found that type I IFN test–high patients, and patients with a higher body weight, had significantly greater clearance of anifrolumab. Stochastic clinical simulations demonstrated that doses <300 mg would lead to a greater-than-proportional reduction in drug exposure owing to type I interferon alpha receptor–mediated drug clearance (antigen-sink effect, more rapid drug clearance at lower concentrations) and suboptimal SRI(4) responses with wider confidence intervals. Conclusions Based on PK, efficacy, and safety considerations, anifrolumab 300 mg every 4 weeks was recommended as the optimal dosage for pivotal phase 3 studies in patients with SLE.

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