Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839

Sparve, Erik; Quartino, Angelica; Lüttgen, Maria; Tunblad, Karin; Gårdlund, Anna Teiling; Fälting, Johanna; Alexander, Robert; Kågström, Jens; Sjödin, Linnea; Булгак, А Г; Al‐Saffar, Ahmad; Bridgland-Taylor, Matthew; Pollard, Chris; Swedberg, Michael D.B.; Vik, Torbjörn; Paulsson, Björn

doi:10.1124/jpet.114.215202

Cited by 13 publications

(15 citation statements)

References 26 publications

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“…However, this risk, appears small when ER analysis is applied to early phase QT studies, provided a wide range of plasma concentrations of the drug has been achieved and an intense ECG/pharmacokinetic schedule has been implemented using the same experimental conditions and ECG methodologies as in TQT studies. Since published examples are relatively few [8,9,23,37,38] and not based on prospective series, a recently published report using a simulation approach can help to gain further understanding of the rate of false negatives and false positives in smallsized studies. A large number of small studies with 6-18 subjects receiving active treatment and six receiving placebo was simulated with data from five TQT studies; three studies with moxifloxacin with mean peak DDQTcF effect of 12.5, 14.0, and 8.0 ms, one study with ketoconazole with a smaller QT effect (DDQTcF 7.6 ms), and one TQT study with a drug with a larger effect (DDQTcF 26 ms).…”

Section: Lack Of Positive Controlmentioning

confidence: 97%

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

et al. 2015

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Exposure-response (ER) analysis has evolved as an important tool to evaluate the effect of a drug on cardiac repolarization, as reflected in the QTc interval. It has been suggested that careful electrocardiogram (ECG) evaluation in 'first-in-human' studies using ER analysis could replace or serve as an alternative to the E14 'thorough QT' study. This commentary shares and discusses the results of a recently conducted study with the objective to evaluate this approach. Six drugs with a well-characterized QT effect, five of which are known QT prolongers, were evaluated in a study design similar to a conventional single-ascending-dose study. Each drug was given to nine healthy subjects (six for placebo) in two dose levels, which for the positive drugs (ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide) were chosen with the intent to cause 10-12 ms and 15-20 ms QTc prolongation. Replicate 12-lead ECGs were extracted from continuous recordings pre-dose and serially after dosing and paired with drug concentration determinations. The ER criteria for the identification of a QT effect, a statistically significant positive ER slope and an effect above 10 ms, were met with all five positive drugs, and an effect exceeding 10 ms could be excluded at the supratherapeutic dose of the negative drug, levocetirizine. The study results thereby provided evidence to support that careful QT assessment in early phase clinical studies can be used as an alternative to the thorough QT study. Clinical and regulatory implications, as well as limitations of this approach, are discussed in the commentary.

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Section: Lack Of Positive Controlmentioning

confidence: 97%

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

et al. 2015

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“…Neither ibrutinib nor acalabrutinib have been associated with clinically relevant prolongation of the QTc interval at therapeutic or supratherapeutic doses during randomized, double-blind, placebo-controlled and positive-controlled thorough QT studies. 11,12,23 Evaluation of the relationship between concentration and QT/QTc using data collected in early phase clinical studies is a validated and US Food and Drug Administrationaccepted alternative strategy to a thorough QT study 13,15,24 and has been widely used to reliably exclude relevant QTc effects during drug development, 18,25,26 supporting waiver of the regulatory requirement for a thorough QT study in some cases. 27 Although our concentration-QT analysis is limited by the small number of subjects in each dose group and the small number of female subjects, pooling of data from parts 1 and 2 and the broad range of plasma concentrations obtained across dosage groups increase the reliability of our results.…”

Section: Evobrutinib In Healthy Volunteersmentioning

confidence: 99%

Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

Becker

Martin

Mitchell³

et al. 2019

Clinical Translational Sci

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Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor and Fc receptor signaling, and a rational therapeutic target for autoimmune diseases. This first‐in‐human phase I, double‐blind, placebo‐controlled trial investigated the safety, tolerability, pharmacokinetics (PK), target occupancy, and effects on QT interval of evobrutinib, a highly selective, oral inhibitor of BTK, in healthy subjects. This dose escalation trial consisted of two parts. Part 1 included 48 subjects in 6 ascending dose cohorts (25, 50, 100, 200, 350, and 500 mg) randomized to a single dose of evobrutinib or placebo. Part 2 included 36 subjects in 3 ascending dose cohorts (25, 75, and 200 mg/day) randomized to evobrutinib or placebo once daily for 14 days. Safety and tolerability, as well as PK and target occupancy (total and free BTK in peripheral blood mononuclear cells), were assessed following single and multiple dosing. PK parameters were determined by noncompartmental methods. QT interval was obtained from 12‐lead electrocardiogram recordings and corrected for heart rate by Fridericia's method (QTcF). Treatment‐emergent adverse events (TEAEs) were mostly mild, occurring in 25% of subjects after single dosing, and 48.1% after multiple dosing. There was no apparent dose relationship regarding frequency or type of TEAE among evobrutinib‐treated subjects. Absorption was rapid (time to reach maximum plasma concentration (Tmax) ~ 0.5 hour), half‐life short (~ 2 hours), and PK dose‐proportional, with no accumulation or time dependency on repeat dosing. BTK occupancy was dose‐dependent, reaching maximum occupancy of > 90% within ~ 4 hours after single doses ≥ 200 mg; the effect was long‐lasting (> 50% occupancy at 96 hours with ≥ 100 mg). After multiple dosing, full BTK occupancy was achieved with 25 mg, indicating slow turnover of BTK protein in vivo. Concentration‐QTcF analyses did not show any impact of evobrutinib concentration on corrected QT (QTc). In summary, evobrutinib was well‐tolerated, showed linear and time‐independent PK, induced long‐lasting BTK inhibition, and was associated with no prolongation of QT/QTc interval in healthy subjects. Evobrutinib is, therefore, suitable for investigation in autoimmune diseases.

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“…While in vitro and in vivo data can be collected and used for decisionmaking, the difficult question remains of translation to human. A comprehensive preclinical risk assessment can be constructed but, with the exception of individual drugs (e.g., Sparve et al, 2014) the paucity of quantitative clinical data limits our knowledge of the predictive value of preclinical information.…”

Section: Preclinical Detection Of Inotropic Effects Of Drugs Dr Chrismentioning

confidence: 99%

Cardiovascular safety risk assessment for new candidate drugs from functional and pathological data: Conference report

Klein¹,

Redfern²

2015

Journal of Pharmacological and Toxicological Methods

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Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839

Cited by 13 publications

References 26 publications

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

Cardiovascular safety risk assessment for new candidate drugs from functional and pathological data: Conference report

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