Dataset Information

No QTc prolongation with CDK 4/6 inhibitor FCN-437c: results of a concentration-QTc analysis from a dedicated study in adult healthy subjects.

ABSTRACT: Cardiotoxicity and QT interval prolongation have been a common cause of withdrawal of drugs from the market. FCN-437c is an oral, second-generation, potent, and selective CDK4/6 inhibitor for the treatment of patients with HR+/HER2- metastatic breast cancer. A single-center, double-blind, randomized, and placebo-controlled clinical study in healthy subjects was conducted to investigate the QTc prolongation potential of FCN-437c utilizing Concentration-QTc (C-QTc) modeling approach. FCN-437c was administered at doses of 300, and 400 mg with single oral administration, along with placebo, in 18 healthy subjects. Electrocardiograms (ECGs) through 24 h holter monitor and blood samples were collected. The C_max of 400 mg single dose in healthy subjects is similar to that from therapeutic dose 200 mg QD at steady state in patients with cancer. The 90% CI upper limit of ΔΔQTcF at the C_max geometric mean in both dose groups were <10 ms. It is concluded that FCN-437c has low risk of prolonging the QT interval at therapeutic dose.

Systematic review registration

https://clinicaltrials.gov/study/NCT06290466?term=NCT06290466&rank=1, identifier [NCT06290466].

SUBMITTER: Zhao L

PROVIDER: S-EPMC11346245 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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No QTc prolongation with CDK 4/6 inhibitor FCN-437c: results of a concentration-QTc analysis from a dedicated study in adult healthy subjects.

Zhao Lin L Sun Yi Y Yang Xiaoran X Tian Ling L Li Lize L Wang Fangfang F Niu Xiaoye X Diao Lei L Li Haiyan H

Frontiers in pharmacology 20240812

Cardiotoxicity and QT interval prolongation have been a common cause of withdrawal of drugs from the market. FCN-437c is an oral, second-generation, potent, and selective CDK4/6 inhibitor for the treatment of patients with HR+/HER2- metastatic breast cancer. A single-center, double-blind, randomized, and placebo-controlled clinical study in healthy subjects was conducted to investigate the QTc prolongation potential of FCN-437c utilizing Concentration-QTc (C-QTc) modeling approach. FCN-437c was ...[more]

PMID: 39188943

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Project description:In adults, alcohol intoxication is associated with prolongation of the QT interval corrected for heart rate (QTc). The QTc is influenced by age and sex. Although alcohol intoxication is increasingly common in adolescents, there are no data on the prevalence of QTc prolongation in adolescents with alcohol intoxication. This study aimed to determine the prevalence of QTc prolongation in adolescents with alcohol intoxication and identify at-risk adolescents. In this observational study including adolescents aged 10-18 years, heart rate and QT interval were automatically assessed from an electrocardiogram (ECG) at alcohol intoxication using a validated algorithm. The QTc was calculated using both the Bazett formula (QTcB) and Fridericia formula (QTcF). If present, an ECG recorded within 1 year of the date of admission to the emergency department was obtained as a reference ECG. A total of 317 adolescents were included; 13.3% had a QTcB and 7.9% a QTcF longer than the sex- and age-specific 95th-percentile. None of the adolescents had a QTcB or QTcF > 500 ms, but 11.8% of the adolescents with a reference ECG had a QTcB prolongation of > 60 ms, while no adolescents had a QTcF prolongation of > 60 ms. QTc prolongation was mainly attributable to an increase in heart rate rather than QT prolongation, which underlies the differences between QTcB and QTcF. Male sex and hypokalaemia increased the likelihood of QTc prolongation.Conclusion: QTc prolongation was seen in approximately 10% of the adolescents presenting with alcohol intoxication, and although no ventricular arrhythmias were observed in this cohort, QTc prolongation increases the potential for malignant QT-related arrhythmias. Clinicians must be aware of the possibility of QTc prolongation during alcohol intoxication and make an effort to obtain an ECG at presentation, measure the QT interval, and give an adequate assessment of the findings. We advocate admitting adolescents with alcohol intoxication and QTc prolongation. During hospital admission, we recommend limiting exposure to QTc-prolonging medication, increasing potassium levels to a high-normal range (4.5-5.0 mmol/L) and obtaining a reference ECG at discharge.

Project description:Sepiapterin is an exogenously synthesized new chemical entity that is structurally equivalent to endogenous sepiapterin, a biological precursor of tetrahydrobiopterin (BH4), which is a cofactor for phenylalanine hydroxylase. Sepiapterin is being developed for the treatment of hyperphenylalaninemia in pediatric and adult patients with phenylketonuria (PKU). This study employed concentration-QT interval analysis to assess QT prolongation risk following sepiapterin treatment. Data from three phase 1 studies and one phase 3 study were pooled for this analysis. Pediatric and adult PKU patients ≥ 2 years received multiple doses at 60 mg/kg and adult healthy volunteers received a single or multiple doses at 20 or 60 mg/kg. Time-matched triplicate ECG measurements and plasma samples for pharmacokinetic analysis were collected. Prespecified linear mixed models relating ΔQTcF to concentrations of sepiapterin and the major active circulating metabolite BH4 were developed for the analysis. The analysis demonstrated that there is no QTcF prolongation risk in patients with PKU following sepiapterin dosing at the highest therapeutic dose, 60 mg/kg/day. The final model showed a marginal but negligible QTcF reduction with increasing sepiapterin and BH4 concentrations. The effect on ΔQTcF was estimated to -2.72 [-3.72, -1.71] and - 1.25 [-2.75, 0.25] ms at mean baseline adjusted BH4 Cmax of 332 ng/mL (therapeutic exposure) and 675 ng/mL (supratherapeutic exposure) at dose 60 mg/kg, respectively, in PKU patients with food and in healthy volunteers with a high fat diet. Various covariates, such as clinical study ID, age, sex, food effect, race, body weight, and disease status, on QTcF interval were investigated and were found insignificant, except for food effect and age. This study concludes that there is no QTcF prolongation risk in patients with PKU following sepiapterin dosing up to 60 mg/kg/day, and BH4 and sepiapterin concentrations minimally affect ΔQTcF after adjustment for time, sex, and meal.

Dataset Information

No QTc prolongation with CDK 4/6 inhibitor FCN-437c: results of a concentration-QTc analysis from a dedicated study in adult healthy subjects.

Systematic review registration

Publications

No QTc prolongation with CDK 4/6 inhibitor FCN-437c: results of a concentration-QTc analysis from a dedicated study in adult healthy subjects.

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