Your browser doesn't support javascript.
loading
Population pharmacokinetic modelling of tremelimumab in patients with advanced solid tumours and the impact of disease status on time-varying clearance.
Hwang, Michael; Chia, Yen Lin; Zheng, Yanan; Chen, Cecil Chi-Keung; He, Jimmy; Song, Xuyang; Zhou, Diansong; Goldberg, Sarah B; Siu, Lillian L; Planchard, David; Peters, Solange; Mann, Helen; Krug, Lee; Even, Caroline.
Afiliación
  • Hwang M; Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, South San Francisco, CA, USA.
  • Chia YL; Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, South San Francisco, CA, USA.
  • Zheng Y; Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, South San Francisco, CA, USA.
  • Chen CC; Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, South San Francisco, CA, USA.
  • He J; Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • Song X; Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • Zhou D; Clinical Pharmacology and Quantitative Pharmacology, Biopharmaceuticals R&D, AstraZeneca, Boston, MA, USA.
  • Goldberg SB; Department of Medicine (Section of Medical Oncology), Yale School of Medicine, New Haven, CT, USA.
  • Siu LL; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Planchard D; Department of Medical Oncology, Thoracic Unit, Institut Gustave-Roussy, Villejuif, France.
  • Peters S; Department of Oncology CHUV-UNIL, University Hospital Lausanne, Lausanne, Switzerland.
  • Mann H; Oncology Biometrics, Oncology R&D, AstraZeneca, Cambridge, UK.
  • Krug L; Late Development Oncology R&D, AstraZeneca, Gaithersburg, MD, USA.
  • Even C; Head and Neck Department, Institut Gustave-Roussy, Villejuif, France.
Br J Clin Pharmacol ; 89(5): 1601-1616, 2023 05.
Article en En | MEDLINE | ID: mdl-36454221
ABSTRACT

AIMS:

Tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 human monoclonal antibody of the immunoglobulin G2 κ isotype, has been studied in oncology clinical trials as both monotherapy and in combination with durvalumab. This study characterized the pharmacokinetics of tremelimumab as monotherapy and in combination with durvalumab and evaluated the impact of patient covariates on pharmacokinetics.

METHODS:

A pooled-analysis population pharmacokinetics model was built using NONMEM methodology. Pharmacokinetic data from 5 studies spanning different tumour types and therapy regimens were pooled for model development (956 patients). A dataset pooled from 4 additional studies was used for external validation (554 patients). Demographic and relevant clinical covariates were explored during model development.

RESULTS:

Tremelimumab exhibited linear pharmacokinetics, well described by a 2-compartment model, with time-varying clearance (0.276 L/day at baseline) associated primarily with therapy regimen and linked with changes in disease status. As monotherapy and combination therapy, tremelimumab clearance over 1 year increased by ~16% and decreased by ~17%, respectively. Pharmacokinetic behaviour was consistent across patient demographics and cancer subtypes. Patients with higher bodyweight and lower albumin levels at baseline had significantly higher clearance; however, no dosage adjustments are warranted. A flat dose (75 mg) was projected to provide comparable exposure to weight-based dosing (1 mg/kg) in adults.

CONCLUSION:

Tremelimumab exhibited linear pharmacokinetics but consistently opposite trends of time-varying clearance as monotherapy and in combination with durvalumab. Baseline bodyweight and albumin were significant covariates, but conversion from weight-based dosing at 1 mg/kg to flat dosing at 75 mg had no clinically relevant impact.
Asunto(s)
Palabras clave

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Límite: Adult / Humans Idioma: En Revista: Br J Clin Pharmacol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Neoplasias Límite: Adult / Humans Idioma: En Revista: Br J Clin Pharmacol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos