Population pharmacokinetics of HM781-36 (poziotinib), pan-human EGF receptor (HER) inhibitor, and its two metabolites in patients with advanced solid malignancies
Abstract
Purpose To develop a population pharmacokinetic (PK) model for HM781-36 (poziotinib) and its metabolites in cancer patients.Methods Blood samples were collected from three phase I studies in which fifty-two patients received oral HM781-36B tablets (0.5-32 mg) once daily for 2 weeks, and another 20 patients received oral HM781-36B tablets (12, 16, 18, 24 mg) in fasting (12 patients) or fed (eight patients) state once daily for 4 weeks. Nonlinear mixed effect modeling was employed to develop the population pharmacokinetic model.Results HM781-36 PK was ascribed to a two-compartment model and HM781-36-M1/-M2 PK to one-compartment model. HM781-36 oral absorption was characterized by first-order input (absorption rate constant: 1.45 ± 0.23 h⁻¹). The central volume of distribution (185 ± 12.7 L) was influenced significantly by body weight. The absorption rate constant was influenced by food. The typical HM781-36 apparent clearance was 34.5 L/h (29.4 %CV), with an apparent peripheral volume of distribution of 164 L (53.5 %CV). Other covariates did not significantly further explain the PKs of HM781-36.Conclusions The proposed model suggests that HM781-36 PKs are consistent across most solid tumor types, and that the absorption process of HM781-36 is affected by the fed state before dosing. HM781-36 PKs are not complicated by patient factors, other than body weight.
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In that prior phase 2 trial, the objective response rate to poziotinib was 8%.
“there was an 8% ORR to poziotinib39”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [39]
In that prior phase 2 trial, 46% of patients had a minor response to poziotinib.
“However, 46% of patients had a minor response to poziotinib39.”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [39]
In a prior phase 2 trial of EGFR-mutant NSCLC with acquired resistance to erlotinib or gefitinib, 49% of patients carried T790M.
“In a recent phase 2 study of EGFR-mutated NSCLC with acquired resistance to erlotinib or gefitinib, in which 49% of patients had a T790M mutation”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [39]
A prior phase 2 study of poziotinib in patients with NSCLC bearing sensitizing EGFR mutations found that MET amplification, PIK3CA mutations, and EGFR T790M mutations were mechanisms of resistance.
“Furthermore, a recent phase 2 study of poziotinib in patients with NSCLC bearing sensitizing mutations in EGFR (exon 19 deletions or the mutation encoding p.L858R) found that MET amplification, PIK3CA mutations, and EGFR T790M mutations were mechanisms underlying resistance39.”
From Mechanisms and clinical activity of an EGFR and HER2 exon 20–selective kinase inhibitor in non–small cell lung cancer (2018) · cites this paper as [39]
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References 17 · Cited by 15
- Authors
- Noh, Y.-H., Lim, H.-S., Jung, J.-A., Song, T. H., & Bae, K.-S.
- Affiliations
- Inje University Busan Paik Hospital (KR)
- Asan Medical Center (KR)
- Hanmi Pharmaceutical (South Korea) (KR)
- Corresponding author
- Bae, Kyun-Seop
- Venue
- Cancer Chemotherapy and Pharmacology
- Published
- 2014-11-07
- Volume
- 75
- Issue
- 1
- Pages
- 97-109
- ISSN
- 0344-5704 (ISSN-L)
- 1432-0843
- OpenAlex
- W2077919240
- Cited by
- 15
- References
- 17
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 3 · 2021: 2 · 2019: 1 · 2018: 3 · 2017: 2 · 2016: 2
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cancer Chemotherapy and Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Keywords
- poziotinib, population pharmacokinetics, EGFR inhibitors, drug metabolites, advanced solid tumors, food effect on absorption, body weight covariate, oral absorption, clearance, volume of distribution
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Biotransformation, Dose-Response Relationship, Drug, Female, Half-Life, Humans, Hydroxylation, Intestinal Absorption, Male, Metabolic Clearance Rate, Methylation, Middle Aged, Models, Biological, Neoplasms, Quinazolines, Tablets, Drugs, Investigational, Food-Drug Interactions, ErbB Receptors
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