Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma

Thomas, Fabienne; Rochaix, Philippe; White-Koning, Mélanie; Hennebelle, Isabelle; Sarini, J.; Benlyazid, A.; Malard, Laurence; Lefebvre, Jean‐Louis; Chatelut, Étienne; Delord, Jean Pierre

doi:10.1016/j.ejca.2009.05.007

Cited by 72 publications

(61 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ABCB1 variants (2677G>T, 2677G>A and 3435C>T) were determined by PCR-RFLP as previously described (26,27). ABCG2 421C>A variant was determined by polymerase chain reaction (PCR) and direct sequencing as published before (21). The presence of CYP3A5*1/CYP3A5*3 alleles was determined on genomic DNA with allele specific real time PCR as previously described (28).…”

Section: Genetic Analysismentioning

confidence: 99%

See 1 more Smart Citation

Population Analysis of Erlotinib in Adults and Children Reveals Pharmacokinetic Characteristics as the Main Factor Explaining Tolerance Particularities in Children

White-Koning

Civade

Geoerger

et al. 2011

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: The aim of this pharmacokinetic-pharmacodynamic (PK-PD) analysis was to evaluate the pharmacologic characteristics of erlotinib and its main metabolite (OSI-420) in pediatric patients compared with those in adult patients.Experimental Design: Plasma concentrations of erlotinib and OSI-420 of 46 children with malignant brain tumors included in a phase I study and 42 adults with head and neck carcinoma were analyzed by a population-pharmacokinetic method (NONMEM). The effect of several covariates and single nucleotide polymorphisms (SNP) in ABCB1, ABCG2, and CYP3A5 on pharmacokinetic parameters was evaluated. PK/ PD relationships between plasma drug exposure Area Under the Curve (AUC) at day 1 and skin toxicity were studied in children and compared with the relationship observed in adults.Results: A significant difference in erlotinib clearance (P ¼ 0.0001), when expressed in LÁh À1 Ákg À1 , was observed between children and adults with mean values of 0.146 and 0.095, respectively (mean difference ¼ 0.051 LÁh À1 Ákg À1 , SD ¼ 0.0594). However, a common covariate model was obtained describing erlotinib clearance according to body weight, alanine aminotransferase, ABCB1, and CYP3A5 polymorphisms (2677G > T/A and 6986G > A) for both children and adult patients. The PK-PD relationship was very consistent between the children and adult groups with risk of skin toxicity rising with increasing erlotinib AUC. Conclusions:The nonlinear population approach applied to pharmacokinetic data combined with a pharmacokinetic-pharmacodynamic analysis revealed that the higher recommended dose in children (125 mg/m 2 /day) compared with adults (90 mg/m 2 /day) is mainly due to pharmacokinetic rather than pharmacodynamic particularities. Clin Cancer Res; 17(14); 4862-71. Ó2011 AACR.

show abstract

Section: Genetic Analysismentioning

confidence: 99%

“…The adult pharmacokinetic data was provided by a neoadjuvant pilot study carried out in patients with head and neck carcinoma (20,21) and the pediatric data come from a phase 1 study in children with malignant brain-tumors (12). First, both datasets were combined to evaluate PK characteristics.…”

Section: Introductionmentioning

confidence: 99%

Population Analysis of Erlotinib in Adults and Children Reveals Pharmacokinetic Characteristics as the Main Factor Explaining Tolerance Particularities in Children

White-Koning

Civade

Geoerger

et al. 2011

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Erlotinib was also approved by the United States for the treatment of locally advanced, unresectable or metastatic pancreatic cancer in combination with gemcitabine [5] . In addition, clinical trials in a number of other solid tumors are also underway [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib

et al. 2011

View full text Add to dashboard Cite

Aim: To ascertain the effects of erlotinib on CYP3A, to investigate the amplitude and kinetics of erlotinib-mediated inhibition of seven major CYP isoforms in human liver microsomes (HLMs) for evaluating the magnitude of erlotinib in drug-drug interaction in vivo. Methods: The activities of 7 major CYP isoforms (CYP1A2, CYP2A6, CYP3A, CYP2C9, CYP2D6, CYP2C8, and CYP2E1) were assessed in HLMs using HPLC or UFLC analysis. A two-step incubation method was used to examine the time-dependent inhibition of erlotinib on CYP3A.Results: The activity of CYP2C8 was inhibited with an IC 50 value of 6.17±2.0 μmol/L. Erlotinib stimulated the midazolam 1′-hydroxy reaction, but inhibited the formation of 6β-hydroxytestosterone and oxidized nifedipine. Inhibition of CYP3A by erlotinib was substratedependent: the IC 50 values for inhibiting testosterone 6β-hydroxylation and nifedipine metabolism were 31.3±8.0 and 20.5±5.3 μmol/L, respectively. Erlotinib also exhibited the time-dependent inhibition on CYP3A, regardless of the probe substrate used: the value of K I and k inact were 6.3 μmol/L and 0.035 min -1 for midazolam; 9.0 μmol/L and 0.045 min -1 for testosterone; and 10.1 μmol/L and 0.058 min -1 for nifedipine. Conclusion: The inhibition of CYP3A by erlotinib was substrate-dependent, while its time-dependent inhibition on CYP3A was substrateindependent. The time-dependent inhibition of CYP3A may be a possible cause of drug-drug interaction, suggesting that attention should be paid to the evaluation of erlotinib's safety, especially in the context of combination therapy.

show abstract

“…Erlotinib is the first targeted therapeutic agent for the treatment of patients with either locally advanced or metastatic NSCLC [6] , which is the most common type of lung cancer and accounts for 80%-85% of lung cancer cases [7] . Erlotinib is a potent EGFR tyrosine kinase inhibitor that blocks EGFRmediated intracellular signaling, which can block the autophosphorylation of EGFR, prevent the generation of pEGFR and subsequently inhibit a series of downstream signaling pathways, which then inhibits cell proliferation and angiogenesis [8] .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

et al. 2013

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: Erlotinib is used to treat non-small-cell lung cancer (NSCLC), which targets epidermal growth factor receptor (EGFR) tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR (pEGFR) levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model. Methods: Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib (4, 12.5, or 50 mg/kg). Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration. The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays. Results: The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC 50 value of 1.80 μg/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a K bio value of 0.507 cm 3 /week, which described the impact of pEGFR degradation on tumor growth. Conclusion: The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.

show abstract

Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma

Cited by 72 publications

References 18 publications

Population Analysis of Erlotinib in Adults and Children Reveals Pharmacokinetic Characteristics as the Main Factor Explaining Tolerance Particularities in Children

Population Analysis of Erlotinib in Adults and Children Reveals Pharmacokinetic Characteristics as the Main Factor Explaining Tolerance Particularities in Children

Substrate-dependent modulation of the catalytic activity of CYP3A by erlotinib

Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model

Contact Info

Product

Resources

About