Erlotinib

Abstract

Erlotinib is currently marketed at fixed standard dosage against pancreatic cancer and non-small-cell lung carcinoma. However, erlotinib pharmacokinetics (PK) is characterized by significant variability that may affect efficacy and tolerability. The aim of this review is to assess evidence that would justify therapeutic drug monitoring (TDM) and provide key information for the interpretation of erlotinib plasma concentrations. Literature was systematically reviewed to evaluate the standard criteria defining the potential clinical usefulness of TDM. Assessment was focused on the existence of unpredictable and wide PK variability and of consistent PK-pharmacodynamic relationships. PK parameters actually show marked variability (apparent clearance estimated to 4.85 ± 4.71 L/h, elimination half-life to 21.86 ± 28.35 hours, and apparent volume of distribution to 208 ± 133 L). Many covariates influence these parameters (CYP3A4 inducers or inhibitors, food, age, liver impairment), but most sources of variability still have to be identified. Some studies have demonstrated a relationship between exposure to erlotinib and clinical outcomes or skin toxicity. Erlotinib activity and target concentrations furthermore depend on tumor characteristics (eg, mutations on epidermal growth factor receptor and on K-ras). These results are in favor of TDM in addition to treatment adjustment for tumor biomarkers, but prospective clinical trials validating its clinical benefits are lacking. This review provides all the relevant information available to assist clinical interpretation of erlotinib plasma measurements. PK percentile curves and consideration to covariates yield information on whether a concentration measured is expected, whereas half maximal inhibitory concentration values determined in vitro provide preliminary insights on target concentration values to reach. Eventually, dosage adaptation might be considered in patients with intolerable toxicity because of excessive plasma levels or conversely nonresponse imputable to insufficient exposure.

The Steps to Therapeutic Drug Monitoring: A Structured Approach Illustrated With Imatinib

“…Covariates commonly include patient's sex, age, body weight, and serum creatinine, but can also comprise defined comorbidities, comedications, genetic traits, etc. When several population PK studies are available, either the "best" one can be selected based on quality criteria, or one may aggregate their results using recent techniques of model-based meta-analysis (Petit-Jean et al, 2015;Nanga et al, 2019). The quintessence of this information can be summarized graphically into prediction percentiles for circulating drug concentrations under a given standard dosage ( Figure 1).…”

Therapeutic Drug Monitoring of Erlotinib in Non-Small Cell Lung Carcinoma: A Case Study

“…The large interindividual variability in systemic exposure, combined with the positive exposure–efficacy relationship and low therapeutic index of TKIs, represents a strong rationale for TDM of these drugs. 3,5…”

“…The large interindividual variability in systemic exposure, combined with the positive exposureefficacy relationship and low therapeutic index of TKIs, represents a strong rationale for TDM of these drugs. 3,5 TDM is a quick and easy tool that allows the determination of plasma concentrations of erlotinib and guides individualized dose adjustments for each patient, facilitating the goal of optimal drug exposure.…”

Preclinical assessment of the interactions between the antiretroviral drugs, ritonavir and efavirenz, and the tyrosine kinase inhibitor erlotinib

“…Currently, it is recommended to avoid the use of erlotinib with a potent inhibitor or a potent inducer, which is further supported by hepatocyte data which demonstrated a 16-fold decrease by ritonavir and a 2.2-fold increase by efavirenz in apparent intrinsic clearance of erlotinib [19, 20]. Erlotinib is a known substrate for ABCB1 and ABCG2 [21]. …”