Erlotinib: another candidate for the therapeutic drug monitoring of targeted therapy of cancer? A pharmacokinetic and pharmacodynamic systematic review of literature.
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.
*Department of Pharmacy, Paul Strauss Cancer Center, Strasbourg, France; †Division of Clinical Pharmacology, University Hospital Center and University of Lausanne; ‡School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland; §Department of Pneumology; and ¶Department of Pharmacy, University Hospital Center and University of Strasbourg; ‖Translational Federation of Medicine and Faculty of Pharmacy, University of Strasbourg, Strasbourg, France; and **Pharmacy of Eastern Vaud Hospitals, Vevey, Switzerland.
Emilie
E
Petit-Jean
Thierry
T
Buclin
Monia
M
Guidi
Elisabeth
E
Quoix
Bénédicte
B
Gourieux
Laurent A
LA
Decosterd
Anne-Cécile
AC
Gairard-Dory
Geneviève
G
Ubeaud-Séquier
Nicolas
N
Widmer
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring / Q000379:methods*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride