Therapeutic drug monitoring to individualize the dosing of pazopanib: a pharmacokinetic feasibility study.

Abstract

Patients treated with the standard dose of pazopanib show a large interpatient variability in drug exposure defined as the area under the plasma concentration-time curve (AUC0-24h). The primary objective of this study was to evaluate the feasibility of pharmacokinetics (PK)-guided individualized dosing to reduce the interpatient variability in pazopanib exposure. Thirteen patients were treated with pazopanib for 3 consecutive periods of 2 weeks. During the first period, all patients received 800 mg of pazopanib once daily to reach steady-state exposure. During the second period, the patients either received a PK-guided individualized pazopanib dose or the registered fixed 800-mg dose. During the third period, these 2 dosing regimens were switched. The interpatient variability in pazopanib AUC0-24h during fixed dosing (27.3 coefficient of variation) was not significantly different when compared with the variability in AUC0-24h during PK-guided dosing (24.8 coefficient of variation). The percentage of patients within the target window during PK-guided dosing (53.9%) was not significantly different from the percentage during fixed dosing (46.2%). Both Ctrough and C24 were significantly (P < 0.001) correlated to pazopanib AUC0-24h (R = 0.596 and R = 0.940, respectively). Pazopanib AUC0-24h decreased 17% over time. PK-guided dosing did not reduce the interpatient variability in pazopanib exposure. In this study, the intrapatient variability in pazopanib exposure was relatively large compared with interpatient variability. This makes it challenging to achieve a target exposure within a predefined window. The causes of intrapatient variability must first be better understood and controlled, before PK-guided dosing can reduce the interpatient variability.