Population Pharmacokinetic Analysis of Pazopanib in Patients and Determination of Target AUC

Abstract

Pazopanib is a potent multi-targeted kinase inhibitor approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib is characterized by a significant inter- and intra-patient variability and a target through plasma concentration of 20.5 mg·L−1. However, routine monitoring of trough plasma concentrations at fixed hours is difficult in daily practice. Herein, we aimed to characterize the pharmacokinetic (PK) profile of pazopanib and to identify a target area under the curve (AUC) more easily extrapolated from blood samples obtained at various timings after drug intake. A population pharmacokinetic (popPK) model was constructed to analyze pazopanib PK and to estimate the pazopanib clearance of a patient regardless of the time of sampling. Data from the therapeutic drug monitoring (TDM) of patients with cancer at Institute Gustave Roussy and a clinical study (phase I/II) that evaluates the tolerance to pazopanib were used. From the individual clearance, it is then possible to obtain the patient’s AUC. A target AUC for maximum efficacy and minimum side effects of 750 mg·h·L−1 was determined. The comparison of the estimated AUC with the target AUC would enable us to determine whether plasma exposure is adequate or whether it would be necessary to propose therapeutic adjustments.

Relation between Plasma Trough Concentration of Pazopanib and Progression-Free Survival in Metastatic Soft Tissue Sarcoma Patients

“…The demographic and biological characteristics of that population were similar to our cohort (median age 53 years old, normal liver, and renal function). Although the population from Yu et al included more male patients (78%) than our cohort (52%), sex is not a significant covariate on pazopanib PK, as previously reported by Ozbey et al [10]., which confirmed that the model by Yu et al could be used to predict PK parameters in our STS patient cohort.…”

“…Blood samples were drawn at steady state every two weeks for the first three months and then monthly. Given that the half-life of pazopanib is approximatively 31 h, the steady state was considered to be reached after at least 15 days following either treatment initiation or dosage adjustment [10,20]. Blood was collected in 5-mL lithium heparinized Vacutainer tubes at any time over the administration interval.…”

“…PAZ is administered orally at a flat-fixed dose, despite a large interpatient pharmacokinetic (PK) variability and a low therapeutic index [4,[7][8][9][10]. Pharmacokinetic/ pharmacodynamic (PK/PD) studies have reported relationships between exposure and treatment outcomes (efficacy and toxicity) for several tyrosine kinase inhibitors (TKI), suggesting a potential interest for drug monitoring [7,[11][12][13][14].…”

Therapeutic Drug Monitoring of Pazopanib in Renal Cell Carcinoma and Soft Tissue Sarcoma: A Systematic Review

“…Pazopanib is metabolized to a lesser extent by CYP1A2 and CYP2C8. Similarly, pazopanib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) 1,9 ; therefore, genetic polymorphisms of these transporters may influence treatment outcomes or the toxicity of some drugs, including TKIs. 10,11 Elimination primarily occurs through feces, with an elimination half-life of approximately 31 hours.…”

“…10,11 Elimination primarily occurs through feces, with an elimination half-life of approximately 31 hours. 1,9 Although the differential pharmacokinetics of pazopanib between patients may be at least in part attributed to any of these factors, sex does not seem to affect pazopanib exposure. 3,12…”