The pharmacokinetics of pazopanib are described by low, non-linear and time-dependent bioavailability and large interpatient variability. |
A multitude of pharmacokinetic and pharmacodynamic biomarkers have been proposed for pazopanib, but only area under the concentration–time curve (AUC) and minimum concentration (C
min) have been studied prospectively to individualize treatment. |
There are opportunities to optimize pazopanib dosing through monitoring of C
min and by switching to twice-daily dosing in selected patients. These strategies hold promise to optimize pazopanib dose selection and individualization and improve treatment outcomes for cancer patients. |
1 Introduction
2 Physiochemical Properties and Preclinical Pharmacology
2.1 Physiochemical Properties
2.2 Mechanism of Action and Preclinical Pharmacology
3 Clinical Pharmacokinetics
3.1 Pharmacokinetics in Cancer Patients
3.2 Pharmacokinetics in Special Populations
3.2.1 Pediatric Cancer Patients
3.2.2 Patients with Renal Impairment
3.2.3 Patients with Hepatic Impairment
3.3 Food Effect
3.4 Drug–Drug Interaction Studies
4 Clinical Pharmacodynamics
4.1 Pharmacodynamic Markers
Study | Tumor type |
N
| Matrix | Biomarker | Association |
p value |
---|---|---|---|---|---|---|
Sleijfer et al. [34] | STS | 85 | Serum | High sVEGFR2 (12 weeks)a
| PFS12wks↑ | 0.0039 |
Low PlGF (12 weeks) | PFS12wks↑ | 0.0318 | ||||
OS ↑ | 0.0009 | |||||
Low IL12 p40 | PFS12wks↑ | 0.0305 | ||||
Low MPC3 | PFS12wks↑ | 0.0271 | ||||
Low HGF | PFS ↑ | 0.0079 | ||||
Low bNGF | PFS ↑ | 0.0044 | ||||
Low ILra2 | OS ↑ | 0.0078 | ||||
ICAM-1 | OS ↑ | 0.0072 | ||||
Tran et al. [36] | RCC | 129 | Plasma | Low IL8 | PFS ↑ | 0.006 |
Low HGF | PFS ↑ | 0.010 | ||||
Low TIMP-1 | PFS ↑ | 0.006 | ||||
Low osteopontin | PFS ↑ | 0.0004 | ||||
Xu et al. [38] | RCC | 397 | Whole blood | IL8 2767A>T | PFS | 0.009 |
IL8 251 T>A | PFS | 0.01 | ||||
HIF1A 1790 G>A | PFS | 0.03 | ||||
RR | 0.02 | |||||
NR1I2 25385 C>T | RR | 0.03 | ||||
VEGFA 2578 A>C | RR | 0.02 | ||||
VEGFA 1498 C>T | RR | 0.02 | ||||
VEGFA 634 G>C | RR | 0.03 | ||||
Sweis et al. [41] | RCC | 18 | DCE-MRI | High Ktrans
| PFS ↑ | 0.036 |
4.1.1 Pharmacodynamics in Soft Tissue Sarcoma
4.1.2 Pharmacodynamics in Renal cell Carcinoma
4.2 Exposure–Response Analyses
Relationship | Pharmacokinetic parameter |
N
| Tumor type | Value | Association |
p value | References |
---|---|---|---|---|---|---|---|
Efficacy |
C
max
| 36 | Thyroid cancer |
r = –0.40†
| Maximum tumor size reduction ↑ | 0.021 | [4] |
C
min
| 177 | Renal cancer | ≥20.5 mg/L threshold | PFS ↑ | 0.0038 | [21] | |
C
min
| 177 | Renal cancer | ≥20.5 mg/L threshold | Maximum tumor size reduction ↑ | <0.001 | [21] | |
C
min
a
| 30 | Advanced solid tumors | ≥20.0 mg/L threshold | Maximum tumor size reduction ↑ | 0.01 | [36] | |
Toxicity |
C
min
| 54 | Renal cancer |
r = 0.95‡
| Blood pressure ↑ | 0.0075 | [21] |
C
min
| 59 | Pediatric advanced solid tumors |
C
min 38.8 ± 11.1 vs. 29.6 ± 13.6 mg/L | Any DLT ↑ | 0.04 | [15] | |
C
min
| 38 | Pediatric advanced solid tumors |
C
min 43.7 ± 13.3 vs. 29.4 ± 13.0 mg/L | Blood pressure ↑ | 0.004 | [15] | |
AUC0–24
| 29 | Pediatric advanced solid tumors |
r = 0.595‡
| DLT cycle 1 ↑ | 0.01 | [15] |