Pharmacokinetics and Pharmacodynamics of Tyrosine Kinase Inhibitors in the Treatment of Metastatic Renal Cell Carcinoma

Figures & data

Table 1. Pharmacokinetic parameters of tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma.

	Axitinib	Pazopanib	Sorafenib	Sunitinib
Recommended daily dose	5 mg b.i.d.	800 mg q.d.	400 mg b.i.d.	50 mg q.d. (4/2)
F (%)	58	14–39	38–49	Unknown
Food effect	No	Yes	Controversed	No
Tmax (h)	3–6	3.5	2–14	6–12
Protein binding (%)	>99.0	>99.9	>99.5	95.0 sunitinib 90.0 SU12662
V/F (l)	160	25.2	213^†	2230
Metabolism	Major: CYP3A4 Minor: CYP1A2, CYP2C19, UGT1A1	Major: CYP3A4 Minor: CYP1A2, CYP2C8	Major: UGT1A9 Minor: CYP3A4	CYP3A4
Active metabolite	–	–	N-oxyde sorafenib	SU12662
Elimination	Hepatic	Hepatic	Hepatic + EC	Hepatic
CL/F (L/h)	38	0.605	8.13	34–62
t1/2(h)	2.5–6.1	31	25–48	40–60 sunitinib 80–110 SU12662
Transporter substrate	P-gp, BCRP, OATP1B1, OATP1B3	P-gp, BCRP, OATP1B1	P-gp, BCRP	P-gp, BCRP
Dose-exposure linearity	Yes	Up to 800 q.d.	Up to 400 mg b.i.d.	Yes
AUCss,0-τ	380 ng.h/ml	275 μg.h/ml	47.8 μg.h/ml	1592 ng.h/ml
Css,max	31.0 ng/ml	45.1 μg/ml	5.40 μg/ml	91.9 ng/ml
Ref.	[4–8,10]	[12–19]	[19–23]	[19,24–31]

^†Assuming median body weight of 80 kg.

4/2: 4-week dosing, followed by 2-week rest; AUC_ss,0-τ: Steady-state area under the concentration–time curve in the dosing interval; b.i.d.: Twice daily; CL/F: Apparent oral clearance; Css,_max: Steady-state maximum plasma concentration; EC: Enterohepatic circulation; F: Absolute bioavailability; NA: Not available; q.d.: Once daily; t_1/2: Elimination half-life; T_max: Time to peak concentration; V/F: Apparent volume of distribution.

Table 2. Drug–drug interactions with tyrosine kinase inhibitors based on reported clinical data.

Drug	Type of interaction	Axitinib	Pazopanib	Sorafenib	Sunitinib
Ketoconazole	CYP3A4 inhibition	Increased AUC (2.06-fold) Increased Cmax (1.5-fold) [37]	Increased AUC (66%) Increased Cmax (45%) [68]		Increased composite AUC (51%) Increased composite Cmax (49%) [26]
Rifampicin	CYP3A4 induction	Decreased AUC (79%) Decreased Cmax (71%) [38]	Possible decrease in AUC and Cmax [68]		Decreased composite AUC (46%) Decreased composite Cmax (23%) [26]
Esomeprazole	Increase in gastric pH		Decreased AUC (40%) Decreased Cmax (40%) [68,69]
Felodipine	CYP3A4 competition			Increased Ctrough [143]
Prednisolone	CYP3A4 induction			Decreased Ctrough (>twofold) [142]
Nicardipine	CYP3A4 inhibition				Increased composite AUC (50%) [96]

AUC: Area under the concentration-time curve; C_max: Maximum plasma concentration level; C_trough: Minimum plasma concentration level; CYP3A4: Cytochrome P450 3A4.

Table 3. Relationship between pharmacokinetic parameters, efficacy and safety of tyrosine kinase inhibitors in metastatic renal cell carcinoma patients.

TKI	N	PK parameter	Outcome	Results	p-value	Ref.
Efficacy
Axitinib	112	Dose titration vs placebo titration	OR	54.0 vs 34.0%	0.019	[42]
		AUC0–24 ≥ vs < 261 ng.h/ml	PFS	13.0 vs 16.5 months	0.981
	49	C1–2: 45.2–56.4 ng/ml	OS	Not reached vs 20.3–27.7 months for patients in 3rd quartile with C1–2: 45.2–56.4 ng/ml compared with other quartiles	NA	[44]
		AUC0–12: 154–620 ng.h/ml	PFS	28.3 vs 7.5–11.8 months	NA
			ORR	81.8 vs 16.7–53.8%	NA
	168	AUC0–24 ≥ vs < 300 ng.h/ml	OS	37.4 vs 15.8 months	<0.001	[33]
			PFS	13.8 vs 7.40 months	0.003
Pazopanib	10	Ctrough ≥ vs < 15 μg/ml	PR + SD	83 vs 0%	NA	[12]
	205	Ctrough ≥ vs < 20.5 μg/ml	PFS	52.0 vs 19.6 weeks	0.0038	[45]
			RR	45.0 vs 19.0%	<0.0001
			Tumor shrinkage	37.9 vs 6.90%	<0.0001
Sunitinib	146	Composite AUC0–24 ≥ vs < 800 ng.h/ml	TTP	Longer TTP with increasing AUC0–24	0.001	[46]
			OS	Longer OS with increasing AUC0–24	0.010
			ORR	ORR increased with increasing AUC0–24	<0.001
	55	AUC ≥ vs < 1973 ng.h/ml	OS	35.2 vs 16.7 months	0.0051	[47]
Sorafenib		No study in mRCC
Safety
Axitinib	20	AUC0–6	Fatigue	129.4 vs 87.1 ng.h/ml for patients with and without fatigue	0.013	[39]
			Hoarseness, diarrhea Hypertension	No correlation	>0.05
		AUC0–6 ≥ vs < 97.3 ng.h/ml	Treatment period without discontinuation or dose reduction due to AE	Median: 35 days vs not reached	0.024
Pazopanib	54	Ctrough 12.6–46 μg/ml	Hypertension	77.0 vs 39.0%	NA	[12]
	205	Ctrough ≥ vs < 15 μg/ml	Diarrhea, hair color change, ALT increase, HFS and stomatitis	Increased incidence of AEs by twofold	NA	[48]
	205	Ctrough	HFS	Positive relationship	<0.01	[49]
Sorafenib	51	AUCcum	Any grade ≥3 toxicity	Odds ratio = 1.07	0.03	[50]
	52	Ctrough	Grade ≥2 HFS	Ctrough higher in patients exhibiting grade ≥2 HFS	0.0045	[51]
			Grade ≥2 hypertension	Ctrough higher in patients exhibiting grade ≥2 hypertension	0.0453
	72	AUC0–12	Any grade 3–4 toxicity	AUC0–12: 61.9 μg.h/ml vs 53.0 μg.h/ml for patients with and without AE	0.017	[52]
	22	Ctrough	Any grade ≥3 toxicity	7.70 vs 4.40 μg.ml for patients with and without AE	0.0083	[53]
	94	Ctrough >10.0 μg/ml	Any grade 3–4 toxicity		<0.042	[54]
Sunitinib	28	Composite Ctrough >100 ng/ml	DLT	More frequent DLT	NA	[29]
	443	Composite AUC0–24	Fatigue	Positive relationship	NA	[46]
		Composite AUCcum	Neutropenia	Negative relationship	NA
		Composite Ctrough	dBP	Positive relationship	NA
	36	Composite Ctrough	Grade ≥2 mucositis	126.5 vs 84.8 ng/ml for patients with ≥ or < grade 2 mucositis	0.04	[55]
			Altered taste	159.9 vs 105.2 ng/ml for patients with ≥ or < grade 2 altered taste	0.05
	21	Composite Ctrough ≥ vs < 100 ng/ml	Any grade ≥3 toxicity	75.0 vs 23.1%	NA	[56]
		Composite Ctrough	Grade ≥3 thrombocytopenia, anorexia	Concentration-dependent severity of AEs	< 0.05
	92	Sunitinib AUC0–24	Any grade ≥3 toxicity	Odds ratio = 1.16	0.005	[47]
		SU12662 AUC0–24	Grade ≥ 2 thrombocytopenia	Odds ratio = 1.27	0.028
	19	Ctrough ≥ vs < 90 ng/ml	Grade ≥2 thrombocytopenia	100 vs 55.6%	0.033	[57]
			Grade ≥2 hypertension	90.0 vs 22.2%	0.0055
	24	Composite Ctrough ≥ vs < 180 ng/ml	QT interval	15.4 vs 9.60 ms	NA	[58]
	52	CL/F	Any grade 3 toxicity	34.4 vs 41.4 L/h for patients with and without grade 3 AE	0.025	[59]
		Composite Ctrough	Fatigue	Positive relationship	0.007

AE: Adverse event; AUC: Area under the concentration-time curve; AUC_cum: Cumulative AUC; C_1–2: Concentration 1–2 h post-dose; CL/F: Apparent oral clearance; C_trough: Minimum plasma concentration level; Composite C_trough: C_trough sunitinib + metabolite; Composite AUC: AUC sunitinib + metabolite; dBP: Diastolic blood pressure; DLT: Dose-limiting toxicity; HFS: Hand-foot syndrome; NA: Not available; OR: Objective response; ORR: Objective response rate; OS: Overall survival; PD: Progressive disease; PFS: Progression-free survival; PR: Partial response; RR: Response rate; SD: Stable disease; sVEGFR2: Soluble VEGF receptor 2; TKI: Tyrosine kinase inhibitor; TTP: Time to progression.

Table 4. Evidences and guidelines for therapeutic drug monitoring of tyrosine kinase inhibitors in metastatic renal cell carcinoma patients.

TKI	Interindividual variability (CV%)		Intraindividual variability (CV%)		Target exposure	Guidelines	Ref.
	Ctrough	AUC0–24	Ctrough	AUC0–24
Axitinib	NA	17–94%	20–22%	20–33%	NA	No guidelines based on pharmacological evidences
Pazopanib	11–90%	19–77%	NA	NA	Ctrough ≥20.5 μg/ml	Ctrough <15.0 μg/ml without grade >2 AE: ↗ 400 mg q.d./step Ctrough <15.0 μg/ml with grade 2 AE: ↗ 200 mg q.d./step 15 μg/ml > Ctrough < 19.90 μg/ml without grade > 3 AE: ↗ 200 mg q.d./step	[45,72,157]
Sorafenib	25–104%	12–117%	NA	31–47%	NA	No guidelines in mRCC patients
Sunitinib	34–59%	13–49%	NA	NA	50 ng/ml > composite Ctrough <100 ng/ml	Composite Ctrough <50 ng/ml without grade ≥3 AE: ↗ 12.5 mg q.d./step Composite Ctrough ≥50 ng/ml with grade ≥3 AE: ↗ 12.5 mg q.d./step	[29,56,124,157]

AE: Adverse event; AUC: Area under the concentration–time curve; b.i.d.: Twice daily; Composite C_trough: C_trough sunitinib + metabolite; C_trough: Minimum plasma concentration level; CV: Coefficient of variation; mRCC: Metastatic renal cell carcinoma; NA: Not available; q.d.: Once daily.

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