Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors

Figures & data

Table 1 Compartmental pharmacokinetic parameters of sum total CPT-11 after IHL-305 in patients with linear and nonlinear disposition

Parameters	Units	Linear pharmacokinetic disposition		Nonlinear pharmacokinetic disposition
		Age <60 years mean ± SD (range) n=15	Age ≥60 years mean ± SD (range) n=15	All ages mean ± SD (range) n=8
k10	(h^−1)	0.031±0.0098 (0.016–0.046)	0.034±0.0077 (0.019–0.047)	–
t½a	(h)	24.9±8.1 (15.0–43.7)	21.3±5.6 (14.8–35.8)	11.6±3.8 (7.8–17.0)
Vc	(L/m^2)	1.6±0.45 (0.90–2.70)	1.6±0.55 (1.14–2.86)	1.6±0.36 (1.08–2.12)
CL	(L/h/m^2)	0.048±0.024 (0.021–0.12)	0.055±0.027 (0.023–0.12)	–
k12	(h^−1)	–	–	0.15±0.070b (0.10–0.20)
k21	(h^−1)	–	–	0.095±0.040b (0.066–0.12)
Km	(ng/mL)	–	–	32.8±31.3 (0.93–92.7)
Vmax	(ng/h)	–	–	4.54±3.39 (1.72–11.3)
Sum total AUC/dosee	(μg/mL·h)/(mg/m^2)	12.9±4.9c,d (8.19–27.5)	14.5±4.6c,d (8.29–25.1)	14.8±5.3d (7.79–23.6)

Notes:

a t½ is the terminal half-life

b estimates are from two patients

c sum total CPT-11 AUC normalized by dose in patients with linear disposition was not significantly different between patients aged ≥60 and <60 years (P>0.05)

d sum total CPT-11 AUC normalized by dose was not significantly different between patients with nonlinear disposition and patients with linear disposition who were aged ≥60 and <60 years (P>0.05)

e sum total AUC was calculated from 0 to the last sampling time point; k₁₀ is the elimination rate constant from the central compartment; V_c is the volume of central compartment; CL is clearance; k₁₂ and k₂₁ are intercompartment distribution rate constants; V_max is maximum rate (velocity); K_m is a Michaelis constant; CPT-11 is irinotecan; IHL-305 is a PEGylated liposomal formulation of irinotecan.

Abbreviations: AUC, area under the concentration versus time curve; SD, standard deviation; –, not applicable.

Figure 1 Relationship between the ratio of TBW/IBW and dose-normalized IHL-305 sum total AUC (AUC/dose). AUC/dose in patients aged <60 and ≥60 years are represented by the solid triangles and open triangles, respectively.

Notes: The best-fit line of the data is represented by the curved solid line (R²=0.12). After controlling for age, there was an inverse relationship between TBW/IBW and AUC/dose, with a low TBW/IBW being associated with high AUC/dose in patients aged <60 years; CPT-11 is irinotecan; IHL-305 is a PEGylated liposomal formulation of irinotecan.

Abbreviations: AUC, area under the concentration versus time curve; TBW/IBW, total body weight to ideal body weight.

Figure 2 Relationship between two factors, age, and the ratio of TBW/IBW, and ratio of released CPT-11 AUC to sum total CPT-11 AUC.

Notes: Patients are divided into four groups according to the median value of age and TBW/IBW. The size of each circle correlates with ratio of released CPT-11 AUC to sum total CPT-11 AUC in a patient at the specific age and ratio of true body weight to ideal body weight. The mean ± standard deviation values for the ratio of released CPT-11 AUC to sum total CPT-11 AUC were 0.0042±0.0028, 0.0038±0.0038, 0.0066±0.0084, and 0.0025±0.0013 in patients aged <60 years and TBW/IBW <1.16, patients aged ≥60 years and TBW/IBW <1.16, patients aged ≥60 years and TBW/IBW ≥1.16, and patients aged <60 years and TBW/IBW ≥1.16, respectively; CPT-11 is irinotecan; IHL-305 is a PEGylated liposomal formulation of irinotecan.

Abbreviations: AUC, area under the concentration versus time curve; TBW/IBW, total body weight to ideal body weight.

Figure 3 Relationship between percent decrease in monocytes and dose normalized CPT-11 AUC (AUC/dose).

Notes: (A, B) Represent the relationship between percent decrease in monocytes and AUC/dose in patients with linear clearance and nonlinear clearance, respectively. The relationship between AUC/dose and percent decrease in monocytes was best described by a linear relationship in patients with linear clearance (P=0.008, y = −0.108x +14.7, R²=0.49); CPT-11 is irinotecan; IHL-305 is a PEGylated liposomal formulation of irinotecan.

Abbreviation: AUC, area under the concentration versus time curve.

Table 2 Summary of ANC and monocyte decrease at nadir after administration of IHL-305

	Units	Monocytes mean ± SD (range)	ANC mean ± SD (range)	Ratio monocytes to ANC mean ± SD (range)
All patients
Percent decrease	%	a42.0±23.9 (0.0–80.1)	a28.8±20.3 (0.0–84.8)	1.40±0.98 (0.067–4.28)
Patients <60 years
Percent decrease	%	b,d44.7±29.9 (0.0–80.1)	b,e29.6±22.6 (0.0–84.8)	1.65±1.36 (0.22–4.28)
Patients ≥60 years
Percent decrease	%	c,d40.2±20.3 (4.35–71.6)	c,e28.1±18.9 (0.0–65.3)	1.24±0.68 (0.067–2.35)

Notes:

a P<0.05 for comparison of percent decrease in monocytes and percent decrease in ANC in all patients

b P<0.05 for comparison of percent decrease in monocytes and percent decrease in ANC in patients aged <60 years

c P<0.05 for comparison of percent decrease in monocytes and percent decrease in ANC in patients aged ≥60 years

d P>0.05 for comparison of percent decrease in monocytes in patients aged <60 years and patients aged ≥60 years

e P>0.05 for comparison of percent decrease in ANC in patients aged <60 years and patients aged ≥60 years; CPT-11 is irinotecan; IHL-305 is a PEGylated liposomal formulation of irinotecan.

Abbreviations: ANC, absolute neutrophil count; SD, standard deviation.

Figure 4 Relationship between percent decrease in monocytes and age in all patients with a dose ≥50 mg/m².

Notes: For patients with a dose ≥50 mg/m² and ≤88 mg/m², individual values are represented by the solid circles. For patients with a dose ≥120 mg/m², individual values are represented by the open triangles. There was a linear relationship between the percent decrease in monocytes and age in all patients (R²=0.32), patients with a dose ≤88 mg/m² (R²=0.49), and in patients with a dose ≥120 mg/m² (R²=0.43); CPT-11 is irinotecan; IHL-305 is a PEGylated liposomal formulation of irinotecan.