Pharmacokinetics of ¹²⁵I-radiolabelled PEG-hemoglobin SB1

Figures & data

Figure 1 Mean concentrations of total radioactivity in plasma and whole blood and of TCA-precipitable radioactivity in plasma following intravenous administration of ¹²⁵I-PEG-hemoglobin SBl (nominal 5 ml/kg/10 minute infusion rate) to male rats.

Table 1. Total radioactivity pharmacokinetic data following intravenous administration of ¹²⁵I-PEG-hemoglobin SBl (nominal 5 ml/kg/10 minute and 12.5ml/kg/25 minute infusion rates) to male rats

	Plasma		Whole-blood
Parameter	5 ml/kg	12.5 ml/kg	5 ml/kg	12.5 ml/kg
Cmax (mg equiv/ml)	9.055	19.000	4.954	10.580
Tmax (hr)	0.20	0.33	0.11	0.33
AUCt (mg equiv.hr/ml)	79.6	223.5	37.6	99.0
AUC (mg equiv.hr/ml)	95.1	283.1	45.3	146.0
λz (hr^−1)	0.0718	0.0651	0.0715	0.0431
t1/2 (hr)	9.6	10.6	9.7	16.1

Table 2. Whole blood: plasma radioactivity concentration ratios, calculated concentrations of radioactivity in blood cells and distribution of systemic radioactivity into blood cells at the time of sacrifice following intravenous administration of ¹²⁵I-PEG-hemoglobin SB1 (nominal 5 ml/kg/10 minute infusion rate) to male rats

Rat no.	Time of sacrifice (hours)	CB:CP	PCV (%)	CC	CC:CP	Distribution of radioactivity in blood cells (%)
1M		0.51	0.381	ND	NC	ND
2M	8	0.47	0.376	ND	NC	ND
3M		0.55	0.383	ND	NC	ND
4M		0.48	0.394	ND	NC	ND
5M	12	0.49	0.476	ND	NC	ND
6M		0.48	0.375	ND	NC	ND
7M		0.56	0.369	ND	NC	ND
8M	24	0.39	0.402	ND	NC	ND
9M		0.58	0.369	ND	NC	ND

ND, No radioactivity detected.

NC, Not calculable.

C_B, C_P, and C_C, represent concentrations of total radioactivity in whole-blood, plasma and blood cells, respectively.

PCV, Packed cell volume (hematocrit).

(Concentration results are expressed as mg equivalents/ml).

Table 3. Proportions of the plasma radioactivity precipitated by 15% trichloroacetic acid solution and concentrations of radioactivity in the precipitate following intravenous administration of ¹²⁵I-PEG-hemoglobin SB1 (nominal 5 ml/kg/10 minute infusion rate) to male rats

	Sub-group
Time (hours)	A	B	C	Mean	SD
Precipitable plasma radioactivity
0.083	78	83	84	.82	3
0.17	78	68	76	74	5
0.25	82	89	79	83	5
0.75	93	67	86	82	13
1	91	64	62	72	16
2	78	76	83	79	4
3	77	89	91	86	8
4	83	77	75	78	4
6	91	80	85	85	6
8	89	93	96	93	4
12	80	83	79	81	2
24	92	89	89	90	2
Precipitable plasma radioactivity concentrations
0.083	5.861	7.431	6.786	6.693	0.789
0.17	6.890	6.657	6.495	6.681	0.199
0.25	7.232	7.557	7.122	7.304	0.226
0.75	6.946	5.309	6.956	6.404	0.948
1	7.147	5.456	4.581	5.728	1.304
2	5.477	4.904	5.343	5.241	0.300
3	4.426	5.435	5.680	5.180	0.665
4	4.738	4.669	4.160	4.522	0.316
6	3.437	3.340	3.721	3.499	0.198
8	2.890	3.267	3.460	3.206	0.290
12	2.100	2.192	2.074	2.122	0.062
24	1.072	0.903	1.033	1.003	0.088

SD, Standard deviation.

(Concentration results are expressed as mg equivalents/ml and represent alternate serial bleeds from three sub-groups (A, B, and C) of three rats (nos. 1–9)).

Figure 2 Mean concentrations of total radioactivity in plasma and whole blood and of TCA-precipitable radioactivity in plasma following intravenous administration of ^I25I-PEG-hemoglobin SBl (nominal 12.5 ml/kg/10 minute infusion rate) to male rats.

Table 4. Whole blood: plasma radioactivity concentration ratios, calculated concentrations of radioactivity in blood cells and distribution of systemic radioactivity into blood cells at the time of sacrifice following intravenous administration of ^I25I-PEG-hemoglobin SB1 (nominal 12.5 ml/kg/25 minute infusion rate) to male rats

Rat no.	Time of sacrifice (hours)	CB:CP	PCV (%)	CC	CC:CP	Distribution of radioactivity in blood cells (%)
10M		0.44	0.349	ND	NC	ND
11M	8	0.43	0.371	ND	NC	ND
12M		0.31	0.387	ND	NC	ND
13M		0.40	0.387	ND	NC	ND
14M	12	0.47	0.384	ND	NC	ND
15M		0.48	0.368	ND	NC	ND
16M		0.49	0.372	ND	NC	ND
17M	24	0.49	0.350	ND	NC	ND
18M		0.49	0.360	ND	NC	ND

ND, No radioactivity detected.

NC, Not calculable.

C_B, C_P, and C_C, represent concentrations of total radioactivity in whole-blood, plasma and blood cells, respectively.

PCV, Packed cell volume (hematocrit).

(Concentration results are expressed as mg equivalents/ml).

Table 5. Proportions of the plasma radioactivity precipitated by 15% trichloroacetic acid solution and concentrations of radioactivity in the precipitate following intravenous administration of ^I25I-PEG-hemoglobin SB1 (nominal 12.5 ml/kg/25 minute infusion rate) to male rats

	Sub-group
Time (hours)	D	E	F	Mean	SD
Precipitable plasma radioactivity
0.083	90	85	84	86	3
0.17	77	86	80	81	5
0.25	80	71	80	77	5
0.75	85	73	85	81	7
1	85	82	84	84	2
2	81	78	81	80	2
3	78	78	84	80	3
4	89	90	78	86	7
6	86	77	70	78	8
8	73	72	80	75	4
12	88	85	71	81	9
24	72	83	75	77	6
Precipitable plasma radioactivity concentrations
0.083	15.96	15.90	15.84	15.90	0.06
0.17	14.46	15.77	13.25	14.49	1.26
0.25	14.68	12.35	17.04	14.69	2.35
0.75	14.23	12.51	14.83	13.86	1.20
1	15.77	14.78	15.58	15.38	0.53
2	12.97	13.09	14.28	13.45	0.72
3	12.07	11.42	11.97	11.82	0.35
4	14.81	13.65	10.15	12.87	2.43
6	11.39	10.46	9.822	10.56	0.79
8	6.380	6.550	7.826	6.919	0.790
12	7.484	6.336	5.256	6.359	1.114
24	3.251	3.327	2.940	3.173	0.205

SD, Standard deviation.

(Results are expressed as mg equivalents/ml and represent alternate serial bleeds from three subgroups (D, E, and F) of three rats (nos. 1–9)).

Figure 3 Mean concentrations of radioactivity in plasma and whole blood following a single intravenous administration of ^l25I-PEG-hemoglobin SBl (nominal 10 ml/kg infused over 50 minutes) to male dogs.

Table 6. Total radioactivity pharmacokinetic data following intravenous administration of ¹²⁵I-PEG-hemoglobin SB1 (nominal 10 ml/kg infused over 50 minutes) to male dogs

	Animal no./Sex
Parameter	1M	2M	3M	Mean	SD
Plasma
Cmax (mg equiv/ml)	11.30	12.93	13.88	12.70	1.30
Tmax (hr)^a	0.083	0.083	0.083	0.083^c
AUC168 (mg equiv.hr/ml)	375.4	431.1	470.7	425.7	47.9
AUC (mg equiv.hr/ml)	393.2	459.4^b	502.0^b	451.5	54.8
λz (hr^−1)	0.0159	0.0142^b	0.0140^b	0.0147	0.0010
t1/2 (hr)	43.7	49.0^b	49.5	47.2^d
Whole blood
Cmax (mg equiv/ml)	7.818	8.485	8.812	8.372	0.507
Tmax (hr)^a	1.003	1.833	0.913	1.003^c
AUC168 (mg equiv.hr/ml)	213.2	286.6	224.1	241.3	39.6
AUC (mg equiv.hr/ml)	226.3	303.6	247.6	259.2	39.9
λz (hr^−1)	0.0144	0.0146	0.0123	0.0138	0.0013
t1/2 (hr)	48.2	47.6	56.4	50.3^d

SD, Standard deviation.

^aPost-end infusion.

^bValues for AUC, λ_z, and t_1/2 are estimated values only as the data did not meet all the acceptance criteria.

^cMedian value.

^dCalcualted as ln2/mean λ_z.

Table 7. Concentrations of radioactivity in plasma precipitated by 15% trichloroacetic acid solution during and after intravenous administration of ¹²⁵I-PEG-hemoglobin SB1 (nominal 10 ml/kg infused over 50 minutes) to male dogs

	Animal no.
Time (hours)	1M	2M	3M	Mean	SD
Pre dose	ND	ND	ND	ND	–
Mid infusion	4.712	6.075	7.195	5.994	1.243
Post infusion	8.044	9.851	12.51	10.14	2.25
0.083	9.188	10.59	11.53	10.44	1.18
0.17	8.314	10.77	8.665	9.250	1.328
0.5	8.062	8.972	10.48	9.171	1.221
0.75	8.117	8.623	9.679	8.806	0.797
1	7.385	8.700	9.945	8.677	1.280
2	6.325	6.840	8.771	7.312	1.290
3	6.828	7.042	9.072	7.647	1.238
4	6.733	7.562	9.055	7.783	1.177
6	5.891	7.167	8.982	7.347	1.553
8	5.873	6.953	8.157	6.994	1.143
24	3.643	4.743	5.193	4.526	0.797
48	1.963	2.413	2.496	2.291	0.287
72	1.034	1.324	1.300	1.219	0.161
96	0.666	0.836	0.962	0.821	0.149
120	0.445	0.643	0.661	0.583	0.120
168	0.207	0.367	0.361	0.312	0.091

*Post-end infusion.

SD, Standard deviation.

ND, No radioactivity detected.

(Results are expressed as mg equivalents/ml).

Table

Matrix	Analyte	Cmax	Tmax	AUC168	AUC	λz	t1/2
Plasma	Total radioactivity	12.703	0.833^a	425.7	451.5	0.0147	47.2^b
Plasma	TCA precipitable radioactivity	10.822	0.913^a	345.3	367.4	0.0144	48.1^b
Whole blood	Total radioactivity	8.372	1.003^c	241.3	259.2	0.0138	50.3^b

^aValue is the median.

^bCalculated as ln2/mean λ_z.