Population pharmacokinetics of pegaptanib sodium (Macugen^®) in patients with diabetic macular edema

Figures & data

Table 1 Summary of covariate data

	Pegaptanib dosage			Total N=58
	0.3 mg n=20	1.0 mg n=23	3.0 mg n=15
Discrete, n (%)
Race
Asian	1 (1.72)	1 (1.72)	0 (0.00)	2 (3.45)
Black	3 (5.17)	3 (5.17)	2 (3.45)	8 (13.79)
Hispanic	1 (1.72)	1 (1.72)	2 (3.45)	4 (6.90)
White	15 (25.86)	18 (31.03)	11 (18.97)	44 (75.86)
Total	20 (34.48)	23 (39.66)	15 (25.86)	58 (100.00)
Sex
Female	11 (18.97)	16 (27.59)	5 (8.62)	32 (55.17)
Male	9 (15.52)	7 (12.07)	10 (17.24)	26 (44.83)
Total	20 (34.48)	23 (39.66)	15 (25.86)	58 (100.00)
Continuous
Age, years
Mean	60.75	62.83	61.27	61.71
Median	60.50	64.00	62.00	61.50
SD	11.80	12.74	10.05	11.61
Minimum	44.00	27.00	42.00	27.00
Maximum	89.00	81.00	76.00	89.00
CRCL, mL/min
Mean	85.12	66.38	85.09	77.68
Median	77.10	64.31	73.27	70.48
SD	39.77	25.78	29.03	32.80
Minimum	36.07	29.94	46.18	29.94
Maximum	189.54	123.49	135.96	189.54
Weight, kg
Mean	83.46	85.33	92.63	86.58
Median	84.45	83.50	90.30	85.15
SD	19.77	14.24	24.46	19.21
Minimum	47.20	59.50	51.10	47.20
Maximum	123.50	109.40	129.40	129.40

Notes: All covariates summary measures are from baseline/screening (prior to treatment) values.

Abbreviations: N, total number of patients; n, number of patients in subgroup; SD, standard deviation; CRCL, creatinine clearance based on the Crockroft-Gault formula; min, minute.

Figure 1 Influence of sex on plasma pegaptanib levels over time.

Notes: (A) Patients treated with a single dose of 0.3 mg pegaptanib/eye had a rate of 47% below the lower limit of quantification (BLQ), and therefore, these data were not pooled by dose-normalization. (B) Patients in the 1.0 mg and 3.0 mg pegaptanib/eye cohorts had similar rates of BLQ readings (17% and 8%, respectively), and were pooled by dose-normalizing, allowing for greater statistical power. This provided evidence that males treated with either 1.0 mg or 3.0 mg pegaptanib had a higher maximum concentration (C_max), but lower plasma concentrations during the terminal phase and thus, a faster terminal elimination rate than females.
Abbreviations: F, females; h, hour; Geo, geometric; M, males; PRED, prediction.

Table 2 Non-compartmental analysis parameter predictions for the final model scaled to 0.3 mg pegaptanib

	n	AUC0–inf, ng·h/mL			Cmax (single dose), ng/mL			Tmax (single dose), h			T½z, d
		Mean	Med	%CV	Mean	Med	%CV	Mean	Med	%CV	Mean	Med	%CV
Sex
Female	322	1,586	1,757	50.0	4.3	4.7	44.6	91.5	103.0	47.3	7.1	7.2	10.2
Male	26	1,635	1,561	23.4	5.0	5.2	24.6	81.4	92.4	31.2	6.5	6.4	14.3
Race
White	44	1,567	1,686	43.8	4.5	4.7	38.7	85.3	92.7	41.5	6.9	6.9	13.0
Black	8	1,843	1,961	27.1	5.6	6.1	28.9	85.9	94.3	37.2	6.4	6.1	12.0
Hispanic	4	1,609	1,707	25.3	3.8	3.5	39.7	123.0	115.4	40.8	7.5	7.6	10.8
Asian	2	1,635	1,635	5.0	5.3	5.3	2.2	65.9	65.9	24.4	6.6	6.6	14.1
Age, y
≤57	21	1,279	1,509	52.1	3.6	3.8	47.9	84.4	92.7	45.4	6.9	6.6	12.0
57–68	21	1,708	1,710	22.3	5.1	4.9	22.9	82.7	83.4	39.4	6.6	6.6	12.3
>68	16	2,004	1,969	22.5	5.4	5.3	19.9	96.1	99.0	37.5	7.1	7.3	14.5
Weight, kg
≤79	20	1,960	2,010	23.2	5.5	5.4	23.2	93.0	94.7	33.9	6.8	6.6	12.4
79–93	19	1,553	1,657	40.1	4.6	5.1	39.0	78.2	80.7	50.5	6.8	7.2	14.8
>93	19	1,351	1,418	46.1	3.8	3.9	40.3	89.6	95.3	37.1	6.9	6.7	12.1
CRCL (mL/min)
≤63	20	1,951	1,989	25.9	5.5	5.9	26.1	91.8	97.5	31.4	6.8	6.6	13.0
63–86	19	1,605	1,744	40.8	4.5	4.8	37.2	87.4	93.7	55.1	6.9	7.2	14.9
>86	19	1,314	1,509	43.0	3.9	4.3	40.4	81.3	91.7	34.1	6.8	6.7	11.4
Total	58	1,608	1,727	40.0	4.6	4.8	37.5	86.8	92.7	41.0	6.8	6.7	12.9
Sim totala		1,592	1,590	45.2	4.5	4.5	40.8	85.0	86.7	51.1	6.8	6.8	19.7

Note:

a Simulation considered 100,000 virtual subjects.

Abbreviations: n, number of patients in subgroup; AUC_0–inf, area under the concentration–time curve from time 0 to infinity; h, hour; C_max, maximum concentration; T_max, time at maximum concentration; T_½z, terminal half-life; d, days; Med, median; CV, coefficient of variation; y, years; CRCL, creatinine clearance; min, minute; Sim, simulation.

Figure 2 Influence of the covariate creatinine clearance (CRCL) on plasma pegaptanib levels over time.

Notes: Data from patients were stratified based on CRCL values >70.5 mL/min or ≤70.5 mL/min, which was the median CRCL value for this study. (A) Patients treated with a single dose of 0.3 mg pegaptanib/eye had a rate of 47% below the lower limit of quantification (BLQ), and therefore, these data were not pooled by dose normalization. (B) Patients in the 1.0 mg and 3.0 mg pegaptanib/eye cohorts had similar rates of BLQ readings (17% and 8%, respectively), and were pooled by dose normalizing, allowing for greater statistical power. This provided evidence that patients with a CRCL ≤70.5 mL/min had higher maximum concentration values and higher plasma concentrations than those with CRCL >70.5 mL/min.
Abbreviations: h, hour; Geo, geometric; min, minute; PRED, prediction.

Figure 3 (A) Influence of creatinine clearance (CRCL) on the predicted pegaptanib exposure for a typical individual. The predictions are based on the final model, with η set to 0 for a typical individual. (B) The ratio of clearance (CL) for a 0.3 mg dose to the CL predicted for a patient with a CRCL of 80 mL/min. The ratio of area under the concentration–time curve (AUC) for a 0.3 mg dose to the AUC predicted for a patient with a CRCL of 80 mL/min is also shown. The 90% confidence intervals (CIs) are displayed as dashed lines in both panels. These were computed by sampling parameter estimates from a multivariate normal distribution (n=10,000) with a covariance matrix equal to the covariance matrix of the estimates from the full working model to avoid overly narrow CI ranges.

Abbreviations: AUC_0–inf, area under the concentration–time curve from time 0 to infinity; h, hour; min, minute; vs, versus.

Figure 4 Clearance (CL) and area under the concentration–time curve (AUC) at creatinine clearance (CRCL) <30 mL/min predicted using two models.

Notes: (A) In order to gain insights into the systemic exposure to pegaptanib in patients with severe renal insufficiency or renal failure, two models (a linear model and a simplified non-linear power model) were used to predict CL and AUC at CRCL <30 mL/min. Note that the 90% CIs for both models overlap over virtually the entire range of CRCL. (B) Closer examination of the CL and AUC at CRCL <30 mL/min. The non-linear power model predicts a rapid decline in pegaptanib CL and divergence from the linear model prediction at CRCL <15 mL/min. In contrast, the linear model predicts residual pegaptanib clearance would occur at CRCL <15 mL/min, consistent with the presence of secondary, non-renal elimination pathways for pegaptanib.
Abbreviations: AUC_0–inf, area under the concentration–time curve from time 0 to infinity; CI, confidence interval; h, hour; inf, infinity; IPRED, individual prediction; min, minute; PRED, prediction.

Figure 5 Forest plot summarizing the influence of diabetic macular edema on the systemic exposure to pegaptanib.

Notes: The mean ± 90% CI of ratios of the area under the concentration–time curve (AUC; black circle) and maximum concentration (C_max; white circle) for the various covariates relative to the reference values for these pharmacokinetic parameters are shown. As an example, if the AUC for a patient with a body weight ≤60 kg was the same as that for the reference population of 60–70 kg, the value indicated on the chart would be 1.
Abbreviations: CI, confidence interval; CRCL, creatinine clearance; F, female; M, male; min, minute; y, years.

Figure S1 Time course of the observed and predicated plasma pegaptanib concentrations.

Notes: Data presented from samples obtained after the first and third doses, respectively, of pegaptanib (a and d) 0.3 mg, (b and e) 1.0 mg, and (c and f) 3.0 mg, per eye. Gray circles represent concentrations below the lower limit of quantification (BLQ); gray squares represent concentrations equal to or less than BLQ. Model predications plotted here determined using the final model assuming a fixed dosing interval of 6 weeks. The median and IPREDmed were calculated by time-interval bins. For visual clarity, only statistics with more than five observations are plotted.

Abbreviations: F, females; h, hours; IPREDmed, median of individual PRED prediction; M, males; PRED, prediction.

Figure S2 Final model predictions of clearance divided by AUC vs creatinine clearance (CRCL) normalized to the 0.3 mg dose of pegaptanib: (CL/AUC) vs CRCL.

Notes: The plot was composed of dose-normalized data to increase the sample size and improve estimate precision. Model (Est =0.49) is the power parameter from the final model, least squares (LS) regressions were performed for Log^CL vs Log^CRCL, and the estimate of the slope coefficient is LSFit (Est =0.494). The P-value for the t-test of the LS regression coefficient against the null value of 0 is LSFit (P<0.0001). A smoother is also provided. These analyses were performed using S-Plus (TIBCO Software, Palo Alto, CA, USA).

Abbreviations: AUC, area under the concentration–time curve; AUC_0–inf, AUC from time 0 to infinity; CL, clearance; Est, estimated slope; h, hour; min, minute; LSFit, least squares regression fit; log^CL, log of clearance; log^CRCL, log of creatinine clearance; vs, versus.

Figure S3 The influence of sex on the relationship between the predicted maximum concentration (C_max) of pegaptanib and creatinine clearance (CRCL).

Notes: CRCL was previously found to influence clearance and thus, C_max, the influence of CRCL on the predicted C_max after a single, 0–3 mg dose of pegaptanib in (A) females and (B) males. The dashed line represents the 90% CI. The ratios of C_max for CRCL 30 and 190 mL/min are predicted to be twofold in both females and males.

Abbreviations: CI, confidence interval; min, minute.

Table S1 Nominal schedule of plasma sampling for pharmacokinetic analysis

Schedule for the first dose	Schedule for the third dose
Predose	Predose (week 12 prior to dosing)
4±2 hours (day 0)	4±2 hours postdose (week 12)
24±4 hours (day 0)	24±4 hours (week 12)
Week 1±3 days	Week 13±3 days
Week 3±3 days	Week 15±3 days
Week 6 (just prior to second dose)	Week 18 (just prior to fourth dose)

Table S2 Number of patients, observations, BLQs, and exclusions

Sample type		Pegaptanib dose group			Total
		0.3 mg	1.0 mg	3.0 mg
Patients	n	20	23	15	58
	Row, %	34.5	39.7	25.9	100
Observations
>BLQ	No. of PK samples	102	173	131	406
	%	18.4	31.2	23.6	73.2
	Row, %	25.1	42.6	32.3	–
	Col, %	52.6	80.8	89.1	–
≤BLQ	No. of PK samples	92	40	12	144
	%	16.6	7.2	2.2	26.0
	Row, %	63.9	27.8	8.3	–
	Col, %	47.4	18.7	8.2	–
Excludeda	No. of PK samples	0	1	4	5
	%	0.00	0.18	0.72	0.90
	Row, %	0.00	20.0	80.0	–
	Col, %	0.00	0.47	2.72	–
Total	No. of PK samples	194	214	147	555
	%	35.0	39.6	26.5	100

Note:

a Excluded from the analysis.

Abbreviations: BLQ, below the lower limit of quantification; No., number; PK, pharmacokinetic; Col, column.