1608121 © 1990 Karger AG, Basel 0302-2838/90/0187-0010 $2 75/0
Eur Urol 1990;18(suppl 3): 10-17
The Pharmacokinetics of Casodex1 in Prostate Cancer Patients after Single and during Multiple Dosing I.D. Cockshotf, K.J. Coopera, D.S. Sweetmorea, N.J. Blacklockb, L. Denisc TCI Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, UK; bUniversity Hospital of South Manchester, West Didsbury, Manchester, UK; 'Algemeen Ziekenhuis Middelheim, Antwerp, Belgium on behalf of the Transatlantic Prostate Cancer Study Group
Key Words. Casodex • Pharmacokinetics • Prostatic carcinoma Abstract. The pharmacokinetics of Casodex have been investigated in patients with prostatic carcinoma following single oral doses of 10 mg, 30 mg and 50 mg and during daily administration at these dose levels. Casodex displays pro longed absorption following a single dose, with peak plasma concentrations observed at up to 8 h for doses of 10 mg and 30 mg and up to 48 h for the 50 mg dose. The area under the plasma concentration-time curve increased linearly with dose, and Casodex was eliminated slowly from plasma (tV2 about 6 days). During daily administration, Casodex accu mulates about 10-fold in plasma at all dose levels; this is consistent with its long plasma elimination half-life, estimated by curve fitting of these multiple dose data to be 7-10 days. Trough plasma concentrations increased linearly with dose after both single and multiple dosing, achieving mean values of 1.80,6.89 and 9.33 pg/ml for the 10 mg, 30 mg and 50 mg dose levels, respectively, after 12 weeks' dosing. Neither efficiency of renal function nor age had any apparent effect on the pharmacokinetics of Casodex. The pharmacokinetics of Casodex make it ideally suited to once-daily administra tion.
Introduction The pharmacokinetics of Casodex (ICI 176,334) have been investigated in patients with prostate carcinoma fol lowing single doses at 3 dose levels. On the basis of these
findings, a study was designed to investigate the efficacy, tolerance and pharmacokinetics of Casodex during daily administration. The pharmacokinetics of Casodex during this multiple-dosing regimen have been studied and com pared with those predicted from single-dose data.
Methods
Casodex is a trademark for ICI 176,334 and the property of
Imperial Chemical Industries PLC.
Subjects In the single-dose, multicenter study, 22 patients with asymptom atic or symptomatically controlled prostate carcinoma were investi-
Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 6:59:41 AM
1
Pharmacokinetics of Casodex
11
Casodex dose 10 mg Single dose Age (years) Mean(±SD) Range Weight (kg) Mean (± SD) Range Multiple dose Age (years) Mean (± SD) Range Weight (kg) Mean (± SD) Range
30 mg
50 mg
71.1+ 5.9 63-81
65.5+ 11.0 45-77
73.3+ 4.9 67-81
68.9 ± 9.8 49.0-79.2
74.9± 15.5 61.5-108.4
72.0 ± 9.9 59.2-84.5
70.7 ± 6.9 57 - 87
68.8 ± 7.7 53 - 86
70.9 ± 8.6 49-93
73.3 ± 13.5 50.0-112.4
74.8 ± 18.5 45.4-152.6
72.1 ± 13.8 43.3-106.0
gated; demographic data are summarized in table 1 Seven patients received a 10 mg dose, 8 patients received a 30 mg dose and a further 7 received a 50 mg dose. All patients had normal liver and renal function according to standard biochemical testing. Patients with severely abnormal ECG and those receiving sex hormone or antiandrogen ther apy were excluded from the study. In the multiple-dose, multicenter study, 190 patients with asymp tomatic or symptomatically controlled prostate carcinoma were investigated; demographic data are summarized in table 1. Pharmaco kinetic data were obtained on 39 patients who received 10 mg daily, 42 patients who received 30 mg daily and 109 patients who received 50 mg daily. All patients had normal liver and renal function according to standard biochemical testing. Patients with severely abnormal ECG and those who had received sex hormone manipulation, including orchidectomy or antiandrogen therapy (other than a single dose of Casodex) were excluded, as were those who had previously received cytotoxic therapy for prostatic carcinoma. All patients had acid phos phatase levels at least twice the upper limit of the normal range for patients at their own centers. All patients gave informed consent to participate in the studies, which received approval from the hospital ethics committee. Dosing Casodex was administered orally as 10 mg uncoated tablets contain ing micronized drug. In the multiple-dose study the treatment was taken for at least 12 weeks at about the same time each morning and when possible with food. Sampling Study day 1 was defined as the first day of dosing with Casodex. In the single-dose study, blood samples were taken before treatment and thenat 1,3,5,8,12.16,24,36 and 48 h after treatment; further samples were taken on study days 4,8, 15, 22 and 29. In the multiple-dose study, blood samples were taken before treat ment and then approximately 24 h after treatment (trough) on study
days 2, 3,4.5,6,7,8,15,22,29, 57 and 85; it was not practical to obtain samples on study days 3-7 from all patients. Blood samples were thoroughly mixed in oxalate or fluoride oxa late tubes, centrifuged and the plasma removed and stored frozen at approximately -20 °C until assayed for Casodex. Sample Assay Plasma samples were extracted with ethyl acetate under neutral conditions, the extract was evaporated to dryness and reconstituted in acetonitrile, water and trifluoroacetic acid. Casodex was detected by its ultraviolet absorbance after elution from a reverse-phase high perfor mance liquid chromatography (HPLC) column. The interassay coeffi cient of variation for this method is about 3%. Data Evaluation In the single-dose study, the peak concentration (Cmdx) and time to peak concentration (Tmjx) were taken directly from the data. The plasma elimination half-life (t,,) was determined by log-linear regres sion of the elimination phase using the STRIPE program [1]. The area under the curve to infinity (AUC.) was derived using the trapezoidal approximation up to the last sampling point and extrapolated to infinity on the basis of the elimination rate constant (X) In the multiple-dose study, the accumulation ratio was derived from the ratio of the trough Casodex plasma concentration after treatment on study day 85 tothat after the 1st dose (study day 2). The steady state plasma concentration (C„) and t|2 were determined after fitting the fol lowing function to each individual data set using the least squares curve fitting program MKMODEL [2] with a weighting of 1/C. C„ = C„ (1—e~'n). where C„ is the plasma concentration at trough following the n' dose.
Results The mean Casodex plasma concentrations for each dose level in the single-dose study are presented in fig. 1, and derived pharmacokinetic parameters are summa rized in table 2. Casodex was absorbed slowly, particu larly after the 50 mg dose; consequently Cmax values increased slightly less than proportionately with dose. How ever, 24 h after treatment plasma concentrations showed a linear dose response (fig.2) as did AUC„. Casodex was eliminated from plasma with a half-life of about 6 days. Mean Casodex plasma concentrations at trough during daily administration are shown in fig. 3a. For all dose lev els, mean concentrations increased rapidly during the first week as they asymptotically approached their steady state values. After 1 month of treatment, mean concentrations were 91%, 73% and 85% of the corresponding 3-month value for the 10 mg, 30 mg and 50 mg dose levels, respec tively; fig. 3b shows the proportion of the study day 85 concentration at each sampling time for the 50 mg dose level. Mean plasma concentrations showed a linear dose
Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 6:59:41 AM
Table 1. Demographic data
Cockshott/Cooper/Sweetmorc/B lacklock/Denis
12
Fig. 1. Mean (±SE) plasma Casodex con centrations following single doses.
Fig. 2. Mean (±SE) plasma Casodex con centrations in response to varying dose, sampled 1 day after the dose.
Table 2. Mean (± SE) single-dose pharmacokinetic parameters
Table 3. Casodex accumulation in plasma and calculated elimina tion half-life during daily dosing
Casodex dose
CmaUng/ml)
Tmj* (h) AUCx (pg/ml) t,/2 (days) n
30 mg
50 mg
0.225 ±0.015 6.0±0.8 41.2 ± 4.6 5.98 ±0.65 7
0.600 ±0.038 5.6 ±0.8 114 ± 10 5.50 ±0.48
0.845 ±0.054 16.3 ±5.8 214 ±19 6.28 ±0.50 7
8
Accumulation ratio Mean ± SE Range n
10 mg
30 mg
50 mg
10.0 ± 0.9 2.6-22.9 29
12.1 ± 1.4 3.2-24.1
21
11.1± 0.7 2.1-35.8 62
9.6± 1.0 2.5-27.6 32
7.6 ± 0.3 2.2-22.4 95
Elimination half-life (days) Mean ± SE 7.3 ± 0.7 Range 1.7-24.3 41 n
Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 6:59:41 AM
Casodex dose 10 mg
Pharmacokinetics of Casodex
13
Fig. 3. Mean (±SE) plasma Casodex con centration at trough (a) during daily dosing and (b) during daily dosing at 50 mg (percentage of study day 85 given above the curve and number of patients given below).
Fig. 4. Mean (±SE) plasma Casodex con centration 1 day after single and daily dosing.
ues covering wide ranges (8-fold to 17-fold). Mean plasma elimination half-lives derived from curve fitting were in the range 7-10 days (table 3); again individual values cov ered wide ranges (10-fold to 14-fold). The differences between the number of data sets contributing to the accu mulation ratio and elimination half-life values are the Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 6:59:41 AM
response at trough after both the 1st and 84th doses (figs. 2 and 4); the data for the 1st dose were in good agreement with those obtained in the single-dose study. The accumulation ratios calculated from the multipledose data are summarized in table 3. Mean accumulation ratios were similar at each dose level with individual val
14
Cockshott/Cooper/Sweetmore/Blacklock/Denis
40
10 mg
a
A 30 mg
35 -
a 50
mg
30 o
O
c o o
B
▲
-
▲ ▲
E
12
▲
▲
At A- 1 Ai Aa A tAàì*£aa^ AAA AJ*/ A
A A
4)
6
(0£
4
Eur Urol 1990;18(suppl 3): 10-17
The Pharmacokinetics of Casodex1 in Prostate Cancer Patients after Single and during Multiple Dosing I.D. Cockshotf, K.J. Coopera, D.S. Sweetmorea, N.J. Blacklockb, L. Denisc TCI Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, UK; bUniversity Hospital of South Manchester, West Didsbury, Manchester, UK; 'Algemeen Ziekenhuis Middelheim, Antwerp, Belgium on behalf of the Transatlantic Prostate Cancer Study Group
Key Words. Casodex • Pharmacokinetics • Prostatic carcinoma Abstract. The pharmacokinetics of Casodex have been investigated in patients with prostatic carcinoma following single oral doses of 10 mg, 30 mg and 50 mg and during daily administration at these dose levels. Casodex displays pro longed absorption following a single dose, with peak plasma concentrations observed at up to 8 h for doses of 10 mg and 30 mg and up to 48 h for the 50 mg dose. The area under the plasma concentration-time curve increased linearly with dose, and Casodex was eliminated slowly from plasma (tV2 about 6 days). During daily administration, Casodex accu mulates about 10-fold in plasma at all dose levels; this is consistent with its long plasma elimination half-life, estimated by curve fitting of these multiple dose data to be 7-10 days. Trough plasma concentrations increased linearly with dose after both single and multiple dosing, achieving mean values of 1.80,6.89 and 9.33 pg/ml for the 10 mg, 30 mg and 50 mg dose levels, respectively, after 12 weeks' dosing. Neither efficiency of renal function nor age had any apparent effect on the pharmacokinetics of Casodex. The pharmacokinetics of Casodex make it ideally suited to once-daily administra tion.
Introduction The pharmacokinetics of Casodex (ICI 176,334) have been investigated in patients with prostate carcinoma fol lowing single doses at 3 dose levels. On the basis of these
findings, a study was designed to investigate the efficacy, tolerance and pharmacokinetics of Casodex during daily administration. The pharmacokinetics of Casodex during this multiple-dosing regimen have been studied and com pared with those predicted from single-dose data.
Methods
Casodex is a trademark for ICI 176,334 and the property of
Imperial Chemical Industries PLC.
Subjects In the single-dose, multicenter study, 22 patients with asymptom atic or symptomatically controlled prostate carcinoma were investi-
Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 6:59:41 AM
1
Pharmacokinetics of Casodex
11
Casodex dose 10 mg Single dose Age (years) Mean(±SD) Range Weight (kg) Mean (± SD) Range Multiple dose Age (years) Mean (± SD) Range Weight (kg) Mean (± SD) Range
30 mg
50 mg
71.1+ 5.9 63-81
65.5+ 11.0 45-77
73.3+ 4.9 67-81
68.9 ± 9.8 49.0-79.2
74.9± 15.5 61.5-108.4
72.0 ± 9.9 59.2-84.5
70.7 ± 6.9 57 - 87
68.8 ± 7.7 53 - 86
70.9 ± 8.6 49-93
73.3 ± 13.5 50.0-112.4
74.8 ± 18.5 45.4-152.6
72.1 ± 13.8 43.3-106.0
gated; demographic data are summarized in table 1 Seven patients received a 10 mg dose, 8 patients received a 30 mg dose and a further 7 received a 50 mg dose. All patients had normal liver and renal function according to standard biochemical testing. Patients with severely abnormal ECG and those receiving sex hormone or antiandrogen ther apy were excluded from the study. In the multiple-dose, multicenter study, 190 patients with asymp tomatic or symptomatically controlled prostate carcinoma were investigated; demographic data are summarized in table 1. Pharmaco kinetic data were obtained on 39 patients who received 10 mg daily, 42 patients who received 30 mg daily and 109 patients who received 50 mg daily. All patients had normal liver and renal function according to standard biochemical testing. Patients with severely abnormal ECG and those who had received sex hormone manipulation, including orchidectomy or antiandrogen therapy (other than a single dose of Casodex) were excluded, as were those who had previously received cytotoxic therapy for prostatic carcinoma. All patients had acid phos phatase levels at least twice the upper limit of the normal range for patients at their own centers. All patients gave informed consent to participate in the studies, which received approval from the hospital ethics committee. Dosing Casodex was administered orally as 10 mg uncoated tablets contain ing micronized drug. In the multiple-dose study the treatment was taken for at least 12 weeks at about the same time each morning and when possible with food. Sampling Study day 1 was defined as the first day of dosing with Casodex. In the single-dose study, blood samples were taken before treatment and thenat 1,3,5,8,12.16,24,36 and 48 h after treatment; further samples were taken on study days 4,8, 15, 22 and 29. In the multiple-dose study, blood samples were taken before treat ment and then approximately 24 h after treatment (trough) on study
days 2, 3,4.5,6,7,8,15,22,29, 57 and 85; it was not practical to obtain samples on study days 3-7 from all patients. Blood samples were thoroughly mixed in oxalate or fluoride oxa late tubes, centrifuged and the plasma removed and stored frozen at approximately -20 °C until assayed for Casodex. Sample Assay Plasma samples were extracted with ethyl acetate under neutral conditions, the extract was evaporated to dryness and reconstituted in acetonitrile, water and trifluoroacetic acid. Casodex was detected by its ultraviolet absorbance after elution from a reverse-phase high perfor mance liquid chromatography (HPLC) column. The interassay coeffi cient of variation for this method is about 3%. Data Evaluation In the single-dose study, the peak concentration (Cmdx) and time to peak concentration (Tmjx) were taken directly from the data. The plasma elimination half-life (t,,) was determined by log-linear regres sion of the elimination phase using the STRIPE program [1]. The area under the curve to infinity (AUC.) was derived using the trapezoidal approximation up to the last sampling point and extrapolated to infinity on the basis of the elimination rate constant (X) In the multiple-dose study, the accumulation ratio was derived from the ratio of the trough Casodex plasma concentration after treatment on study day 85 tothat after the 1st dose (study day 2). The steady state plasma concentration (C„) and t|2 were determined after fitting the fol lowing function to each individual data set using the least squares curve fitting program MKMODEL [2] with a weighting of 1/C. C„ = C„ (1—e~'n). where C„ is the plasma concentration at trough following the n' dose.
Results The mean Casodex plasma concentrations for each dose level in the single-dose study are presented in fig. 1, and derived pharmacokinetic parameters are summa rized in table 2. Casodex was absorbed slowly, particu larly after the 50 mg dose; consequently Cmax values increased slightly less than proportionately with dose. How ever, 24 h after treatment plasma concentrations showed a linear dose response (fig.2) as did AUC„. Casodex was eliminated from plasma with a half-life of about 6 days. Mean Casodex plasma concentrations at trough during daily administration are shown in fig. 3a. For all dose lev els, mean concentrations increased rapidly during the first week as they asymptotically approached their steady state values. After 1 month of treatment, mean concentrations were 91%, 73% and 85% of the corresponding 3-month value for the 10 mg, 30 mg and 50 mg dose levels, respec tively; fig. 3b shows the proportion of the study day 85 concentration at each sampling time for the 50 mg dose level. Mean plasma concentrations showed a linear dose
Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 6:59:41 AM
Table 1. Demographic data
Cockshott/Cooper/Sweetmorc/B lacklock/Denis
12
Fig. 1. Mean (±SE) plasma Casodex con centrations following single doses.
Fig. 2. Mean (±SE) plasma Casodex con centrations in response to varying dose, sampled 1 day after the dose.
Table 2. Mean (± SE) single-dose pharmacokinetic parameters
Table 3. Casodex accumulation in plasma and calculated elimina tion half-life during daily dosing
Casodex dose
CmaUng/ml)
Tmj* (h) AUCx (pg/ml) t,/2 (days) n
30 mg
50 mg
0.225 ±0.015 6.0±0.8 41.2 ± 4.6 5.98 ±0.65 7
0.600 ±0.038 5.6 ±0.8 114 ± 10 5.50 ±0.48
0.845 ±0.054 16.3 ±5.8 214 ±19 6.28 ±0.50 7
8
Accumulation ratio Mean ± SE Range n
10 mg
30 mg
50 mg
10.0 ± 0.9 2.6-22.9 29
12.1 ± 1.4 3.2-24.1
21
11.1± 0.7 2.1-35.8 62
9.6± 1.0 2.5-27.6 32
7.6 ± 0.3 2.2-22.4 95
Elimination half-life (days) Mean ± SE 7.3 ± 0.7 Range 1.7-24.3 41 n
Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 6:59:41 AM
Casodex dose 10 mg
Pharmacokinetics of Casodex
13
Fig. 3. Mean (±SE) plasma Casodex con centration at trough (a) during daily dosing and (b) during daily dosing at 50 mg (percentage of study day 85 given above the curve and number of patients given below).
Fig. 4. Mean (±SE) plasma Casodex con centration 1 day after single and daily dosing.
ues covering wide ranges (8-fold to 17-fold). Mean plasma elimination half-lives derived from curve fitting were in the range 7-10 days (table 3); again individual values cov ered wide ranges (10-fold to 14-fold). The differences between the number of data sets contributing to the accu mulation ratio and elimination half-life values are the Downloaded by: University of Exeter 144.173.6.94 - 5/4/2020 6:59:41 AM
response at trough after both the 1st and 84th doses (figs. 2 and 4); the data for the 1st dose were in good agreement with those obtained in the single-dose study. The accumulation ratios calculated from the multipledose data are summarized in table 3. Mean accumulation ratios were similar at each dose level with individual val
14
Cockshott/Cooper/Sweetmore/Blacklock/Denis
40
10 mg
a
A 30 mg
35 -
a 50
mg
30 o
O
c o o
B
▲
-
▲ ▲
E
12
▲
▲
At A- 1 Ai Aa A tAàì*£aa^ AAA AJ*/ A
A A
4)
6
(0£
4
