BIOPHARMACEUTICS & DRUG DISPOSITION, VOL. 13, 663-669 (1992)
CLINICAL PHARMACOKINETICS OF PROCATEROL: DOSE PROPORTIONALITY AFTER ADMINISTRATION OF SINGLE ORAL DOSES MICHAEL A. ELDON*, DEBBIE S. BLAKE'', MICHAEL J. COON' GERALD D. NORDBLOM', ALLEN J. SEDMAN*, and WAYNE A. COLBURN'*
*Clinical Pharmacology Department and tPharmacokinetics/Dnrg Metabolism Department, Parke-Davis Pharmaceutical Research Div&ion, Warner-Lambert Co., 2800 Plymouth Rd, Ann Arbor, MI. U.S.A.
ABSTRACT Procaterol is a potent, orally active &-agonist bronchodilator useful in the treatment of reversible bronchospastic disease. It is effectivewhen administered as single or multiple (Q8H) 50 and 7 5 p g doses. As part of the clinical development of procaterol, the pharmacokinetics and dose proportionality of single 25, 50, 75, and 100 pg doses were investigated in 14 healthy subjects. Serial blood samples were collected for 16 h and urine was quantitatively collected for 48 h following administration of each dose. Procaterol concentrations in plasma and urine were determined using sensitive and specific radioimmunoassay methods. Mean values for t,,, the apparent elimination rate constant, CVF, renal clearance, and per cent of dose excreted unchanged in urine were similar for all doses. Dose-normalized AUC, C,,, and amount excreted unchanged in urine (A,) were also similar across dosage levels. Thus, the pharmacokinetics of procaterol appear to be proportional to dose over the range of doses studied. KEY WORDS Procaterol Bronchodilator Healthy volunteers Pharmacokinetics Dose proportionality
INTRODUCTION Procaterol hydrochloride (Pro-Air, Parke-Davis), ( f )-(R*, S*)-8-hydroxy-5[ 1-hydroxy-2- [ (1-methylethy1)amino1 butyl ] -2( 1H)quinolone monohydrochloride hemihydrate] is an orally active &-adrenergic receptor agonist demonstrated to be safe and effective for the treatment of reversible bronchospastic
Current affiliations: *MarionMerrell Dow, Inc., 9550 N. Zionsville Rd, Indianapolis, IN 46268, U.S.A. $Harris Clinical Development, 7432 E. Stetson Drive, Scottsdale, AZ 85251, U.S.A. Correspondenceto: Dr Michael A. Eldon, Parke-Davis Pharmaceutical Research, 2800 Plymouth Rd, Ann Arbor, MI 48106-1047, U.S.A.
0142-2782/92/090663-07~08. 50 0 1992 by John Wiley & Sons, Ltd.
Received 6 January 1992 Accepted 20 April 1992
664
M . A. ELDON ET A L .
In the United States, Pro-Air tablets have been studied in adults and children over the age of 12 at doses of 50 to 75 pg administered every 8 h. Since procaterol is administered in microgram doses, concentrations of drug in plasma and urine are lower than those of less potent &-adrenergic agonists such as albuterol, metaproterenol, and terbutaline. In previous evaluations of procaterol disposition in humans, tritiated drug was used to quantify procaterol and metabolites in plasma and urine. Unfortunately, detailed pharmacokinetic analysis was not possible due to limitations in assay sensitivity using radiolabeled drug. Recent pharmacokinetic studies were made possible by the development of specific and sensitive radioimmunoassay methods capable of detecting picomolar amounts of procaterol in plasma and urine. Procaterol pharmacokinetics and relative bioavailability following administration of 100 pg doses of procaterol tablets and solution have recently been r e p ~ r t e d .Procaterol ~ was rapidly absorbed after oral administration of both tablets and solution, with an elimination half-life of approximately 4 h, and plasma clearance of nearly lo00 ml min- I . Approximately 18 per cent of plasma clearance was by renal elimination of unchanged drug, indicating that hepatic metabolism is the primary route of disposition. Procaterol appears to undergo first-pass metabolism. In addition, enterohepatic recycling of procaterol and metabolites may occur in humans. The purpose of the present study was to assess the pharmacokinetics and dose proportionality of single 25 to lOOpg doses of procaterol administered as an oral solution to healthy subjects.
METHODS
Subjects Fourteen healthy volunteers (12 male, 2 female) participated in the study conducted at the Parke-Davis Community Research Clinic, Ann Arbor, Michigan. All subjects had acceptable clinical laboratory profiles and physical examinations. Mean (range) subject weight, age, and height were 71 - 4kg (54.5 to 91 * 2kg), 29 yr (21 to 40 yr), and 176 cm (164 to 190 cm), respectively. The protocol was approved by the Community Research Clinic Institutional Review Board. All subjects provided informed consent.
Protocol The study used a single-dose, nonblind, randomized, four-way crossover design. Each subject received single 25, 50, 75, and 1OOpg doses of procaterol as a HCl hemihydrate solution (Pro-Air Syrup, 25 p g 5 ml- I , Parke-Davis, Morris Plains, NJ) at weekly intervals according to a randomized schedule. Each dose was administered with 8 ounces of water following a 10-h overnight fast, and subjects continued fasting for an additional 4 h after dosing. Identical
PROCATEROL KINETICS
665
lunches and identical dinners were served on each dosing day after the 4 and 10-h blood samples were drawn, respectively. Heparinized blood samples were drawn before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, and 16 h after dosing. Plasma was separated and stored frozen until assayed for procaterol. Urine was collected before dosing and quantitatively during the intervals 0-2,2-4,4-6,6-8,8-10, 10-12, 12-16, 16-24,24-36, and 36-48 h postdose. Total urine voided was measured for each collection period, and a 20ml aliquot was stored frozen until assayed for unchanged procaterol.
Sample analysis Procaterol concentrations in plasma and urine were assayed using sensitive, specific, and validated radioimmunoa~says.~ Plasma (100 pl) and urine (10 pl) samples were incubated with fixed amounts of antibody and 125-I-labeled procaterol. The antibody bound fraction was precipitated with sheep antirabbit immunoglobulin antibody and counted in a gamma counter. In plasma, crossreactivities of the three major metabolites of procaterol, N-desisopropyl procaterol, 5-formy1-8-hydroxycarbostyri1,and procaterol glucuronide, were 0.46 per cent or less. Logit-log standard curves in plasma were linear over the calibration range of 15 pg ml- to 2ng ml-I. The lower limit of quantitation for procaterol in plasma was 15 pg ml- l; values below this concentration were reported as zero. Precision of plasma quality control standards assayed during sample analysis ranged from 10- 1 per cent to 24.9 per cent and accuracy ranged from - 1.8 per cent to 6.0 per cent of procaterol concentrations determined during validation. In urine, cross-reactivites of the procaterol metabolites described above were 0.029 per cent or less. Logit-log standard curves in urine were linear over the calibration range of 800 pg ml- * to 50 ng ml- I . The lower limit of quantitation for procaterol in urine was 800 pg ml- I ; values below this concentration were reported as zero. Precision of urine quality control standards assayed during sample analysis ranged from 11 * 4 per cent to 21 - 7 per cent and accuracy ranged from - 5.67 per cent to 18.0 per cent of theoretical procaterol concentrations.
Data analysis Pharmacokinetic parameters AUC, C,,, t,, XZ, and t l / , were calculated from plasma procaterol concentration-time data using established methods5 (see Table 1 for definitions of parameters). The cumulative amount of procaterol excreted unchanged in urine (Ae)was determined from urine drug concentration and urine volume data and expressed as per cent of dose (A,Vo). Apparent plasma clearance (CVF) was calculated as Dose/AUC. Renal clearance (Cl,) was calculated as AJAUC. Nonrenal clearance (Clnr)was calculated as Cl/F minus Cl,.
666
M. A. ELDON E T A L .
Plasma pharmacokinetic parameters and urinary excretion parameters were analyzed using an analysis of variance (ANOVA) model with sequence, subject (within sequence), period, and treatment main effects, followed by Tukey's studentized range test, to evaluate the statistical significance of differences among treatment means.6 The ANOVA was repeated using AUC, C,,, and A, data normalized to a 75 pg dose, and linear regression analysis of unweighted AUC and C,, values against dose was performed to aid in the evaluation of dose proportionality.
RESULTS All 14 subjects completed the study. The terminal phase of drug disposition was not determined for Subject 5 after administration of the 50pg dose due to an insufficient plasma concentration-time profile. Subject 14 did not receive the 100 pg dose due to a personal time conflict. Accordingly, data from these subjects for these treatments were not available for inclusion in the statistical analyses. Mean plasma procaterol concentration-time profiles are presented in Figure 1. Plasma pharmacokinetic parameters, urinary excretion parameters, and ANOVA results are given in Table 1.
0.0
4.0
8.0
12.0
16.0
TIME (hours)
Figure 1. Mean procaterol plasma concentration-time profiles following oral administration of 25 (O), 50 ( ), 75 ( ), and 100 ( 0 )pg doses of procaterol solution to fourteen healthy subjects
667
PROCATEROL KINETICS
Table 1. Mean (olo RSD) procaterol pharmacokinetic parameters following oral administration of procaterol solution to fourteen healthy subjects
Pharmacokinetic parameter 518 (54.2) AUC
1100 (24.1)
1380 (28.6)
1590 (19.7)
Cma
113 (54.0)
205 (47.6)
233 (29.9)
276 (47.8)
tmax
1.5 (46.9)
2 - 4 (54.1)
2.0 (55.1)
1.5 (33.3)
0.295 (59-4)
0.226 (21.9)
0.211 (35.2)
0.210 (24.2)
3.2 (23.8)
3.7 (40.0)
xz
3.1 (47.4)
3-5 (20.61
t, Cl/F
1130 (64.7)
797 (24.9)
996 (35.3)
1090 (21.0)
A, A,%
3.89 (48.0) 15.6 (48.0)
7.46 (42.7) 14.9 (42.7)
12.0 (36-7) 16.1 (36.7)
15.1 (31.2) 15.1 (31.2)
c1r
143 (43.7)
122 (28.6)
Normalized* parameters AUC Cmax
4
146 (25.8)
158 (24.1)
1550
1650
1380
1190
338
308
233
207
11.7
11.2
12.0
11.3
Underlined means are not significantly different at p = 0.05. %RSD = relative standard deviation expressed as per cent of mean. AUC = area under the plasma concentration-time curve from time = 0 to infinity (pg-h ml-I). C,, = maximum observed plasma concentration (pg ml-I). (,,,=time of C,, (h). XZ = apparent elimination rate constant (h-I). t,h=apparent elimination half-life (h). CI/F= apparent plasma clearance (ml min-l). A, = cumulative amount of unchanged procaterol excreted in urine. A,% =per cent of dose excreted in urine as unchanged procaterol. C1, = renal clearance (ml min- I). *Parameter values normalized to 75 pg dose.
Mean values for tm, hz, t f i , CVF, A,%, and C1, were similar and not statistically different among doses, whereas AUC, C,,, and A, were statistically different among doses as expected. Sporadic significant differences among the four procaterol dose levels were observed for dose-normalized AUC ,, (see overlapping underlines, Table l), but not for mean doseand C normalized A, values. The power of the study to detect 20 per cent differences between dose-normalized mean parameter values was 0.99 for AUC and 0.67 for Cm,. Linear regression analysis showed (Figure 2) significant relationships between dose and AUC (r=0-773; p
CLINICAL PHARMACOKINETICS OF PROCATEROL: DOSE PROPORTIONALITY AFTER ADMINISTRATION OF SINGLE ORAL DOSES MICHAEL A. ELDON*, DEBBIE S. BLAKE'', MICHAEL J. COON' GERALD D. NORDBLOM', ALLEN J. SEDMAN*, and WAYNE A. COLBURN'*
*Clinical Pharmacology Department and tPharmacokinetics/Dnrg Metabolism Department, Parke-Davis Pharmaceutical Research Div&ion, Warner-Lambert Co., 2800 Plymouth Rd, Ann Arbor, MI. U.S.A.
ABSTRACT Procaterol is a potent, orally active &-agonist bronchodilator useful in the treatment of reversible bronchospastic disease. It is effectivewhen administered as single or multiple (Q8H) 50 and 7 5 p g doses. As part of the clinical development of procaterol, the pharmacokinetics and dose proportionality of single 25, 50, 75, and 100 pg doses were investigated in 14 healthy subjects. Serial blood samples were collected for 16 h and urine was quantitatively collected for 48 h following administration of each dose. Procaterol concentrations in plasma and urine were determined using sensitive and specific radioimmunoassay methods. Mean values for t,,, the apparent elimination rate constant, CVF, renal clearance, and per cent of dose excreted unchanged in urine were similar for all doses. Dose-normalized AUC, C,,, and amount excreted unchanged in urine (A,) were also similar across dosage levels. Thus, the pharmacokinetics of procaterol appear to be proportional to dose over the range of doses studied. KEY WORDS Procaterol Bronchodilator Healthy volunteers Pharmacokinetics Dose proportionality
INTRODUCTION Procaterol hydrochloride (Pro-Air, Parke-Davis), ( f )-(R*, S*)-8-hydroxy-5[ 1-hydroxy-2- [ (1-methylethy1)amino1 butyl ] -2( 1H)quinolone monohydrochloride hemihydrate] is an orally active &-adrenergic receptor agonist demonstrated to be safe and effective for the treatment of reversible bronchospastic
Current affiliations: *MarionMerrell Dow, Inc., 9550 N. Zionsville Rd, Indianapolis, IN 46268, U.S.A. $Harris Clinical Development, 7432 E. Stetson Drive, Scottsdale, AZ 85251, U.S.A. Correspondenceto: Dr Michael A. Eldon, Parke-Davis Pharmaceutical Research, 2800 Plymouth Rd, Ann Arbor, MI 48106-1047, U.S.A.
0142-2782/92/090663-07~08. 50 0 1992 by John Wiley & Sons, Ltd.
Received 6 January 1992 Accepted 20 April 1992
664
M . A. ELDON ET A L .
In the United States, Pro-Air tablets have been studied in adults and children over the age of 12 at doses of 50 to 75 pg administered every 8 h. Since procaterol is administered in microgram doses, concentrations of drug in plasma and urine are lower than those of less potent &-adrenergic agonists such as albuterol, metaproterenol, and terbutaline. In previous evaluations of procaterol disposition in humans, tritiated drug was used to quantify procaterol and metabolites in plasma and urine. Unfortunately, detailed pharmacokinetic analysis was not possible due to limitations in assay sensitivity using radiolabeled drug. Recent pharmacokinetic studies were made possible by the development of specific and sensitive radioimmunoassay methods capable of detecting picomolar amounts of procaterol in plasma and urine. Procaterol pharmacokinetics and relative bioavailability following administration of 100 pg doses of procaterol tablets and solution have recently been r e p ~ r t e d .Procaterol ~ was rapidly absorbed after oral administration of both tablets and solution, with an elimination half-life of approximately 4 h, and plasma clearance of nearly lo00 ml min- I . Approximately 18 per cent of plasma clearance was by renal elimination of unchanged drug, indicating that hepatic metabolism is the primary route of disposition. Procaterol appears to undergo first-pass metabolism. In addition, enterohepatic recycling of procaterol and metabolites may occur in humans. The purpose of the present study was to assess the pharmacokinetics and dose proportionality of single 25 to lOOpg doses of procaterol administered as an oral solution to healthy subjects.
METHODS
Subjects Fourteen healthy volunteers (12 male, 2 female) participated in the study conducted at the Parke-Davis Community Research Clinic, Ann Arbor, Michigan. All subjects had acceptable clinical laboratory profiles and physical examinations. Mean (range) subject weight, age, and height were 71 - 4kg (54.5 to 91 * 2kg), 29 yr (21 to 40 yr), and 176 cm (164 to 190 cm), respectively. The protocol was approved by the Community Research Clinic Institutional Review Board. All subjects provided informed consent.
Protocol The study used a single-dose, nonblind, randomized, four-way crossover design. Each subject received single 25, 50, 75, and 1OOpg doses of procaterol as a HCl hemihydrate solution (Pro-Air Syrup, 25 p g 5 ml- I , Parke-Davis, Morris Plains, NJ) at weekly intervals according to a randomized schedule. Each dose was administered with 8 ounces of water following a 10-h overnight fast, and subjects continued fasting for an additional 4 h after dosing. Identical
PROCATEROL KINETICS
665
lunches and identical dinners were served on each dosing day after the 4 and 10-h blood samples were drawn, respectively. Heparinized blood samples were drawn before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, and 16 h after dosing. Plasma was separated and stored frozen until assayed for procaterol. Urine was collected before dosing and quantitatively during the intervals 0-2,2-4,4-6,6-8,8-10, 10-12, 12-16, 16-24,24-36, and 36-48 h postdose. Total urine voided was measured for each collection period, and a 20ml aliquot was stored frozen until assayed for unchanged procaterol.
Sample analysis Procaterol concentrations in plasma and urine were assayed using sensitive, specific, and validated radioimmunoa~says.~ Plasma (100 pl) and urine (10 pl) samples were incubated with fixed amounts of antibody and 125-I-labeled procaterol. The antibody bound fraction was precipitated with sheep antirabbit immunoglobulin antibody and counted in a gamma counter. In plasma, crossreactivities of the three major metabolites of procaterol, N-desisopropyl procaterol, 5-formy1-8-hydroxycarbostyri1,and procaterol glucuronide, were 0.46 per cent or less. Logit-log standard curves in plasma were linear over the calibration range of 15 pg ml- to 2ng ml-I. The lower limit of quantitation for procaterol in plasma was 15 pg ml- l; values below this concentration were reported as zero. Precision of plasma quality control standards assayed during sample analysis ranged from 10- 1 per cent to 24.9 per cent and accuracy ranged from - 1.8 per cent to 6.0 per cent of procaterol concentrations determined during validation. In urine, cross-reactivites of the procaterol metabolites described above were 0.029 per cent or less. Logit-log standard curves in urine were linear over the calibration range of 800 pg ml- * to 50 ng ml- I . The lower limit of quantitation for procaterol in urine was 800 pg ml- I ; values below this concentration were reported as zero. Precision of urine quality control standards assayed during sample analysis ranged from 11 * 4 per cent to 21 - 7 per cent and accuracy ranged from - 5.67 per cent to 18.0 per cent of theoretical procaterol concentrations.
Data analysis Pharmacokinetic parameters AUC, C,,, t,, XZ, and t l / , were calculated from plasma procaterol concentration-time data using established methods5 (see Table 1 for definitions of parameters). The cumulative amount of procaterol excreted unchanged in urine (Ae)was determined from urine drug concentration and urine volume data and expressed as per cent of dose (A,Vo). Apparent plasma clearance (CVF) was calculated as Dose/AUC. Renal clearance (Cl,) was calculated as AJAUC. Nonrenal clearance (Clnr)was calculated as Cl/F minus Cl,.
666
M. A. ELDON E T A L .
Plasma pharmacokinetic parameters and urinary excretion parameters were analyzed using an analysis of variance (ANOVA) model with sequence, subject (within sequence), period, and treatment main effects, followed by Tukey's studentized range test, to evaluate the statistical significance of differences among treatment means.6 The ANOVA was repeated using AUC, C,,, and A, data normalized to a 75 pg dose, and linear regression analysis of unweighted AUC and C,, values against dose was performed to aid in the evaluation of dose proportionality.
RESULTS All 14 subjects completed the study. The terminal phase of drug disposition was not determined for Subject 5 after administration of the 50pg dose due to an insufficient plasma concentration-time profile. Subject 14 did not receive the 100 pg dose due to a personal time conflict. Accordingly, data from these subjects for these treatments were not available for inclusion in the statistical analyses. Mean plasma procaterol concentration-time profiles are presented in Figure 1. Plasma pharmacokinetic parameters, urinary excretion parameters, and ANOVA results are given in Table 1.
0.0
4.0
8.0
12.0
16.0
TIME (hours)
Figure 1. Mean procaterol plasma concentration-time profiles following oral administration of 25 (O), 50 ( ), 75 ( ), and 100 ( 0 )pg doses of procaterol solution to fourteen healthy subjects
667
PROCATEROL KINETICS
Table 1. Mean (olo RSD) procaterol pharmacokinetic parameters following oral administration of procaterol solution to fourteen healthy subjects
Pharmacokinetic parameter 518 (54.2) AUC
1100 (24.1)
1380 (28.6)
1590 (19.7)
Cma
113 (54.0)
205 (47.6)
233 (29.9)
276 (47.8)
tmax
1.5 (46.9)
2 - 4 (54.1)
2.0 (55.1)
1.5 (33.3)
0.295 (59-4)
0.226 (21.9)
0.211 (35.2)
0.210 (24.2)
3.2 (23.8)
3.7 (40.0)
xz
3.1 (47.4)
3-5 (20.61
t, Cl/F
1130 (64.7)
797 (24.9)
996 (35.3)
1090 (21.0)
A, A,%
3.89 (48.0) 15.6 (48.0)
7.46 (42.7) 14.9 (42.7)
12.0 (36-7) 16.1 (36.7)
15.1 (31.2) 15.1 (31.2)
c1r
143 (43.7)
122 (28.6)
Normalized* parameters AUC Cmax
4
146 (25.8)
158 (24.1)
1550
1650
1380
1190
338
308
233
207
11.7
11.2
12.0
11.3
Underlined means are not significantly different at p = 0.05. %RSD = relative standard deviation expressed as per cent of mean. AUC = area under the plasma concentration-time curve from time = 0 to infinity (pg-h ml-I). C,, = maximum observed plasma concentration (pg ml-I). (,,,=time of C,, (h). XZ = apparent elimination rate constant (h-I). t,h=apparent elimination half-life (h). CI/F= apparent plasma clearance (ml min-l). A, = cumulative amount of unchanged procaterol excreted in urine. A,% =per cent of dose excreted in urine as unchanged procaterol. C1, = renal clearance (ml min- I). *Parameter values normalized to 75 pg dose.
Mean values for tm, hz, t f i , CVF, A,%, and C1, were similar and not statistically different among doses, whereas AUC, C,,, and A, were statistically different among doses as expected. Sporadic significant differences among the four procaterol dose levels were observed for dose-normalized AUC ,, (see overlapping underlines, Table l), but not for mean doseand C normalized A, values. The power of the study to detect 20 per cent differences between dose-normalized mean parameter values was 0.99 for AUC and 0.67 for Cm,. Linear regression analysis showed (Figure 2) significant relationships between dose and AUC (r=0-773; p
