EUROPEAN JOURNAL OF DRUG MEfABOLISM AND PHARMACOKINETICS, 1990, Vol. IS, No.4, pp. 317-322
Pharmacokinetics and tolerance of romazarit after oral administration of ascending single doses to healthy human volunteers 1 1 1 " P.E.O. WILLIAMS, GJ. MUIRHEAD, E. WORTH, R . ZIMMER2 and P. LUCKER3
[Pharmacokinetics and Metabolism, Roche Products Ltd, Welwyn Garden City, Herts, UK 2Department PKFIPD, F HOffmann-La Roche Ltd, Basle, Switzerland 3Institutflir Klinische Pharmakologie, Bobenheim, Grunstadt, FRG
Receivedfor publication: January 29, 1990
Keywords: Romazarit, pharmacokinetics, dose proportionality, non-linearity
SUMMARY Forty-four healthy male volunteers participated in an investigation of the pharmacokinetics and tolerance of single oral doses of romazarit, a potential disease-modifying antirheumatic drug. The study design involved single oral doses in ascending sequence from 40 to 1500 mg. At each dosage 9 volunteers were studied, of whom 6 received romazarit and 3 received placebo capsules in a double-blind manner. Tolerance was assessed before and after each of the 57 romazarit and 27 placebo doses. Plasma and urinary concentrations of romazarit were measured by HPLC with UV detection. Model-independent pharmacokinetic analyses showed that romazarit was rapidly and extensively absorbed in a dose-proportional manner. Urinary recovery of drug related material was about 70% of the dose and almost all in the form of labile metabolites (probably acyl glucuronides). Clearance was faster (>3 l/h) at doses below 700 mg, than in the range 700-1500 mg (1.7 l/h), It is suggested that two or more clearance mechanisms are present. One of these mechanisms is saturable and may involve a reversible ester glucuronide formation coupled with saturable tubular secretion of glucuronides. Romazarit was well tolerated in these healthy volunteers. There were two reports of stomach pain, one associated with vomiting. Changes in laboratory safety test results and in measurements of vital signs were similar in frequency and magnitude after romazarit and after placebo doses.
INTRODUCTION Romazarit has a novel profile of anti-inflammatory activity; it is highly effective in chronic models of inflammation, but shows no activity in acute models and no direct inhibition of arachidonic acid metabolism (1). By extrapolation from the chronic models, it has been estimated that plasma concentrations in the range 50 to 100 mgll may be required if the drug is to be efficacious in man. Please send reprint requests to : Dr P.E.O. Williams, Pharmacokinetics & Metabolism Department, Roche Products Ltd, PO Box 8, Welwyn Garden City, Herts AL7 3AY, UK
Accordingly, this first study of romazarit in humans was a placebo-controlled assessment of tolerance and pharmacokinetics.
MATERIALS AND METHODS Clinical subjects A total of 44 healthy male volunteers were recruited after a medical history and examination. All participants had to be between 18 and 35 years old, and within ± 15% of their age-corrected ideal weight according to Metropolitan Life Assurance Tables,
Eur. J. Drug Metab. Pharmacokinet., 1990, No.4
318
of 9 volunteers; 6 subjects in each group received romazarit and 3 received matching placebo capsules. The doses were given at 5 day intervals to 3 alternating groups of volunteers. The washout period between administrations for a given subject was a minimum of 15 days. Not all the volunteers were able to complete the study for logistical reasons, and so replacements were recruited for dosages above 700 mg (Table I). Volunteers fasted overnight before each dose, and for 3 h after dosing. Vital signs (blood pressure, pulse rate, oral temperature, lung function and EeG) were
1983. The volunteers gave informed written consent The protocol was reviewed and approved by an independent ethics committee before starting. Before the placebo-controlled phase, a pilot study was performed in two pairs of subjects. One pair received single oral doses of 10 mg romazarit and the other pair 40 mg, to monitor tolerance and verify that the scheduled washout period was appropriate. The main study was performed as a double-blind placebo-controlled, randomized trial. Oral doses of 40, 100, 200, 300, 450, 700, 1000, 1200 and 1500 mg romazarit were given in ascending sequence to groups Table I : Design of main study
Dose ofromazarit (mg) or concurrent placebo Vol. No.
40
100
547 657 796 866 898 931 949 976 994 313 572 894 901 961 1061 1072 1107 1108 613 617 726 792 *852 887 927 975 1043 591 695 723 872 905 920 664 1093 569 600 838 1094 1095 1101
+
+
0
+ + +
200
WOO
1200
0
0
0
+ + +
0
+
0
0
300
0
0
+
+
+ 0
+
450
700
1500
+
0 0
0
+
+
0
0
+ + +
+ + +
0
0
+ +
+ +
0
+ + +
+ +
0
0 0
0 +
+
+
+ 0
0
+
+
+
+
+
+
+ + + +
+
+
0
+ +
+ 0 +
+ + + 0
* This volunteer
also participated in the pilot study (see text).
+ = romazarit; 0 - placebo
P. E. O. Williams et al., Romazarit pharmacokinetics
recorded before and at intervals up to 12 h after each dose. Blood and urine specimens for laboratory tests of biochemistry, haematology and urinalysis were collected immediately before 2 days and 5 days after each dose. Subjective impressions were recorded before and for 6 days after each dose. The doses were administered to the volunteers in the sitting position as hard gelatin capsules containing 10 or 100 mg romazarit or as matching placebo capsules, with 150 ml of tap water. A standard light breakfast was given 3 h after dosing. Venous blood samples (5 ml) for determination of romazarit concentrations were obtained at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 120 h after each dose. Samples were taken into heparinized Vacutainers ®, centrifuged at 4T and the plasma was stored at -20T in plain plastic tubes prior to drug analysis. Complete collections of all urine were made 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, 72-96 and 96-120 h after each dose. The total weight of each collection was recorded and then duplicate aliquots (10 ml) were deep frozen prior to drug analysis.
319
quality assurance samples was ±8% in plasma, ± 3% in urine before hydrolysis and ±3% after hydrolysis. The accuracy was 101.2% in plasma and 101.6% in urine.
Pharmacokinetics Individual data sets were analysed by 'model-independent' methods. The peak concentration, Cmax, and time to peak, Imax, were observed values. The rate of decline in plasma concentrations seemed to be dose-dependent and so elimination half-lives have not been calculated. Area under the plasma concentration versus time curve, AUC, was derived by the trapeziodal method up to the last time-point, '1' with quantifiable drug concentration, Apparent plasma clearance, Cl/F, was Dose/AUCt, where F was the unknown fractional bioavailability. Urinary recoveries, UR, were expressed as the amount of all drug-related material, before and after hydrolysis, in the various urine collections.
Analytical Statistical Plasma and urine samples were analysed for romazarit by sensitive, specific HPLC methods. For plasma, aliquots (0.2 ml) were mixed with internal standard solutions and precipitated with acidified acetonitrile. After centrifugation, the supernatant was blown to dryness under nitrogen and the residue was dissolved in mobile phase. The mobile phase consisted of 50% acetonitrile in water with 0.1% v/v trifluoroacetic acid. It was pumped through a Waters Z-module fitted with a 4 micron Novapak C18 cartridge, at a flow rate of 2.3 ml/min. Aliquots (100 ul) were injected into the column by a Wisp auto-injector and absorbance was detected by a Kratos 773 ultraviolet monitor set at 273 Dill. Approximate retention times were 4.2 min for romazarit and 5.4 min for the internal standard, a trifluoromethyl analogue of romazarit Standards for the calibration range 0.010 to 200 mg/l and quality assurance samples were processed along with each batch of unknowns. For urine, each sample was analysed both before and after hydrolysis for 60 min with 2M NaOH. Pre-study assay validation established an intra-assay precision of ±2% in plasma and ±4% in urine with quantitation limits set at the lowest standard concentrations of 0.010 mg/l in plasma and 0.100 mg/l in urine. During the study, the inter-assay precision from
Linear regression was applied to Cmax values. Mean values and percentage coefficients of variation (%CV) were calculated.
RESULTS Results from the pilot study of 10 and 40 mg romazarit doses without placebo control suggested that the schedule of sampling was appropriate to the main study. During the main study, the mean age of the 31 different volunteers who received one or more romazarit doses was 27 years with a range of 20 to 35 years. Similarly their mean weight was 73.1 kg, range 57.6 to 96.5 kg. Corresponding figures for the 10 volunteers who received only placebo doses were 25 (20 to 32) years and 73.1 (63.0-86.9) kg. One of the four volunteers from the pilot study participated in the main study. Therefore, 44 different volunteers were recruited in total. No volunteer had any significant abnormality of history or medical examination, and no volunteer was taking medications at the start of the study. In total, 57 oral doses of romazarit were given and 27 doses of placebo. There were 9 adverse events
Eur. J. Drug Metab. Pharmacokinet., 1990, No.4
320
100.00 40, 700 100, 1000 200, 1200 300, 1500 450 mg
10.00
mg mg mg mg
Drug cone mg/L
1. 00
0.10
O. 01.L+---+-...;...---f------i1-----1-----+---+_ 48 16 24 32 40 8 o
Time after dosing (h) Fig 1 : Mean plasma concentrations of romazarit after ascending single oral doses in healthy male volunteers
reported by 4 different volunteers during the entire study. Two volunteers reported headaches both one and two days after 40 mg romazarit during the pilot study. On one occasion the headache was accompanied by slight visual disturbance. During the main study, one volunteer reported stabbing pains in the stomach starting one hour after 200 mg romazarit and lasting 6.5 h. The same volunteer did not report any adverse events after receiving 700 mg romazarit 15 days later. One volunteer had stomach cramps and then vomited 5-10 min after taking 450 mg romazarit (phannacokinetic results after this dose have been excluded.) The same volunteer reported tiredness after a placebo dose 20 days later. None of the adverse events required treatment or withdrawal from the study. There were some minor changes in the vital signs (blood pressure, heart rate, EeG, spirometry, oral temperatures during the study. These changes were of equal magnitude and incidence after romazarit and after placebo. Therefore the changes were attributed to the study rather than the drug. There were few trends among the results of the biochemical, haematological and urinalysis tests. Decreases of packed cell volume, haemoglobin concentration and red blood count occurred in some
subjects after both romazarit and placebo. Low results of these haematological tests before and after 1000 mg romazarit led to the withdrawal of one volunteer, 4 days after dosing. These decreases were attributable to the blood sampling for pharmacokinetics, One volunteer was found to have abnormal serum transaminase activities 15 days after 200 mg romazarit although the values had been normal 1 and 4 days after the dose. This volunteer was withdrawn from the study and followed until return to normal. The final medical examination was normal in all subjects.
Pharmacokinetics Mean plasma concentrations are shown in Figure 1. The mean plots illustrate the rapid rise to peak concentrations after all the doses but indicate some broadening of the peak for doses above 700 mg. The peak mean concentrations were approximately dose-proportional but some of this proportionality was lost after the peaks. Mean levels after 300 mg doses were lower than after 200 mg doses by 2 h after dosing. In most individual profiles, there was an initial phase of log-linear decline until 12 or 24 h after
P. E. O. Williams et al., Romazarit pharmacokinetics
321
Table II : Phannacokinetic parameters of romazarit after single oral doses in healthy volunteers Mean (%CV) parameter value [units]
Dose (No. of evaluable
Cmax
t max
AUCt
CUF
UR
volunteers)
[mgll]
[hI
[mg.h1l]
[Uh]
[% dose]
40mg (n=6)
2.95 (76)
0.542 (90)
4.43 (36)
9.66 (28)
79.2 (33)
100mg (n=6)
11.1 (26)
0.833 (75)
22.1 (14)
4.56 (14)
71.9 (31)
200mg (n=6)
21.2 (32)
1.46 (91)
63.3 (37)
3.48 (32)
61.3 (20)
300mg (n=5)
25.6 (14)
0.850 (49)
60.0 (17)
5.13 (20)
81.7 (11)
450mg (n=5)
40.6 (40)
0.950 (54)
152 (29)
3.16 (29)
60.9 (14)
700mg (n=6)
79.8 (17)
1.25 (49)
439 (35)
1.74 (31)
66.9 (21)
1000mg (n=6)
104 (22)
1.83 (54)
691 (38)
1.60 (32)
76.1 (5.4)
1200mg (n=6)
118 (13)
1.62 (76)
787 (43)
1.69 (28)
68.8 (19)
1500 mg (n=6)
144 (34)
1.42 (40)
958 (36)
1.73 (33)
68.1 (22)
dosing and then an indication of a second slower phase. Since concentrations at the start of the second phase, were generally 1-2% of the peak concentrations, most of the drug elimination seemed to be associated with the initial phase. Because the rate of decline was dose-dependent, no half-lives have been calculated. Mean pharmacokinetic parameters values are shown in Table II. The only parameter which was linearly related to dose was Cmax (y = O.lOx + 0.47, P
Pharmacokinetics and tolerance of romazarit after oral administration of ascending single doses to healthy human volunteers 1 1 1 " P.E.O. WILLIAMS, GJ. MUIRHEAD, E. WORTH, R . ZIMMER2 and P. LUCKER3
[Pharmacokinetics and Metabolism, Roche Products Ltd, Welwyn Garden City, Herts, UK 2Department PKFIPD, F HOffmann-La Roche Ltd, Basle, Switzerland 3Institutflir Klinische Pharmakologie, Bobenheim, Grunstadt, FRG
Receivedfor publication: January 29, 1990
Keywords: Romazarit, pharmacokinetics, dose proportionality, non-linearity
SUMMARY Forty-four healthy male volunteers participated in an investigation of the pharmacokinetics and tolerance of single oral doses of romazarit, a potential disease-modifying antirheumatic drug. The study design involved single oral doses in ascending sequence from 40 to 1500 mg. At each dosage 9 volunteers were studied, of whom 6 received romazarit and 3 received placebo capsules in a double-blind manner. Tolerance was assessed before and after each of the 57 romazarit and 27 placebo doses. Plasma and urinary concentrations of romazarit were measured by HPLC with UV detection. Model-independent pharmacokinetic analyses showed that romazarit was rapidly and extensively absorbed in a dose-proportional manner. Urinary recovery of drug related material was about 70% of the dose and almost all in the form of labile metabolites (probably acyl glucuronides). Clearance was faster (>3 l/h) at doses below 700 mg, than in the range 700-1500 mg (1.7 l/h), It is suggested that two or more clearance mechanisms are present. One of these mechanisms is saturable and may involve a reversible ester glucuronide formation coupled with saturable tubular secretion of glucuronides. Romazarit was well tolerated in these healthy volunteers. There were two reports of stomach pain, one associated with vomiting. Changes in laboratory safety test results and in measurements of vital signs were similar in frequency and magnitude after romazarit and after placebo doses.
INTRODUCTION Romazarit has a novel profile of anti-inflammatory activity; it is highly effective in chronic models of inflammation, but shows no activity in acute models and no direct inhibition of arachidonic acid metabolism (1). By extrapolation from the chronic models, it has been estimated that plasma concentrations in the range 50 to 100 mgll may be required if the drug is to be efficacious in man. Please send reprint requests to : Dr P.E.O. Williams, Pharmacokinetics & Metabolism Department, Roche Products Ltd, PO Box 8, Welwyn Garden City, Herts AL7 3AY, UK
Accordingly, this first study of romazarit in humans was a placebo-controlled assessment of tolerance and pharmacokinetics.
MATERIALS AND METHODS Clinical subjects A total of 44 healthy male volunteers were recruited after a medical history and examination. All participants had to be between 18 and 35 years old, and within ± 15% of their age-corrected ideal weight according to Metropolitan Life Assurance Tables,
Eur. J. Drug Metab. Pharmacokinet., 1990, No.4
318
of 9 volunteers; 6 subjects in each group received romazarit and 3 received matching placebo capsules. The doses were given at 5 day intervals to 3 alternating groups of volunteers. The washout period between administrations for a given subject was a minimum of 15 days. Not all the volunteers were able to complete the study for logistical reasons, and so replacements were recruited for dosages above 700 mg (Table I). Volunteers fasted overnight before each dose, and for 3 h after dosing. Vital signs (blood pressure, pulse rate, oral temperature, lung function and EeG) were
1983. The volunteers gave informed written consent The protocol was reviewed and approved by an independent ethics committee before starting. Before the placebo-controlled phase, a pilot study was performed in two pairs of subjects. One pair received single oral doses of 10 mg romazarit and the other pair 40 mg, to monitor tolerance and verify that the scheduled washout period was appropriate. The main study was performed as a double-blind placebo-controlled, randomized trial. Oral doses of 40, 100, 200, 300, 450, 700, 1000, 1200 and 1500 mg romazarit were given in ascending sequence to groups Table I : Design of main study
Dose ofromazarit (mg) or concurrent placebo Vol. No.
40
100
547 657 796 866 898 931 949 976 994 313 572 894 901 961 1061 1072 1107 1108 613 617 726 792 *852 887 927 975 1043 591 695 723 872 905 920 664 1093 569 600 838 1094 1095 1101
+
+
0
+ + +
200
WOO
1200
0
0
0
+ + +
0
+
0
0
300
0
0
+
+
+ 0
+
450
700
1500
+
0 0
0
+
+
0
0
+ + +
+ + +
0
0
+ +
+ +
0
+ + +
+ +
0
0 0
0 +
+
+
+ 0
0
+
+
+
+
+
+
+ + + +
+
+
0
+ +
+ 0 +
+ + + 0
* This volunteer
also participated in the pilot study (see text).
+ = romazarit; 0 - placebo
P. E. O. Williams et al., Romazarit pharmacokinetics
recorded before and at intervals up to 12 h after each dose. Blood and urine specimens for laboratory tests of biochemistry, haematology and urinalysis were collected immediately before 2 days and 5 days after each dose. Subjective impressions were recorded before and for 6 days after each dose. The doses were administered to the volunteers in the sitting position as hard gelatin capsules containing 10 or 100 mg romazarit or as matching placebo capsules, with 150 ml of tap water. A standard light breakfast was given 3 h after dosing. Venous blood samples (5 ml) for determination of romazarit concentrations were obtained at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 and 120 h after each dose. Samples were taken into heparinized Vacutainers ®, centrifuged at 4T and the plasma was stored at -20T in plain plastic tubes prior to drug analysis. Complete collections of all urine were made 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, 72-96 and 96-120 h after each dose. The total weight of each collection was recorded and then duplicate aliquots (10 ml) were deep frozen prior to drug analysis.
319
quality assurance samples was ±8% in plasma, ± 3% in urine before hydrolysis and ±3% after hydrolysis. The accuracy was 101.2% in plasma and 101.6% in urine.
Pharmacokinetics Individual data sets were analysed by 'model-independent' methods. The peak concentration, Cmax, and time to peak, Imax, were observed values. The rate of decline in plasma concentrations seemed to be dose-dependent and so elimination half-lives have not been calculated. Area under the plasma concentration versus time curve, AUC, was derived by the trapeziodal method up to the last time-point, '1' with quantifiable drug concentration, Apparent plasma clearance, Cl/F, was Dose/AUCt, where F was the unknown fractional bioavailability. Urinary recoveries, UR, were expressed as the amount of all drug-related material, before and after hydrolysis, in the various urine collections.
Analytical Statistical Plasma and urine samples were analysed for romazarit by sensitive, specific HPLC methods. For plasma, aliquots (0.2 ml) were mixed with internal standard solutions and precipitated with acidified acetonitrile. After centrifugation, the supernatant was blown to dryness under nitrogen and the residue was dissolved in mobile phase. The mobile phase consisted of 50% acetonitrile in water with 0.1% v/v trifluoroacetic acid. It was pumped through a Waters Z-module fitted with a 4 micron Novapak C18 cartridge, at a flow rate of 2.3 ml/min. Aliquots (100 ul) were injected into the column by a Wisp auto-injector and absorbance was detected by a Kratos 773 ultraviolet monitor set at 273 Dill. Approximate retention times were 4.2 min for romazarit and 5.4 min for the internal standard, a trifluoromethyl analogue of romazarit Standards for the calibration range 0.010 to 200 mg/l and quality assurance samples were processed along with each batch of unknowns. For urine, each sample was analysed both before and after hydrolysis for 60 min with 2M NaOH. Pre-study assay validation established an intra-assay precision of ±2% in plasma and ±4% in urine with quantitation limits set at the lowest standard concentrations of 0.010 mg/l in plasma and 0.100 mg/l in urine. During the study, the inter-assay precision from
Linear regression was applied to Cmax values. Mean values and percentage coefficients of variation (%CV) were calculated.
RESULTS Results from the pilot study of 10 and 40 mg romazarit doses without placebo control suggested that the schedule of sampling was appropriate to the main study. During the main study, the mean age of the 31 different volunteers who received one or more romazarit doses was 27 years with a range of 20 to 35 years. Similarly their mean weight was 73.1 kg, range 57.6 to 96.5 kg. Corresponding figures for the 10 volunteers who received only placebo doses were 25 (20 to 32) years and 73.1 (63.0-86.9) kg. One of the four volunteers from the pilot study participated in the main study. Therefore, 44 different volunteers were recruited in total. No volunteer had any significant abnormality of history or medical examination, and no volunteer was taking medications at the start of the study. In total, 57 oral doses of romazarit were given and 27 doses of placebo. There were 9 adverse events
Eur. J. Drug Metab. Pharmacokinet., 1990, No.4
320
100.00 40, 700 100, 1000 200, 1200 300, 1500 450 mg
10.00
mg mg mg mg
Drug cone mg/L
1. 00
0.10
O. 01.L+---+-...;...---f------i1-----1-----+---+_ 48 16 24 32 40 8 o
Time after dosing (h) Fig 1 : Mean plasma concentrations of romazarit after ascending single oral doses in healthy male volunteers
reported by 4 different volunteers during the entire study. Two volunteers reported headaches both one and two days after 40 mg romazarit during the pilot study. On one occasion the headache was accompanied by slight visual disturbance. During the main study, one volunteer reported stabbing pains in the stomach starting one hour after 200 mg romazarit and lasting 6.5 h. The same volunteer did not report any adverse events after receiving 700 mg romazarit 15 days later. One volunteer had stomach cramps and then vomited 5-10 min after taking 450 mg romazarit (phannacokinetic results after this dose have been excluded.) The same volunteer reported tiredness after a placebo dose 20 days later. None of the adverse events required treatment or withdrawal from the study. There were some minor changes in the vital signs (blood pressure, heart rate, EeG, spirometry, oral temperatures during the study. These changes were of equal magnitude and incidence after romazarit and after placebo. Therefore the changes were attributed to the study rather than the drug. There were few trends among the results of the biochemical, haematological and urinalysis tests. Decreases of packed cell volume, haemoglobin concentration and red blood count occurred in some
subjects after both romazarit and placebo. Low results of these haematological tests before and after 1000 mg romazarit led to the withdrawal of one volunteer, 4 days after dosing. These decreases were attributable to the blood sampling for pharmacokinetics, One volunteer was found to have abnormal serum transaminase activities 15 days after 200 mg romazarit although the values had been normal 1 and 4 days after the dose. This volunteer was withdrawn from the study and followed until return to normal. The final medical examination was normal in all subjects.
Pharmacokinetics Mean plasma concentrations are shown in Figure 1. The mean plots illustrate the rapid rise to peak concentrations after all the doses but indicate some broadening of the peak for doses above 700 mg. The peak mean concentrations were approximately dose-proportional but some of this proportionality was lost after the peaks. Mean levels after 300 mg doses were lower than after 200 mg doses by 2 h after dosing. In most individual profiles, there was an initial phase of log-linear decline until 12 or 24 h after
P. E. O. Williams et al., Romazarit pharmacokinetics
321
Table II : Phannacokinetic parameters of romazarit after single oral doses in healthy volunteers Mean (%CV) parameter value [units]
Dose (No. of evaluable
Cmax
t max
AUCt
CUF
UR
volunteers)
[mgll]
[hI
[mg.h1l]
[Uh]
[% dose]
40mg (n=6)
2.95 (76)
0.542 (90)
4.43 (36)
9.66 (28)
79.2 (33)
100mg (n=6)
11.1 (26)
0.833 (75)
22.1 (14)
4.56 (14)
71.9 (31)
200mg (n=6)
21.2 (32)
1.46 (91)
63.3 (37)
3.48 (32)
61.3 (20)
300mg (n=5)
25.6 (14)
0.850 (49)
60.0 (17)
5.13 (20)
81.7 (11)
450mg (n=5)
40.6 (40)
0.950 (54)
152 (29)
3.16 (29)
60.9 (14)
700mg (n=6)
79.8 (17)
1.25 (49)
439 (35)
1.74 (31)
66.9 (21)
1000mg (n=6)
104 (22)
1.83 (54)
691 (38)
1.60 (32)
76.1 (5.4)
1200mg (n=6)
118 (13)
1.62 (76)
787 (43)
1.69 (28)
68.8 (19)
1500 mg (n=6)
144 (34)
1.42 (40)
958 (36)
1.73 (33)
68.1 (22)
dosing and then an indication of a second slower phase. Since concentrations at the start of the second phase, were generally 1-2% of the peak concentrations, most of the drug elimination seemed to be associated with the initial phase. Because the rate of decline was dose-dependent, no half-lives have been calculated. Mean pharmacokinetic parameters values are shown in Table II. The only parameter which was linearly related to dose was Cmax (y = O.lOx + 0.47, P
