The pharmacokinetics of baclofen derived from intestinal infusion. The pharmacokinetics of badofen, a centrally acting muscle relaxant, have been elucidated in ...
The pharmacokinetics of baclofen derived from intestinal infusion The pharmacokinetics of badofen, a centrally acting muscle relaxant, have been elucidated in man. The pharmacokinetic disposition was determined form plasma concentration-time data and urinary recovery after the administration of rate-limiting intestinal infusions and an oral bolus dose. Based on comparisons between the plasma concentration-time profiles from the intestinal infusions and the oral bolus doses, relative regression parameter assignments were made. The intestinal absorption of baclofen after intestinal infusion was very rapid, such that badofen disposition was well characterized by an open two-compartment pharmacokinetic model with zero-order input. Intravenous administration of baclofen was precluded from this study because of the potential for severe adverse reactions. The average distribution phase constant (a) was 1.29 hours' and the average elimination phase constant (13) was 0.191 hours.' Average volume of the central compartment (Vc/F), volume of the body compartment (VaJF), systemic clearance (CL/F), and renal clearance were 28.8 L, 59.0 L, 180 ml/min, and 103 ml/min, respectively. Pharmacokinetics were dose proportional in the dose range studied. The use of these pharmacokinetic parameters as determined in normal subjects in therapeutic management is particularly relevant, because badofen is targeted to a patient population subject to renal dysfunction. (CLIN PHARMACOL THER 38:251257, 1985.)
Gregory M. Kochak, Ph.D., Ashok Raldiit, Ph.D., William E Wagner, M.D., Frank Honc, M.S., Lorraine Waldes, B.S., and Richard A. Kershaw, Ph.D. Ardsley, N. Y., and Columbus, Ohio
Baclofen (4 - amino -3- ( p - chlorophenyl ) - butanoic acid) is a centrally acting muscle relaxant. It has proved efficacious in the treatment of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscle rigidity. Baclofen may also be of some value in patients with spinal cord injuries and other spinal cord diseases. Despite its presence on the United States market for nearly 6 years and previously in Europe, little is known about its pharmacokinetic disposition in man. This may be due in part to baclofen's potential for severe adverse effects resulting in central nervous system, respiratory, and cardiovascular depression, and, therefore, the reluctance to administer the drug intravenously. Ideally, dosage adjustment, particularly in patient populations, is most rationally accomplished based on the pharmacokinetics of a drug. Riegelman et al." reported that when an oral solution is administered directly into the intestine, the absorption
Abbreviations A, B Infusion preexponential intercepts A', B' Postinfusion preexponential intercepts a, [3, lc Exponential terms C, D Oral bolus preexponential intercepts C, Plasma concentration in the central compartment CL Total systemic clearance CLR Renal clearance Administered dose by intestinal infusion or oral bolus Absolute bioavailable fraction Infusion duration Time t' t-T t,p Lag time V, Volume of the central compartment Vaa Volume of the body
From the Pharmaceuticals Division, CIBA-GEIGY Corporation, Ardsley, and Department of Pharmacology, College of Medicine, The Ohio State University, Columbus. Received for publication Jan. 7, 1985; accepted May 29, 1985. Reprint requests to: Gregory M. Kochak, Ph.D., Pharmaceuticals Division, CIBA-GEIGY Corporation, Ardsley, NY 10502.
process is extremely fast for some drugs and the plasma concentration-time profile is virtually equivalent to that after an intravenous injection. Because intravenous administration of baclofen has not been reported in man, this study was undertaken to determine the pharma-
251
CL1N PHARMACOL TF1ER SEPTEMBER 1985
252 Kochak et al. 800
k12 2
DiT
'21
600
400
Fig. 1. Schematic representation of a two-compartment pharmacokinetic model with zero-order input.
cokinetic disposition and dose proportionality at the absorption site of baclofen by direct infusion of baclofen solution into the duodenum over a prolonged infusion interval. Evaluations of the assumption of near instantaneous absorption and appropriateness of treating the data with zero-order input were made.
METHODS Clinical. Four healthy nonsmoking men 21 to 26 years old were informed of the nature of the experiment and gave written consent to participate. All were within 15% of the standards for body weight,' had a history of good health, and denied using prescription drugs, over-the-counter medications, and other drugs during the 7 days before the study. Consumption of alcoholic beverages was prohibited for the 3-day period before any drug study day. A standard physical examination, routine laboratory workup of blood and urine samples, and ECG showed no deviations from accepted values. Each of the four subjects received an aqueous solution of baclofen over approximately an 8-hour period through a nasogastric tube directly into the duodenum. Intestinal infusions were repeated three times, such that the total delivered doses were approximately 12, 24, and 48 mg. Actual delivered doses were determined as indicated below. In addition to the three infusions, each subject received an oral bolus dose (24 mg) of baclofen in an aqueous solution. The sequence of administration of each preparation followed a four-way Latin squares design balanced for residual effects. Baclofen was infused by a new portable and disposable infusor unit, the Travenol 24-Hour Infusor (Travenol Laboratories, Inc.). These pumps are designed to deliver 2 ml/hr of 5% dextrose in water injection solution at 30° C with a dynamic viscosity of 0.907 cp. In vitro calibration of the pumps with aqueous solutions of baclofen (density 0.996 gm/ml; viscosity 0.798 cp) at ambient temperature indicated an average ( ± SD) flow rate of 2.20 ± 0.163 ml/hr (n = 63) over a 9hour period after allowing dynamic equilibration for the
200
6
4
2
-
L)
,
hr
Fig. 2. Loo-Riegelman cumulative absorption profiles for subject 3 showing infusion ratelimited absorption after baclofen administration by three intestinal infusions at rates of 5.86 (0), 2.66 (A), and 1.31 (0) mg/hr. L, lag factor (tag).
first hour. Stability of the flow rate indicated an average ( -.± SD) decline in the initial rate of 0.03 -± 0.018 ml/ hr (n = 7). At intervals of 1 week, the subjects were admitted to the clinical pharmacology unit on the evening before drug dosing. Specially fabricated nasogastric feeding tubes, 43 in long with 8-F end fittings and tungsten weights (Enteriflex feeding tube; Biosearch Medical Products Inc.) were passed through one nostril and fed into the stomach. Enough slack was allowed so that normal peristalsis would carry the tip of the feeding tube into the small bowel overnight. Once the tubes were in place, all subjects, including the nonintubated control, were allowed only 100 ml apple juice and 2 soda crackers per hour to prevent excessive hunger. Three hours after the tube was introduced, a small fluid sample was withdrawn through the nasogastric tube to check for patency. A second sample was taken just before the start of the drug infusion and its pH and color were noted to confirm placement of the tube in the small intestine and to check for patency of the tube. To prepare the infusion solutions, 66.8, 133.6, and 267.3 mg baclofen was added to 100 ml distilled water. The oral solution was prepared by adding 24 mg drug to 50 ml water. The infusors were loaded with 60 ml of the appropriate infusion solution. Flow was allowed to stabilize for 1 hour before the infusor pumps were capped and weighed. The pumps were then attached to the enteric feeding tubes and the flow rate was approximated by measuring the time needed for the advancing meniscus to traverse a 10 cm distance marked on the tube. The start of the infusion (to) was calculated as: to (hr) = t, + lLG X t11600, where t, is the time the
VOLUME 38 NUMBER 3
253
Bacloftn pharmacokinetics after intestinal infusion
infusor pump was attached to the nasogastric tube, LG is the length of the nasogastric tube, and t is time in min for the solution to traverse 10 cm. The oral baclofen solution was swallowed and followed by three 50 ml washings of the container. At t, the three subjects receiving the infusions drank 200 ml water. Serial 7 ml blood samples were collected by venipuncture in Venoject tubes (Terumo Medical Corp.) containing 143 IU sodium heparin. Blood samples were drawn at 0, 0.5, 1, 1.5, 2, 3, 5, 7, 8, 9, 10, 12, 14, 16, 18, 20, and 24 hours for subjects receiving the drug by infusion. Blood samples after oral bolus dosing were drawn at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours. Plasma was separated by centrifugation and stored for analysis. Urine collections were made at 0, 2, 4, 6, 8, 12, 16, 24, and 48 hours. Total volume and pH of the urine collected during each period were measured and a 10 ml portion was retained for analysis. At the end of the oral infusion, the enteric feeding tube was clamped and removed from each subject. The capped infusion pump was reweighed and the weight of infusion solution delivered was calculated. The actual dose delivered was calculated as: Dose (mg) = [(Net weight delivered (gm)/p) residual volume in the nasogastric tube (m1)J x concentration of baclofen solution (mg/ml), where p is the density of baclofen solution (gm/mi). Sample analysis and storage. All plasma and urine samples were kept frozen at approximately 20° C until analyzed. Plasma and urine concentrations of baclofen were determined by a previously reported GLC
method.' Computational. The plasma concentration-time profiles were analyzed by standard nonlinear regression techniques with a weighting factor of 1/C. Initially, the postinfusion curves were fit to an open two-compartment pharmacokinetic model described by the following equation (see Appendix): Cc.
=
A'e'
+
The cumulative absorption profiles determined by the method of Loo and Riegelman7 were then generated to determine if the input rates were zero order and limiting. Comparisons were made between the absorption rate normalized for a bioavailable fraction of 1 and the infusion rates determined experimentally in vitro from the net volume of solution delivered and the time interval from attachment of the infusor to the nasogastric tube until removal of the nasogastric tube from the subject. Subsequently, the entire plasma concentration-time
Table I. Infusion and absorption rates Subject No. 1
2
(mg)
Infusion rate (mg/hr)
11.8 23.7
1.48
1.37
2.95
41.6
5.21
2.86 5.44
11.8 23.5 43.3
1.45 2.93 5.43
2.67 6.07
Dose
11.6 23.1
3
47.0 4
12.1 17.1
44.5
Absorption rate (mgIhr)*
1.41
1.45
1.31
2.87 5.88
2.66 5.86
1.52
1.53
2.12 5.59
2.03 5.14
*Calculated from in vivo data by the method of Loo and Riegelman and normalized for an F of 1.
profile was fit to the pharmacokinetic model shown in Fig. 1 when the experimentally determined infusion rate coincided with the absorption rate calculated from in vivo data. The equation used to describe the model in Fig. 1 is as follows: Cc =
A(e''
e-
'tho
+ B(e-0" -
e
3" -
'10
where T = t during the infusion and is fixed as a constant after infusion. The oral bolus dose was fitted to a standard classical two compartment pharmacokinetic model with first-order input. The equation used to describe the model is as follows: = Ce
""
"ao
+ De
>>
lag'
(C
D)e-""
"g'
The absorption rate constant was determined directly from regression analysis. Disposition parameter estimates as determined from the intestinal infusions were used as initial estimates in fitting the data after oral bolus dosing. Data are reported as X ± SD.
RESULTS Experimental. The cumulative absorption profiles (Fig. 2) for each subject and dose were linear, indicating that the infusion rates were limiting. There is good agreement between the infusion rate and the absorption rate (Table I). Pairwise comparison of the infusion rate and the absorption rate for each subject and dose by the t test found no significant differences (P 0.05). The plasma concentrations of baclofen after the intestinal infusions and oral bolus doses are listed in Table
CLIN PHARMACOL THER
254 Kochak et al.
SEPTEMBER. 1985
Table II. Baclofen plasma concentrations (ng/ml) after intestinal infusion and oral bolus Hr after dosing Subject No. 1
cf
Dose (mg)
(hr)*
0.5
1.0
1.5
2.0
3.0
11.8 23.7
+0.60 +0.30
15
20 55
35 87
54
22
100
63 195
5
49 282
61
131
106
293
322
29 75
119
69 140
283 501
432 338
to
-0.34
41.6 24.012
+0.38 +0.75
11.8 23.5 43.3
+0.86 +0.71 +0.00
11.6 23.1
47.0 24.0t 4
25
54 132
171
557
554
462
10
29 75 43 610
36 80 89 590
-0.87
24.0t 3
19
23
62 15
363
12.1 17.1
44.5
49
176
247
5.0
156
73 175
21
66
17
44 54
47
+0.41 +0.66
71
39 330
85
477
145 481
160 169
292 337
405
111
75
118
118
220 697
248 754
225 788
170 75
207
129
217
188 161
108
122
85 208 444
102
95 194
77 264 312 156
116 156 331
123
204 386 70
191
141
9.0
115
62
260
8.0
229 363
107
107
7.0
105
59
580
6.0
217 352
90
-0.09
24.0t
234 303
4.0
100
99
200 233 77
159 160
48 253 308
83
81
299 427
345 419 45
k (hr-')
(ng
88
cf = Correction factor; ND = not detectable (
