Epilepsiu, 33(5):955-960
Raven Press, Ltd., New York 0 International League Against Epilepsy
Pharmacokinetics of Felbamate in Pediatric and Adult Beagle Dogs V. E. Adusumalli, J. R. Gilchrist, J. K. Wichmann, N. Kucharczyk, and R. D. Sofia Department of Biochemistry, Wallace Laboratories, Division of Carter- Wallace, Cranbury, New Jersey, U.S.A .
Summary: The relative bioavailability and pharmacokinetics of felbamate (FBM) after a single oral dose and after 10 once-daily oral doses of 60 mg/kg were investigated in adult and pediatric dogs of both sexes. The pediatric and adult dogs were aged 4-6 weeks and 1-2 years, respectively. Analysis of variance (ANOVA) was performed on the bioavailability parameters among all groups and between the first and last doses. No sexrelated differences in bioavailability and pharmacokinetic parameters were observed. The bioavailability of FBM in pediatric dogs was significantly less as compared with that in adult dogs. Rapid overall elimination of the drug in pediatric dogs appears to be responsible for the lower
bioavailability. The bioavailability of FBM after the last dose was also significantly lower than after the first dose for both age groups. No major differences in the rate constant of FBM absorption (ka) and volume of distribution at steady state (VJ were observed between the two age groups. As with other clinically useful antiepileptic drugs (AEDs), higher doses of FBM may be required in pediatric populations to achieve optimum drug levels, assuming that age-related changes in FBM disposition will also be confirmed in humans. Key Words: FelbamatePharmacokinetics-Dogs-Aging-Sex-Anticonvulsants.
Felbamate, (FBM), 2-phenyl- I ,3-propanediol dicarbamate, (Fig. 1) is a novel orally active and relatively nontoxic anticonvulsant compound with a unique profile of activity in laboratory animals (Swinyard et al., 1986; Lockard et al., 1987). This profile of activity and toxicity has also been observed in extensive clinical trials (Leppik and Graves, 1989). FBM has been consistently reported to induce liver microsomal enzymes in laboratory animals (Segelman et al., 1985; Swinyard et al., 1987), but no tolerance to the anticonvulsant effects of FBM has been noted in either laboratory animals (Swinyard et al., 1987) or humans (Wilensky et al., 1985; Perhach et al., 1986). Because FBM is also expected to be administered to children, determination of optimum regulation of antiepileptic therapy based on knowledge of the age dependency of FBM kinetics is necessary. No pharmacokinetic studies in pediatric animal models have been reported that would allow assessment of FBM disposition in chil-
dren. We investigated age- and sex-related changes in relative bioavailability and pharmacokinetic parameters of FBM in beagle dogs. MATERIALS AND METHODS Materials diFBM and 2-methyl-2-phenyl-l,3-propanediol carbamate, internal standard for F B M highperformance liquid chromatography (HPLC) assay, were from Wallace Laboratories (Cranbury, NJ, U.S.A.). All other supplies and reagent-grade chemicals were obtained from commercial sources. Animal procedures Adult male and female beagle dogs (aged 1-2 years and weighing 8-17 kg) and pediatric male and female beagle dogs (aged 5 weeks old and weighing 1.5-2.8 kg) were purchased from White Eagle Laboratories, Doylestown, PA, U.S.A., and Harlan Industries, Indianapolis, IN, U.S.A., respectively. Adult dogs were fed once daily at approximately Noon, and pediatric dogs were fed three times daily at approximately Noon, 4 p.m., and 9 p.m. Four groups of 20 dogs each (male and female adult and pediatric dogs, total 80) received a 60-mg/kg dose of FBM contained in a hard gelatin capsule at -8 a.m.
Received April 1991; revision accepted February 1992. Presented at the Annual Meeting of the American Epilepsy Society, San Diego, California, November 1990 and published in abstract form in Epilepsia 1990;31:641. Address correspondence and reprint requests to Dr. N. Kucharczyk at Department of Biochemistry, Wallace Laboratories, Half-Acre Rd., Cranbury, NJ 08512, U.S.A.
955
956
V . E . ADUSUMALLI ET AL.
CH,OCONH,
\C H ,OCONH, FIG. 1 . Chemical structure of felbamate, 2-phenyl-l,3propanediol dicarbamate.
on study day 1. After capsules were administered, -20 and 5 ml water was administered to each adult and pediatric dog, respectively. No FBM was administered on study day 2. FBM was again administered to each dog once daily on study days 3-12 (10 consecutive doses). Blood samples of 0.6-ml vol were taken from each dog before dosing and at 0.5, 1.O, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, and 48 h after the first and last dose. Blood samples of the same volume were also collected immediately before the eighth, ninth, and tenth dose for steady-state confirmation. A blood sample was withdrawn from either the cephalic, jugular, or saphenous vein of each dog with a 1-ml nonheparinized syringe. The sample was immediately transferred to a 0.7-ml heparinized Microtainer tube (Becton Dickinson, Rutherford, NJ, U .S .A.). The Microtainer tubes were centrifuged at -2,500 rpm for 10-25 min. Duplicate plasma samples of 0.100-ml aliquots each were stored frozen until analyzed. FBM HPLC assays Study plasma samples were analyzed for FBM by a specific automated HPLC method (Clark et al., 1992). The proteins in 0.100-ml aliquot plasma samples were precipitated with 0.200 ml acetonitrile containing the internal standard. After mixing and centrifugation, 0.010 ml supernatant was injected onto a 15-cm Spherisorb ODS-2 (3 km) HPLC column. The mobile phase was 25% acetonitrile in 10 mM phosphate buffer, pH 6.5, with ultraviolet (UV) detection at 210 nm, column temperature 40"C, and flow rate of 0.7 ml/min. The linear quantitation range for the assay was 0.147-150 kg/ml FBM; the lower limit of quantitation was 0.147 pg/ml. The analyses were made with a Waters 712 WISP autoinjector (Milford, MA, U.S.A.), a Waters 590 pump, an ABI 7836 UV absorbance detector (Foster City, CA, U.S.A.), a PE-Nelson 2600 chromatography system (Cupertino, CA, U.S.A.), and a Hewlett Packard 3357 Laboratory Automation System (Avondale, PA, U.S.A.). Data analysis Plasma FBM concentration data were processed using BIOPAK software (Statistical Consultants, Epilepsia, Vol. 33, No. 5 , 1992
Inc., 1987) and the following bioavailability parameters were determined: peak concentration (C,,,), time of peak concentration (t,,,), area under the curve from time zero to time infinity (AUC) and elimination of half-life (t,/,). Analysis of variance (ANOVA) was performed on the bioavailability parameters to test differences among all groups. The ANOVA test was also performed on the bioavailability parameters obtained for the first and last doses. In all statistical analyses, a difference at p < 0.05 was considered significant. Mean plasma FBM concentration data for each group (i.e., adult male, adult female, pediatric male, and pediatric female) were subjected to exponential curve stripping and nonlinear least-squares optimization by the RSTRIP program (MicroMath Scientific Software, 1989) to the following equation
c, = A
. e - k c ~ . t + B . ,-k.t
t 11
where C,, is the plasma concentration of the drug at time t, A and B are the Y-intercepts derived from the exponential fitting and k, and k,, are the first order rate constants for drug absorption and elimination from the body, respectively. No weighting factor was used in these analyses. The estimates of FBM absorption and elimination t,,,, AUC, lag time for absorption ( t , a g ) , and mean residence time (MRT) were also obtained based on the best-fit curves from the RSTRIP analyses. The total body clearance (CL) and volume of distribution at steady-state (VSJ were calculated by using eq. 2 and 3 , respectively, CL
F x dose =
vss =
AUC
F x dose x AUMC ' AUC x AUC
[31
where AUC is area under the curve from time zero to infinity, F is absolute bioavailability , and AUMC is area under the first moment curve. In these calculations, F was assumed to be unity based on previous studies in dogs (Adusumalli et al., 1991). RESULTS The mean FBM plasma concentration versus time curves for the adult and pediatric groups showed a major difference in the FBM plasma concentrations between the two age groups (Fig. 2). The bioavailability data for male and female groups were compared separately (Tables 1 and 2). In the AUC, and t,/, for the last adult male group, the t,,, dose were significantly (p < 0.05) less than those for
95 7
FBM AGE-DEPENDENT KINETICS IN DOGS
1' 0
70
l0 o
first dose in the pediatric dogs was about threefold less than that observed in adult dogs. These quantitative relationships between the two age groups were also true after the last dose. The mean observed FBM concentration versus time data and the best-fit curves for each group for the first dose showed a close fit of concentration data to the biexponential equation for both age groups (Fig. 3). FBM elimination was faster in the pediatric group than in the adult group. The best-fit optimized pharmacokinetic parameters for all four AUC and groups are shown in Table 3. C,,,, t,,, tliZvalues from the RSTRIP analyses, based on fitted curve estimations, were slightly different than those based on observed data obtained with BIOPAK (Tables 1 and 2), but both sets were well within the ranges defined by the mean +. SD for each parameter. The absorption tliz(t,,,k") of FBM were similar (ranging from 1.49 to 2.18 h) for the first and last doses and for all four groups. The absorption lag time (t,,J for all groups was very brief (range 0-0.09 h). MRT in adult dogs for the first and last doses was -12-15 and 10 h, respectively. MRT in pediatric dogs for the first and last doses was similar (-6 h). CL was higher in pediatric dogs (0.194-0.326 L/h/kg) than in adult dogs (0.069-0.11 1 Llhlkg). The apparent V,, for FBM was similar in adult dogs (0.90-1.07 Llkg) and pediatric dogs (1.19-1.89 L/kg). These V,, values suggested higher distribution of FBM into tissue than that corresponding to total body water (0.6 L/h/kg). No sexrelated differences in CL and V,, were observed between the two age groups.
1 j
I
the first dose. In the pediatric male group, C,,, and AUC for the last dose were significantly less than and tl,, were simithose for the first dose, but t,, and AUC lar. In the adult female group, C,,,, t,,, were significantly less than those for the first dose and the tlizwas similar. In pediatric females, as in pediatric males, C,,, and AUC were less than those for the first dose. Comparison of the bioavailability parameters for adult and pediatric dogs (Tables 1 and 2) showed that C,,, after the first dose in pediatric dogs was -30% less than that in adult dogs. t,, after the first dose in the pediatric dogs was -2 h less than that in the adult dogs. The AUC for the
DISCUSSION Many drugs administered to children exhibit differences in absorption, distribution, metabolism, and excretion from values observed in adults because of pharmacogenetic factors, age, and growth. The pharmacokinetics of antiepileptic drugs (AEDs) are dependent on many physiologic variables, of which age is a major factor (Morselli,
TABLE 1. FBM hioavailahility parameters in adult and pediatric male dogs Adult
Parameter
C,,
( w W (h) AUC (pg/h/ml) t% (h) tmx
First dose
Last dose
Column 1
Column 2
48.6 f 8.4 4.8 -t 2.3 866 t 223 6.71 -+ 1.64
45.9 f 3.6"." t 613'132't 5.24(132) t
10.3 1.3 130 1.05
FBM, felbamate; AUC, area under the curve. Values are 2SD. Superscripts identify statistical significance of the difference between the two columns for each parameter (p < 0.05). Epilepsia, Vol. 33, N o . 5 , 1992
V . E. ADUSUMALLI ET AL.
958
TABLE 2. FBM bioavailability parameters in adult and pediatric f e m a l e d o g s Pediatric _ _ _
Adult
________-__--Parameter
First dose ___ Column 1 52.9 2 8.6 4.7 1.6 803 178 4.68 & 1.09
**
Last dose
_____
Column 2 46.8".2' 3.4",2' 542'i,2' 4.43
-t-
_ _
First dose
.
Column 3
10.9
33.7'1.3' 5 3.0'i.3' 2 281".3' ? 2.93('73) 2
** 1.8 161
* 1.24
4.5 0.6 55 0.33
- -
Ld5t d m e _ _ _ _ Column 4
25.5'2.4"3.4' 2 2.8 ? 184(2,4)(3,412 2.71'2,4' &
5.8 0.8 46 0.32
Abbreviations as in Table I . Values are ?SD. Superscripts identify statistical significance of the difference between the two columns for each parameter (p < 0.0s).
1983). The age-related differences in elimination are documented for several drugs (Boreus, 1982). For safe and effective drug therapy in the pediatric population, the pharmacokinetic behavior of any drug must be thoroughly characterized and any differences in the kinetics between the adult and pediatric populations must be identified. For ethical reasons, no pharmacokinetic data has yet been obtained with FBM in very young children. Therefore, in this study, we determined the relative bioavailability and pharmacokinetics of FBM in pediatric and adult dogs to provide needed data in animal models. The statistically significant differences observed for C,,,, AUC, and ti,, indicated that the relative bioavailability of FBM was about threefold less in pediatric dogs than in adult dogs. Apparently, the more rapid overall elimination of FBM in pediatric versus adult dogs was responsible for the lower bioavailability observed in the younger animals. Yang et al. (1991) reported that in adult dogs -47-52% of the FBM dose was excreted unchanged in urine and FBM was cleared equally by hepatic and renal routes. For FBM and other drugs with significant hepatic metabolism, tli2depends on hepatic metabolic clearance, binding to blood components, and Vss. The V,, of FBM in pediatric dogs was similar to that in adult dogs and therefore was not responsible for the threefold difference in tl/, values. In children, liver volume determined by ultrasound scans is greater than that of adults and the liver volume approximates functional hepatic mass and metabolic activity (Evans et al., 1989). This higher metabolic capacity in children could explain the shorter tl,, for the most widely prescribed AEDs: phenobarbital, phenytoin, ethosuximide, and carbamazepine in this population (Morrow and Richens, 1989). No pharmacokinetic data for these drugs in pediatric animals models have been reported, however. Therefore, the larger liver volume of pediatric dogs may be partially responsible for the higher clearance of FBM in that group. Another Epilepsiu, Vol. 33, No. 5 , 1992
plausible explanation for the shorter tl,, in pediatric dogs could be the higher free fraction of FBM in blood. The determined hematocrit value in pediatric dog blood in the present study was -0.25 as compared with 0.45 in adult dog blood. Because we showed previously that FBM was distributed equally between plasma and red blood cells (RBC) of dog blood (Adusumalli et al., 1991) and because the RBC fraction was significantly lower in pediatric dog blood, a higher free fraction of FBM could exist in pediatric dog blood. Free FBM is readily
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Raven Press, Ltd., New York 0 International League Against Epilepsy
Pharmacokinetics of Felbamate in Pediatric and Adult Beagle Dogs V. E. Adusumalli, J. R. Gilchrist, J. K. Wichmann, N. Kucharczyk, and R. D. Sofia Department of Biochemistry, Wallace Laboratories, Division of Carter- Wallace, Cranbury, New Jersey, U.S.A .
Summary: The relative bioavailability and pharmacokinetics of felbamate (FBM) after a single oral dose and after 10 once-daily oral doses of 60 mg/kg were investigated in adult and pediatric dogs of both sexes. The pediatric and adult dogs were aged 4-6 weeks and 1-2 years, respectively. Analysis of variance (ANOVA) was performed on the bioavailability parameters among all groups and between the first and last doses. No sexrelated differences in bioavailability and pharmacokinetic parameters were observed. The bioavailability of FBM in pediatric dogs was significantly less as compared with that in adult dogs. Rapid overall elimination of the drug in pediatric dogs appears to be responsible for the lower
bioavailability. The bioavailability of FBM after the last dose was also significantly lower than after the first dose for both age groups. No major differences in the rate constant of FBM absorption (ka) and volume of distribution at steady state (VJ were observed between the two age groups. As with other clinically useful antiepileptic drugs (AEDs), higher doses of FBM may be required in pediatric populations to achieve optimum drug levels, assuming that age-related changes in FBM disposition will also be confirmed in humans. Key Words: FelbamatePharmacokinetics-Dogs-Aging-Sex-Anticonvulsants.
Felbamate, (FBM), 2-phenyl- I ,3-propanediol dicarbamate, (Fig. 1) is a novel orally active and relatively nontoxic anticonvulsant compound with a unique profile of activity in laboratory animals (Swinyard et al., 1986; Lockard et al., 1987). This profile of activity and toxicity has also been observed in extensive clinical trials (Leppik and Graves, 1989). FBM has been consistently reported to induce liver microsomal enzymes in laboratory animals (Segelman et al., 1985; Swinyard et al., 1987), but no tolerance to the anticonvulsant effects of FBM has been noted in either laboratory animals (Swinyard et al., 1987) or humans (Wilensky et al., 1985; Perhach et al., 1986). Because FBM is also expected to be administered to children, determination of optimum regulation of antiepileptic therapy based on knowledge of the age dependency of FBM kinetics is necessary. No pharmacokinetic studies in pediatric animal models have been reported that would allow assessment of FBM disposition in chil-
dren. We investigated age- and sex-related changes in relative bioavailability and pharmacokinetic parameters of FBM in beagle dogs. MATERIALS AND METHODS Materials diFBM and 2-methyl-2-phenyl-l,3-propanediol carbamate, internal standard for F B M highperformance liquid chromatography (HPLC) assay, were from Wallace Laboratories (Cranbury, NJ, U.S.A.). All other supplies and reagent-grade chemicals were obtained from commercial sources. Animal procedures Adult male and female beagle dogs (aged 1-2 years and weighing 8-17 kg) and pediatric male and female beagle dogs (aged 5 weeks old and weighing 1.5-2.8 kg) were purchased from White Eagle Laboratories, Doylestown, PA, U.S.A., and Harlan Industries, Indianapolis, IN, U.S.A., respectively. Adult dogs were fed once daily at approximately Noon, and pediatric dogs were fed three times daily at approximately Noon, 4 p.m., and 9 p.m. Four groups of 20 dogs each (male and female adult and pediatric dogs, total 80) received a 60-mg/kg dose of FBM contained in a hard gelatin capsule at -8 a.m.
Received April 1991; revision accepted February 1992. Presented at the Annual Meeting of the American Epilepsy Society, San Diego, California, November 1990 and published in abstract form in Epilepsia 1990;31:641. Address correspondence and reprint requests to Dr. N. Kucharczyk at Department of Biochemistry, Wallace Laboratories, Half-Acre Rd., Cranbury, NJ 08512, U.S.A.
955
956
V . E . ADUSUMALLI ET AL.
CH,OCONH,
\C H ,OCONH, FIG. 1 . Chemical structure of felbamate, 2-phenyl-l,3propanediol dicarbamate.
on study day 1. After capsules were administered, -20 and 5 ml water was administered to each adult and pediatric dog, respectively. No FBM was administered on study day 2. FBM was again administered to each dog once daily on study days 3-12 (10 consecutive doses). Blood samples of 0.6-ml vol were taken from each dog before dosing and at 0.5, 1.O, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 30, 36, and 48 h after the first and last dose. Blood samples of the same volume were also collected immediately before the eighth, ninth, and tenth dose for steady-state confirmation. A blood sample was withdrawn from either the cephalic, jugular, or saphenous vein of each dog with a 1-ml nonheparinized syringe. The sample was immediately transferred to a 0.7-ml heparinized Microtainer tube (Becton Dickinson, Rutherford, NJ, U .S .A.). The Microtainer tubes were centrifuged at -2,500 rpm for 10-25 min. Duplicate plasma samples of 0.100-ml aliquots each were stored frozen until analyzed. FBM HPLC assays Study plasma samples were analyzed for FBM by a specific automated HPLC method (Clark et al., 1992). The proteins in 0.100-ml aliquot plasma samples were precipitated with 0.200 ml acetonitrile containing the internal standard. After mixing and centrifugation, 0.010 ml supernatant was injected onto a 15-cm Spherisorb ODS-2 (3 km) HPLC column. The mobile phase was 25% acetonitrile in 10 mM phosphate buffer, pH 6.5, with ultraviolet (UV) detection at 210 nm, column temperature 40"C, and flow rate of 0.7 ml/min. The linear quantitation range for the assay was 0.147-150 kg/ml FBM; the lower limit of quantitation was 0.147 pg/ml. The analyses were made with a Waters 712 WISP autoinjector (Milford, MA, U.S.A.), a Waters 590 pump, an ABI 7836 UV absorbance detector (Foster City, CA, U.S.A.), a PE-Nelson 2600 chromatography system (Cupertino, CA, U.S.A.), and a Hewlett Packard 3357 Laboratory Automation System (Avondale, PA, U.S.A.). Data analysis Plasma FBM concentration data were processed using BIOPAK software (Statistical Consultants, Epilepsia, Vol. 33, No. 5 , 1992
Inc., 1987) and the following bioavailability parameters were determined: peak concentration (C,,,), time of peak concentration (t,,,), area under the curve from time zero to time infinity (AUC) and elimination of half-life (t,/,). Analysis of variance (ANOVA) was performed on the bioavailability parameters to test differences among all groups. The ANOVA test was also performed on the bioavailability parameters obtained for the first and last doses. In all statistical analyses, a difference at p < 0.05 was considered significant. Mean plasma FBM concentration data for each group (i.e., adult male, adult female, pediatric male, and pediatric female) were subjected to exponential curve stripping and nonlinear least-squares optimization by the RSTRIP program (MicroMath Scientific Software, 1989) to the following equation
c, = A
. e - k c ~ . t + B . ,-k.t
t 11
where C,, is the plasma concentration of the drug at time t, A and B are the Y-intercepts derived from the exponential fitting and k, and k,, are the first order rate constants for drug absorption and elimination from the body, respectively. No weighting factor was used in these analyses. The estimates of FBM absorption and elimination t,,,, AUC, lag time for absorption ( t , a g ) , and mean residence time (MRT) were also obtained based on the best-fit curves from the RSTRIP analyses. The total body clearance (CL) and volume of distribution at steady-state (VSJ were calculated by using eq. 2 and 3 , respectively, CL
F x dose =
vss =
AUC
F x dose x AUMC ' AUC x AUC
[31
where AUC is area under the curve from time zero to infinity, F is absolute bioavailability , and AUMC is area under the first moment curve. In these calculations, F was assumed to be unity based on previous studies in dogs (Adusumalli et al., 1991). RESULTS The mean FBM plasma concentration versus time curves for the adult and pediatric groups showed a major difference in the FBM plasma concentrations between the two age groups (Fig. 2). The bioavailability data for male and female groups were compared separately (Tables 1 and 2). In the AUC, and t,/, for the last adult male group, the t,,, dose were significantly (p < 0.05) less than those for
95 7
FBM AGE-DEPENDENT KINETICS IN DOGS
1' 0
70
l0 o
first dose in the pediatric dogs was about threefold less than that observed in adult dogs. These quantitative relationships between the two age groups were also true after the last dose. The mean observed FBM concentration versus time data and the best-fit curves for each group for the first dose showed a close fit of concentration data to the biexponential equation for both age groups (Fig. 3). FBM elimination was faster in the pediatric group than in the adult group. The best-fit optimized pharmacokinetic parameters for all four AUC and groups are shown in Table 3. C,,,, t,,, tliZvalues from the RSTRIP analyses, based on fitted curve estimations, were slightly different than those based on observed data obtained with BIOPAK (Tables 1 and 2), but both sets were well within the ranges defined by the mean +. SD for each parameter. The absorption tliz(t,,,k") of FBM were similar (ranging from 1.49 to 2.18 h) for the first and last doses and for all four groups. The absorption lag time (t,,J for all groups was very brief (range 0-0.09 h). MRT in adult dogs for the first and last doses was -12-15 and 10 h, respectively. MRT in pediatric dogs for the first and last doses was similar (-6 h). CL was higher in pediatric dogs (0.194-0.326 L/h/kg) than in adult dogs (0.069-0.11 1 Llhlkg). The apparent V,, for FBM was similar in adult dogs (0.90-1.07 Llkg) and pediatric dogs (1.19-1.89 L/kg). These V,, values suggested higher distribution of FBM into tissue than that corresponding to total body water (0.6 L/h/kg). No sexrelated differences in CL and V,, were observed between the two age groups.
1 j
I
the first dose. In the pediatric male group, C,,, and AUC for the last dose were significantly less than and tl,, were simithose for the first dose, but t,, and AUC lar. In the adult female group, C,,,, t,,, were significantly less than those for the first dose and the tlizwas similar. In pediatric females, as in pediatric males, C,,, and AUC were less than those for the first dose. Comparison of the bioavailability parameters for adult and pediatric dogs (Tables 1 and 2) showed that C,,, after the first dose in pediatric dogs was -30% less than that in adult dogs. t,, after the first dose in the pediatric dogs was -2 h less than that in the adult dogs. The AUC for the
DISCUSSION Many drugs administered to children exhibit differences in absorption, distribution, metabolism, and excretion from values observed in adults because of pharmacogenetic factors, age, and growth. The pharmacokinetics of antiepileptic drugs (AEDs) are dependent on many physiologic variables, of which age is a major factor (Morselli,
TABLE 1. FBM hioavailahility parameters in adult and pediatric male dogs Adult
Parameter
C,,
( w W (h) AUC (pg/h/ml) t% (h) tmx
First dose
Last dose
Column 1
Column 2
48.6 f 8.4 4.8 -t 2.3 866 t 223 6.71 -+ 1.64
45.9 f 3.6"." t 613'132't 5.24(132) t
10.3 1.3 130 1.05
FBM, felbamate; AUC, area under the curve. Values are 2SD. Superscripts identify statistical significance of the difference between the two columns for each parameter (p < 0.05). Epilepsia, Vol. 33, N o . 5 , 1992
V . E. ADUSUMALLI ET AL.
958
TABLE 2. FBM bioavailability parameters in adult and pediatric f e m a l e d o g s Pediatric _ _ _
Adult
________-__--Parameter
First dose ___ Column 1 52.9 2 8.6 4.7 1.6 803 178 4.68 & 1.09
**
Last dose
_____
Column 2 46.8".2' 3.4",2' 542'i,2' 4.43
-t-
_ _
First dose
.
Column 3
10.9
33.7'1.3' 5 3.0'i.3' 2 281".3' ? 2.93('73) 2
** 1.8 161
* 1.24
4.5 0.6 55 0.33
- -
Ld5t d m e _ _ _ _ Column 4
25.5'2.4"3.4' 2 2.8 ? 184(2,4)(3,412 2.71'2,4' &
5.8 0.8 46 0.32
Abbreviations as in Table I . Values are ?SD. Superscripts identify statistical significance of the difference between the two columns for each parameter (p < 0.0s).
1983). The age-related differences in elimination are documented for several drugs (Boreus, 1982). For safe and effective drug therapy in the pediatric population, the pharmacokinetic behavior of any drug must be thoroughly characterized and any differences in the kinetics between the adult and pediatric populations must be identified. For ethical reasons, no pharmacokinetic data has yet been obtained with FBM in very young children. Therefore, in this study, we determined the relative bioavailability and pharmacokinetics of FBM in pediatric and adult dogs to provide needed data in animal models. The statistically significant differences observed for C,,,, AUC, and ti,, indicated that the relative bioavailability of FBM was about threefold less in pediatric dogs than in adult dogs. Apparently, the more rapid overall elimination of FBM in pediatric versus adult dogs was responsible for the lower bioavailability observed in the younger animals. Yang et al. (1991) reported that in adult dogs -47-52% of the FBM dose was excreted unchanged in urine and FBM was cleared equally by hepatic and renal routes. For FBM and other drugs with significant hepatic metabolism, tli2depends on hepatic metabolic clearance, binding to blood components, and Vss. The V,, of FBM in pediatric dogs was similar to that in adult dogs and therefore was not responsible for the threefold difference in tl/, values. In children, liver volume determined by ultrasound scans is greater than that of adults and the liver volume approximates functional hepatic mass and metabolic activity (Evans et al., 1989). This higher metabolic capacity in children could explain the shorter tl,, for the most widely prescribed AEDs: phenobarbital, phenytoin, ethosuximide, and carbamazepine in this population (Morrow and Richens, 1989). No pharmacokinetic data for these drugs in pediatric animals models have been reported, however. Therefore, the larger liver volume of pediatric dogs may be partially responsible for the higher clearance of FBM in that group. Another Epilepsiu, Vol. 33, No. 5 , 1992
plausible explanation for the shorter tl,, in pediatric dogs could be the higher free fraction of FBM in blood. The determined hematocrit value in pediatric dog blood in the present study was -0.25 as compared with 0.45 in adult dog blood. Because we showed previously that FBM was distributed equally between plasma and red blood cells (RBC) of dog blood (Adusumalli et al., 1991) and because the RBC fraction was significantly lower in pediatric dog blood, a higher free fraction of FBM could exist in pediatric dog blood. Free FBM is readily
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