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Journal of Clinical Pharmacology, 2004; 44:1230-1234
© 2004 the American College of Clinical Pharmacology

DRUG INTERACTIONS

Lack of a Clinically Significant Effect of Zonisamide on Phenytoin Steady-State Pharmacokinetics in Patients With Epilepsy

René H. Levy, PhD, Isabelle Ragueneau-Majlessi, MD, William R. Garnett, PharmD, Michael Schmerler, MD, William Rosenfeld, MD, Jaymin Shah and Wei-Jian Pan

From the Department of Pharmaceutics, University of Washington, Seattle, Washington (Dr Levy, Dr Ragueneau-Majlessi); Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia (Dr Garnett); Riverhills Healthcare, Inc, Cincinnati, Ohio (Dr Schmerler); Comprehensive Epilepsy Care Center for Children and Adults, Chesterfield, Missouri (Dr Rosenfeld); Gilead Sciences, Inc, Foster City, California (Dr Shah, formerly at Elan Pharmaceutical, Inc); and Elan Pharmaceuticals, Inc, San Diego, California (Dr Pan).

Address for reprints: Dr René H. Levy, University of Washington, H-272N Health Sciences, Box 357610, Seattle, WA 98195.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 CONCLUSION
 REFERENCES
 
This study was designed to measure the effect of the addition of zonisamide on phenytoin pharmacokinetics under steady-state conditions in patients with epilepsy. Nineteen patients stabilized under phenytoin monotherapy were included in a 3-center, open-label, 1-way drug interaction trial. Zonisamide was gradually increased to 400 mg/day, taken twice daily. Three pharmacokinetic profiles were performed: on days -7 and -1, to assess pharmacokinetic parameters of oral phenytoin administered alone, and on day 35, after 14 days of zonisamide treatment, to evaluate the effect of zonisamide on phenytoin pharmacokinetics and to characterize zonisamide pharmacokinetics in the presence of phenytoin. Fourteen patients completed the study; the coadministration of zonisamide and phenytoin was safe and well tolerated. Zonisamide did not significantly affect the mean Cmin, Cmax, AUC0-12, and CL/F of phenytoin measured before and after zonisamide administration. The pharmacokinetic measures of zonisamide in the presence of phenytoin were consistent with previous reports of induction of zonisamide metabolism by phenytoin.

Key Words: Zonisamide • phenytoin • pharmacokinetics • epilepsy • drug interactions

Zonisamide, 1,2-benzisoxazole-3-methanesulfonamide, is an antiepileptic drug indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy. Although zonisamide was approved in the United States only recently (March 2000), it has been prescribed in Japan for more than a decade, and the potential for drug interactions between zonisamide and coprescribed anticonvulsants has been evaluated (reviewed in Hachad et al1). In the case of phenytoin, several clinical studies have indicated that zonisamide has no significant effect on the serum concentrations of phenytoin.2-4 However, in a population pharmacokinetic analysis, Odani et al5 observed a small (16%) but statistically significant increase in phenytoin serum concentrations in patients receiving zonisamide concurrently, and the authors suggested that zonisamide might inhibit phenytoin metabolism. Phenytoin has a narrow therapeutic index and exhibits nonlinear pharmacokinetics; thus, the addition of an inhibitor may produce a disproportionately large and clinically significant change in phenytoin levels. The major metabolic pathway of phenytoin in humans is 4-hydroxylation to 5-(-4-hydroxyphenyl)-5-phenyl-hydantoin (HPPH) mediated by CYP2C9 and CYP2C19, with a major contribution by CYP2C9.6,7 In human liver microsomes, zonisamide (200-1000 µM) has been shown to weakly inhibit CYP2C9 and CYP2C19.8 At present, there is no consensus on methodologies to obtain reliable quantitative predictions of clinical drug interactions based on in vitro inhibition parameters,9 and thus the weak inhibitory effect of zonisamide observed in vitro on CYP2C9 and CYP2C19 is difficult to interpret in terms of clinical consequences.

Thus, the present study was designed to assess the effect of steady-state zonisamide dosing (200 mg bid) on phenytoin steady-state concentrations in patients with epilepsy.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS AND DISCUSSION
 CONCLUSION
 REFERENCES
 
Population and Study Design
The study was performed in accordance with the Declaration of Helsinki and its amendments and in compliance with the guidelines of good clinical practice. The study protocol and informed consent form were approved by an independent ethics committee before recruitment of any patients. The study was a 3-center, steady-state, open-label, 1-sequence drug interaction trial in otherwise healthy male or female volunteers (18-55 years old) with a seizure disorder controlled by oral phenytoin monotherapy. A total of 19 patients were enrolled in the study. While maintaining their stable oral phenytoin dose throughout the study (200-600 mg/day, taken bid), the patients received a gradual oral dose titration of zonisamide as follows: 100 mg (AM only) on days 1 to 3, 200 mg (100 mg bid) on days 4 to 10, 300 mg (100 mg AM and 200 mg PM) on days 11 to 17, and 400 mg (200 mg bid) from days 18 to 34. A final 200-mg dose of zonisamide was administered in the morning of day 35. Subjects were provided with a diary to record the time of dosing of study medications, adverse events, and concomitant medications.

Study Procedures
Three pharmacokinetic profiles were performed: on days -7 and -1, to assess the steady-state pharmacokinetic parameters of phenytoin administered alone, and on day 35, to assess the pharmacokinetics of zonisamide and phenytoin taken in combination. Plasma samples for the measurement of phenytoin were collected prior to morning dosing on day -7 and day -1, and phenytoin plasma and zonisamide serum pharmacokinetic (PK) samples were collected prior to morning dose on day 35. Additional phenytoin plasma samples were collected at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose on days -7, -1, and 35. Zonisamide predose serum samples were also collected on days 1, 33, and 34. Additional zonisamide serum samples were collected at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours postdose on day 35. Follow-up zonisamide serum samples were collected at 24, 36, and 72 hours and 7, 10, and 14 days after the day 35 final zonisamide dose.

Phenytoin and Zonisamide Determination
Plasma concentrations of phenytoin and zonisamide were determined using a validated high-performance liquid chromatography method (HPLC) with ultraviolet (UV) detection at Kansas City Analytical Services, Inc (Shawnee, Kan). The lower limits of quantitation were established at 0.10 µg/mL and 0.50 µg/mL for phenytoin and zonisamide, respectively.

Safety
Safety was measured throughout the study by recording adverse events (AEs), laboratory tests (hematology, biochemistry, urinalysis), physical examination, vital signs, electrocardiogram (ECG), and concomitant medications. Serum pregnancy tests were performed at screening and at termination for women of childbearing potential.

Pharmacokinetic and Statistical Analyses
The pharmacokinetic analysis included the calculation of the following parameters for phenytoin on days -7, -1, and 35 and for zonisamide on Day 35: tmax, the time to maximum observed plasma/serum concentration; Cmax, the maximum observed plasma/serum concentration; Cmin, the minimum observed plasma/serum concentration; AUC0-12, the area under the plasma/serum concentration versus time curve from the time of dosing to 12 hours postdose, calculated using the linear log-trapezoidal method; and CL/F, the apparent oral clearance, calculated as dose/AUC0-12. For zonisamide (day 35), the following additional PK parameter was computed: t1/2, the half-life of zonisamide, defined as 0.693/{lambda}z, where {lambda}z is the slope of the terminal elimination phase of the serum concentration versus time curve.

All PK analyses were performed using noncompartmental methods with WinNonlin® Professional, version 3.1 (2001, Pharsight Corp, Mountain View, Calif). Because phenytoin exhibits nonlinear pharmacokinetic properties,10 an initial analysis was performed using the observed plasma concentrations, and a pairwise comparison (paired t test) was used to compare the phenytoin Cmax and AUC0-12 observed before (day -1) and in combination with zonisamide (day 35). In a further analysis, phenytoin concentrations of all subjects were normalized to a common 200-mg dose of phenytoin, and a repeated-measures analysis of variance (ANOVA) on change from baseline was performed. Statistical analyses were also performed on day -7 and day -1 of phenytoin dosing to evaluate the baseline steady-state.


   RESULTS AND DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
CONCLUSION
 REFERENCES
 
Disposition of Patients
A total of 19 patients were enrolled, and 14 completed the study. Five patients discontinued the study, 3 prior to zonisamide administration and 2 during zonisamide administration (dose titration) due to noncompliance. Of the 16 patients who received zonisamide, 9 were male and 7 were female. Mean age at baseline was 43.2 years (range: 29-59 years), and mean weight was 76.3 kg (range: 49.9-109.3 kg). All patients who completed the study were able to reach and maintain the maximum titrated zonisamide dosage level of 400 mg and had stabilized at this dose level for a minimum of 14 days prior to day 35; they also had received a stable dose of phenytoin throughout the study (200-600 mg/day in 2 divided doses).

Phenytoin Pharmacokinetics
The mean phenytoin Cmin values fluctuated less than 10% between days -7 and -1, and there were no statistically significant differences between days -7 and -1 for Cmax, AUC0-12, and CL/F, indicating that phenytoin pharmacokinetics in these subjects had reached steady-state before zonisamide administration. Summary statistics (before dose normalization) of phenytoin Cmax and AUC0-12 before (day -1) and after (day 35) zonisamide administration are presented in Table I, together with the geometric mean ratios and the associated 90% confidence interval values. There were no statistically significant differences between the 2 periods of treatment (paired t test, P = .37 and P = .41 for Cmax and AUC0-12, respectively). The geometric mean ratios for day 35/day -1 were estimated to be 1.07 and 1.06, respectively, both of which were close to unity. The associated 90% confidence intervals for the 2 one-sided t tests were 0.85 to 1.34 and 0.85 to 1.32 for Cmax and AUC0-12, respectively (Table I). Even though the upper bounds of the 90% confidence intervals were slightly outside of the 0.8 to 1.25 default no-effect boundary, this result could be due to the fact that the study-estimated sample size (n = 15) was not prospectively powered for a no-effect claim with the 0.8 to 1.25 confidence interval. The mean plasma phenytoin concentration (dose normalized to 200 mg phenytoin) versus time profiles are presented in Figure 1. The dose-normalized phenytoin parameters Cmin, Cmax, AUC0-12, and CL/F were unchanged following addition of zonisamide (Table II). This result further supports the notion that coadministration of zonisamide has no effect on phenytoin pharmacokinetics.


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  		Table I Steady-State Pharmacokinetic Parameters of Phenytoin Given Alone (Day –7 and Day –1) and With Zonisamide (Day 35) (n = 14)

 


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  		Figure 1. Mean plasma phenytoin concentration-time profiles at steady state (dose normalized to 200 mg) before (day -7 and day -1) and after treatment with zonisamide (day 35).

 

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  		Table II Steady-State Phenytoin Pharmacokinetic Parameters, Normalized to 200-mg Dose

 

These findings are consistent with earlier clinical studies showing no effect of zonisamide on phenytoin disposition in epileptic patients.2-4 Phenytoin metabolism to its primary metabolite, HPPH, is essentially mediated by CYP2C9 and CYP2C19, with a major contribution by CYP2C9.6,7 In a previous in vitro study performed in our laboratory, only a weak inhibition of CYP2C9 and CYP2C19 enzymatic activities by zonisamide was observed,8 suggesting that these in vitro data were predictive. Based on the fact that the disposition of phenytoin was not altered by zonisamide administration in the present study, it appears that dosage adjustment of phenytoin is not necessary after addition of zonisamide. Phenytoin unbound levels were not measured in our study because zonisamide is only 40% to 60% protein bound and is unlikely to displace phenytoin from its binding sites. This lack of displacement interaction is confirmed by previous results of Tasaki et al,4 who observed that zonisamide had no effect on phenytoin protein binding in 9 pediatric patients.

Zonisamide Pharmacokinetics
The PK measures (mean ± SD) of zonisamide exposure at steady-state were the following: Cmax = 15.6 ± 4.3 µg/mL and AUC0-12 = 165.0 ± 47.4 µg•h/mL. For zonisamide elimination, the values were as follows: CL/F = 1291.7 ± 311.2 mL/h and t1/2 = 28.3 ± 10.7 h. The half-life and the apparent oral clearance found in this study are consistent with previous results showing induction of zonisamide metabolism when it is associated with phenytoin.11-13 Phenytoin is a significant inducer of CYP3A4 in vivo,14 and CYP3A4 has been shown to be the main isozyme involved in zonisamide metabolism.15,16

Adverse Events
A total of 10 patients (62.5%) reported treatment-emergent AEs, with 4 patients (25%) reporting AEs considered by the investigator to be related to study drugs. The most frequently reported AEs during phenytoin monotherapy prior to day 1 (pre-zonisamide period) were headache (18.8% of patients) and pharyngitis (12.5%). The most frequently reported AEs during zonisamide/post-zonisamide periods were headache (31% of patients) and pain (25%). All AEs were mild or moderate in severity.


   CONCLUSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 CONCLUSION
REFERENCES
 
In conclusion, the present study provides evidence that the coadministration of zonisamide, at a dose of up to 400 mg/day (200 mg twice daily), does not affect the pharmacokinetics of phenytoin in patients with epilepsy to any clinically relevant extent.


   FOOTNOTES
 
DOI: 10.1177/0091270004268045

Submitted for publication January 25, 2004; Revised version accepted June 6, 2004.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS AND DISCUSSION
 CONCLUSION
 REFERENCES
 

1. Hachad H, Ragueneau-Majlessi I, Levy RH. New antiepileptic drugs: review on drug interactions. Ther Drug Monit. 2002;24: 91-103.[CrossRef][Medline] [Order article via Infotrieve]

2. Browne T, Szabo G, Kres J. Drug interactions of zonisamide (CI-912) with phenytoin and carbamazepine. J Clin Pharmacol. 1986;26: 555.

3. Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res. 1993;15: 67-73.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

4. Tasaki K, Minami T, Ieiri I, et al. Drug interactions of zonisamide with phenytoin and sodium valproate: serum concentrations and protein binding. Brain Dev. 1995;17: 182-185.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

5. Odani A, Hashimoto Y, Takayanagi K, et al. Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model. Biol Pharm Bull. 1996;19: 444-448.[Medline] [Order article via Infotrieve]

6. Giancarlo GM, Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ. Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Eur J Clin Pharmacol. 2001;57: 31-36.[CrossRef][Medline] [Order article via Infotrieve]

7. Bajpai M, Roskos LK, Shen DD, Levy RH. Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos. 1996;24: 1401-1403.[Web of Science][Medline] [Order article via Infotrieve]

8. Mather G, Carlson S, Trager W, Buchanan R, Levy R. Prediction of zonisamide interactions based on metabolic isozymes. Epilepsia. 1997;38(suppl 8): 108.

9. Yao C, Levy RH. Inhibition-based metabolic drug-drug interactions: predictions from in vitro data. J Pharm Sci. 2002;91: 1923-1935.[CrossRef][Medline] [Order article via Infotrieve]

10. Browne T, Leduc B. Phenytoin: chemistry and biotransformation. In: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs. New York: Raven; 2001.

11. Ojemann LM, Shastri RA, Wilensky AJ, et al. Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy. Ther Drug Monit. 1986;8: 293-296.[Web of Science][Medline] [Order article via Infotrieve]

12. Hashimoto Y, Odani A, Tanigawara Y, Yasuhara M, Okuno T, Hori R. Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients. Biol Pharm Bull. 1994;17: 323-326.[Web of Science][Medline] [Order article via Infotrieve]

13. Shinoda M, Akita M, Hasegawa M, Hasegawa T, Nabeshima T. The necessity of adjusting the dosage of zonisamide when coadministered with other anti-epileptic drugs. Biol Pharm Bull. 1996;19: 1090-1092.[Medline] [Order article via Infotrieve]

14. Ragueneau-Majlessi I, Bajpai M, Levy RH. Phenytoin: interactions with other drugs, in: Levy RH, Mattson RH, Meldrum BS, eds. Antiepileptic Drugs. New York: Raven, 2001.

15. Nakasa H, Komiya M, Ohmori S, Rikihisa T, Kiuchi M, Kitada M. Characterization of human liver microsomal cytochrome P450 involved in the reductive metabolism of zonisamide. Mol Pharmacol. 1993;44: 216-221.[Abstract]

16. Nakasa H, Nakamura H, Ono S, et al. Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data. Eur J Clin Pharmacol. 1998;54: 177-183.[CrossRef][Medline] [Order article via Infotrieve]
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