Lack of Tolerance to Drug Therapy: Observations from Topiramate Clinical Studies.
Abstract number :
1.287
Submission category :
Year :
2001
Submission ID :
617
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
B. Abou-Khalil, MD, Neurology, Vanderbilt University, Nashville, TN; W. Neto, MD, R.W.Johnson Pharmaceutical Research Institute, Raritan, NJ; G. Pledger, PhD, R.W.Johnson Pharmaceutical Research Institute, Raritan, NJ; S-C. Wu, PhD, R.W.Johnson Pharmaceut
RATIONALE: Initial controlled studies to evaluate the therapeutic potential of a new antiepileptic drug (AED) usually involve no more than 8- or 12-weeks of maintenance treatment. Such studies may not be of sufficiently long duration to assess whether an agent[scquote]s therapeutic effect is maintained over time since tolerance may develop gradually. In clinical practice, re-emergence of seizures after a period of adequate seizure control may not be recognized as a loss of AED effectiveness, particularly if seizure control returns when the dose is increased. Because dose and seizure data are systematically collected during long-term extensions of controlled clinical trials, these data sets can provide information about the occurrence of tolerance. In animal studies of topiramate (TPM), antiseizure effects were maintained with repeated administration, suggesting low potential for tolerance. To verify this finding clinically, data from TPM clinical studies with long-term patient follow-up were analyzed.
METHODS: Patients who had been treated with TPM for at least 6 mos were included in the analyses. Databases from long-term studies involving adults and children with partial-onset seizures with or without secondary generalization, patients with Lennox-Gastaut syndrome, and patients with primary generalized tonic-clonic seizures were analyzed.
RESULTS: In a cohort of 467 adults with treatment-resistant partial-onset seizures with or without secondary generalization treated with TPM for at least 6 mos, discontinuations due to drug ineffectiveness for subsequent 6-mo intervals were: [gt]6-12 mos, 6% (27/467); [gt]12-18 mos, 6% (21/334); [gt]18-24 mos, 3% (6/233); [gt]24-30 mos, 4% (8/200); [gt]30-36 mos, 1% (1/153); [gt]36-42 mos, 3% (4/119); [gt]42-48 mos, 4% (3/72); and [gt]48 mos, 3% (1/37). Dosages needed to maintain seizure control remained stable.
CONCLUSIONS: Data from long-term clinical studies support observations from animal studies that TPM is not associated with the development of tolerance, i.e., loss of effectiveness.
Support: The R.W. Johnson Pharmaceutical Research Institute
Disclosure: Salary - Neto, Pledger, Wu, and Smith- R.W.Johnson Pharmaceutical Research Institute; Grant - Clinical studies- Abou-Khalil- from Ortho-McNeil and R.W.Johnson Pharmaceutical Research Institute; Stock - Neto, Pledger, Wu, and Smith- R.W.Johnson Pharmaceutical Research Institute