Abstracts

To discuss the purpose and methodology of comparative daily profiles of Lamotrigine (LTG)., In Denmark, legislature since 2005 enforces, for all drugs including AEDs, delivery by the pharmacy of the cheapest preparation. For AEDs, the bioequivalence range has been set to 90 111 % of the original. Bioequivalence is tested by comparison of a single dose of two preparations in a group of healthy volunteers. Frequent changes in price of 7 different generic Lamotrigine preparations expose patients to multiple preparation shifts. Some patients report problems following shifts, sometimes of a serious kind. In view of obtaining sufficiently detailed pharmacokinetic data including C^max, C^min, t^max, C^max/min and C^x, we have started in selected cases to compare daily profiles of the preparations in question.
There are no standard methods to establish such profiles. Ideally, blood sampling would have to take place at 30 60 min intervals after drug intake, followed by increasing intervals until the next dose. But compromises are necessary because blood sampling needs to be integrated into daily hospital routine. Another question is the adequate interval between the two comparative profiles. In addition, possible pharmacokinetic interactions with co-medications need to be considered., We present preliminary findings with sampling intervals of three and four hours, and with intervals between profiles of one to three weeks. The three hour schedule appears to provide reasonably informative data, whereas a four hour schedule may fail to detect differences in t^max and carries a risk of rather imprecise C^max measurements from which other calculations depend. Deviations clearly exceeding the accepted bioequivalence range were observed under realistic clinical conditions, and could confirm and explain reports of both status epilepticus with lower bioavailability, and locomotor ataxia with the consequence of fall, skull fracture and intracranial bleeding with higher bioavailability. The deviations observed in the daily profiles were not necessarily apparent when only morning trough levels were compared., Comparative daily profiles provide differentiated information on the bioequivalence of different LTG preparations. In clinical conditions, deviations outside the accepted bioequivalence range were observed and could explain serious morbidity following preparation shift. For clinical purposes, a 3 hour sampling schedule seems to be adequate.,