Protease Inhibitors versus Lamotrigine
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Study Design
The interaction between these agents has not been formally studied. However, interaction studies do exist between lamotrigine and other boosted protease inhibitors, including lopinavir/ritonavir.
Twenty‐four healthy subjects received 50 mg lamotrigine once daily on days 1 and 2 and 100 mg twice daily on day 3 through day 23. Lopinavir (400 mg twice daily)/ritonavir (100 mg twice daily) was added on day 11. Depending on the decrease in lamotrigine trough level between days 10 and 20, either the study was stopped (<20% decrease) or a dose increase was applied from day 23 to day 31, as follows: increase to 150 mg lamotrigine twice daily if there was a 20% to 33% decrease, increase to 200 mg twice daily if there was a 34% to 66% decrease, and increase to 300 mg twice daily if there was a greater than 66% decrease. On days 10, 20, and 31, 12‐hour pharmacokinetic curves were drawn.
Study Results
The mean decrease in lamotrigine trough level between days 10 and 20 was 55.4% (n = 18). A dose increment to 200 mg lamotrigine twice daily was used in all subjects. The area under the plasma concentration‐time curve (AUC) values of lamotrigine on day 20 (with lopinavir/ritonavir) and day 10 (without lopinavir/ritonavir) were bioinequivalent, with a point estimate of 0.50 (90% confidence interval, 0.47–0.54). After dose adjustment of lamotrigine to 200 mg twice daily, the AUC on day 31 (n = 15) was bioequivalent to that on day 10, with a point estimate of 0.91 (90% confidence interval, 0.82–1.02). The median AUC ratios of lamotrigine 2N‐glucuronide to lamotrigine on day 10 and day 20 were 0.57 (interquartile range, 0.39–0.75) and 1.12 (interquartile range, 0.87–1.31). Pharmacokinetic parameters for lopinavir/ritonavir were similar to historical controls.
Study Conclusions
Lopinavir/ritonavir decreases the AUC of lamotrigine, probably by induction of glucuronidation. A dose increment to 200% of the initial lamotrigine dose is needed to achieve concentrations similar to those with lamotrigine alone. Lamotrigine does not appear to affect the pharmacokinetics of lopinavir/ritonavir.
Other boosted protease inhibitors can reduce lamotrigine concentrations though to variable effects. It is expected that increases in lamotrigine levels may be required to maintain similar therapeutic efficacy in patients beginning boosted protease inhibitors. Dose adjustments should be done only after careful monitoring for both safety and efficacy.
References
Lee MJ, Dawood L, Hofstede HJ, Graaff-Teulen MJ, Ewijk-Beneken Kolmer EW, Caliskan-Yassen N, Burger DM. Lopinavir/ritonavir reduces lamotrigine plasma concentrations in healthy subjects. Clinical Pharmacology And Therapeutics. 2006; 2: 159-168.
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