Lopinavir/ritonavir reduces lamotrigine plasma concentrations in healthy subjects

Background Limited data are available about the effect of lopinavir and low‐dose ritonavir on glucuronidation. Lamotrigine undergoes glucuronidation. We studied the effect of lopinavir/ritonavir on the pharmacokinetics of lamotrigine and vice versa. Methods Twenty‐four healthy subjects received 50 m...

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Published in:	Clinical pharmacology and therapeutics Vol. 80; no. 2; pp. 159 - 168
Main Authors:	Lee, Manon J., Dawood, Lara, Hofstede, Hadewych J.M., Graaff‐Teulen, Marga J.A., Ewijk‐Beneken Kolmer, Eleonora W.J., Caliskan‐Yassen, Nurcan, Koopmans, Peter P., Burger, David M.
Format:	Journal Article
Language:	English
Published:	New York, NY Nature Publishing 01-08-2006
Subjects:	Adolescent Adult Aged Anti-HIV Agents - adverse effects Anticonvulsants - blood Anticonvulsants - pharmacokinetics Area Under Curve Biological and medical sciences Biotransformation Contraceptives, Oral, Hormonal - adverse effects Depression, Chemical Double-Blind Method Drug Interactions Female Glucuronides - blood Humans Lopinavir Male Medical sciences Middle Aged Patient Compliance Pharmacology. Drug treatments Pyrimidinones - adverse effects Sex Characteristics Triazines - blood Triazines - pharmacokinetics Human Biological fluid Antiretroviral agent Healthy subject Enzyme Ritonavir Lopinavir Enzyme inhibitor Anticonvulsant Concentration Blood plasma Peptidases Triazine derivatives Hydrolases Antiviral Protease inhibitor Lamotrigine
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Summary:	Background Limited data are available about the effect of lopinavir and low‐dose ritonavir on glucuronidation. Lamotrigine undergoes glucuronidation. We studied the effect of lopinavir/ritonavir on the pharmacokinetics of lamotrigine and vice versa. Methods 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. Results The mean defcrease 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. Conclusion 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. Clinical Pharmacology & Therapeutics (2006) 80, 159–168; doi: 10.1016/j.clpt.2006.04.014
ISSN:	0009-9236 1532-6535
DOI:	10.1016/j.clpt.2006.04.014