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 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 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.


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.
van der Lee
Manon J
MJ
Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.vanderlee@akf.umcn.nl
Dawood
Lara
L
ter Hofstede
Hadewych J M
HJ
de Graaff-Teulen
Marga J A
MJ
van Ewijk-Beneken Kolmer
Eleonora W J
EW
Caliskan-Yassen
Nurcan
N
Koopmans
Peter P
PP
Burger
David M
DM
D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000009:adverse effects*; D000927:Anticonvulsants / Q000097:blood* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001711:Biotransformation; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects; D003864:Depression, Chemical; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D020719:Glucuronides / Q000097:blood; D006801:Humans; D000077213:Lamotrigine; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D010349:Patient Compliance; D011744:Pyrimidinones / Q000009:adverse effects*; D012727:Sex Characteristics; D014227:Triazines / Q000097:blood* / Q000493:pharmacokinetics
D019380:Anti-HIV Agents; D000927:Anticonvulsants; D003278:Contraceptives, Oral, Hormonal; D020719:Glucuronides; D011744:Pyrimidinones; D014227:Triazines; D061466:Lopinavir; D000077213:Lamotrigine