Corroborating a previously reported finding that valproate reduces the clearance of lamotrigine in adults with bipolar disorder (thereby raising its blood concentrations), and suggesting that it may do so in pediatric epileptic youth, is a study reported recently on the Web (B. Koriskova and colleagues, Basic and Clinical Pharmacology and Toxicology, published online, ahead of print, on January 25, 2019).
The authors calculated the clearance of lamotrigine in youth (15-years-old or younger) before and after beginning conjoint treatment with valproate or conjoint treatment with both valproate and carbamazepine (an inducer of hepatic metabolic and conjugating enzymes, referred to as a “universal inducer” by virtue of its enhancement of the clearance of several drugs).
Having drawn blood for lamotrigine serum concentrations from 530 children and adolescents pursuant to therapeutic drug monitoring of epilepsy, the authors calculated lamotrigine clearances during valproate coadministraion that were 54-percent lower than those during lamotrigine monotherapy, before initiation of valproate. In lamotrigine-treated patients who added both valproate and carbamazepine, lamotrigine clearance diminished by only 21 percent.
The authors’ findings comport with those reported in adults receiving coadministered lamotrigine and valproate (reported to inhibit the uridinyl glucuronosyltransferase (UGT) enzyme that conjugates lamotrigine with glucuronic acid, resulting in enhancement of water solubility and excretion of lamotrigine). They additionally suggest that carbamazepine (and other inductive anticonvulsants) may mitigate valproate-mediated inhibition of lamotrigine conjugation, by increasing valproate clearance (also by conjugation), lamotrigine clearance, or both. (Obiter: Lamotrigine, whose steady-state blood concentrations have been reported to double during valproate coadministration, tantamount to doubling lamotrigine dosage, has not been reported to affect valproate clearance.)