Intersex Effect of Lamotrigine on the Pharmacokinetic Parameters of CDRI-97/78, a Novel Trioxane Antimalarial Compound, in Rats

Abstract

Reports regarding drug toxicity and adverse events resulting from coadministration of multiple drugs are increasing at an alarming rate. CDRI-97/78 is an 1,2,4-trioxane antimalarial agent under development which gets metabolized to the in vivo active metabolite 97/63. In order to assess its drug interaction potential, CDRI-97/78 was administered alone and in combination with lamotrigine to male and female rats via the oral route. Quantification of the active metabolite 97/63 in rat plasma was achieved with an LC-MS/MS assay. After oral administration of 97/78, the T_max and C_max values of 97/63 in male rats were 1.75±0.77 h and 862±306 ng/mL while female rats showed values for C_max of 622.75±95.09 ng/mL and for T_max of 7.5±0.5 h. Coadministration of 97/78 and lamotrigine resulted in decreased T_max and C_max values in both male and female rats (T_max and C_max of 0.77±0.16 h and 58.58±6.43 ng/mL in male rats; 1.13±0.22 h and 62.95±12.00 ng/mL in female rats, respectively). A statistically significant difference (P<0.05) was observed for the pharmacokinetic parameters of 97/63 after oral administration of 97/78 alone and upon its coadministration with lamotrigine except for the C_max and T_max values in male and for the T_1/2 value in female rats. Statistically, no significant difference for the pharmacokinetic parameters of 97/63 between male and female rats after oral administration of 97/78 alone or in combination with lamotrigine was determined except for T_max. The study indicates that coadministration of 97/78, an antimalarial agent, and the antiepileptic lamotrigine may require dose adjustments. Additional clinical drug interaction trials may be required to confirm these findings.

Key words

drug interaction - lamotrigine - LC-MS/MS - metabolite 97/63 - pharmacokinetics - antimalarial

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