title: 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 Tmax and Cmax values of 97/63 in male rats were 1.75±0.77 h and 862±306 ng/mL while female rats showed values for Cmax of 622.75±95.09 ng/mL and for Tmax of 7.5±0.5 h. Coadministration of 97/78 and lamotrigine resulted in decreased Tmax and Cmax values in both male and female rats (Tmax and Cmax 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 Cmax and Tmax values in male and for the T1/2 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 Tmax. 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.
authors.affiliation: CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: H N
authors.initials: HN
authors.lastname: Kushwaha
authors.forename: N
authors.initials: N
authors.lastname: Gautam
authors.forename: A
authors.initials: A
authors.lastname: Misra
authors.forename: B
authors.initials: B
authors.lastname: Singh
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: H H
authors.initials: HH
authors.lastname: Siddiqui
authors.forename: S K
authors.initials: SK
authors.lastname: Singh
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D000962:Antimalarials / Q000493:pharmacokinetics*; D019540:Area Under Curve; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D007202:Indicators and Reagents; D000077213:Lamotrigine; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D053719:Tandem Mass Spectrometry; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D000962:Antimalarials; D019086:Bridged Bicyclo Compounds, Heterocyclic; C574493:CDRI-97-78; D007202:Indicators and Reagents; D014227:Triazines; D000077213:Lamotrigine