Abstract
Pemetrexed, an anionic anti-cancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The IVIVE approach used in this work was developed to predict possible DDIs that may occur following co-administration of pemetrexed and NSAIDs, and included in vitro assays, risk assessment models, and physiologically-based pharmacokinetic models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing OAT3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp®. The bottom-up approach under predicted the clearance by 2 fold. The model built using a scaling factor of 5.3 for the Vmax of OAT3, estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m2 of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and AUC0-inf of pemetrexed when ibuprofen was co-administered were 1.0 and 1.1, respectively. The co-administration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf and Cmax of pemetrexed. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.
- drug-drug interactions
- human/clinical
- in vitro-in vivo prediction (IVIVE)
- pharmacokinetics
- physiologically-based pharmacokinetic modeling/PBPK
- Transporter-mediated drug/metabolite disposition
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics