The influence of hyperhydration on pemetrexed concetrations in blood.

Pemetrexed is a pharmacotherapeutic cornerstone for treatment of non-small cell lung cancer and mesothelioma. Besides dose, renal function is the only determinant for systemic exposure: with decreasing renal function, systemic exposure increases accordingly. Since systemic exposure to pemetrexed (area under the concentration versus time curve (AUC)) is closely related with both efficacy measures (time to progressive disease) as (severe) toxicity, individualized dosing is of utmost importance to balance the dual risk of inefficacy and toxicity associated with treatment. We hypothesize that hyperhydration, which is given to promote excretion of cisplatin that is co-administered the first four cycles during combination therapy, causes augmented clearance of pemetrexed, resulting in decreased pemetrexed exposure. On the contrary, when in subsequent cycles cisplatin is not administered and hyperhydration is not performed, higher exposure and increased toxicity may be observed. Testing this hypothesis will further elucidate the pharmacokinetics of pemetrexed and may provide new insights regarding renal function as a determinant for optimal pemetrexed dosing and may be a next step to improved dosing with this cytotoxic agent.

Hyperhydration may cause augmented clearance of pemetrexed

To obtain pharmacokinetic parameters and renal function parameters blood samples are drawn at set times during one cycle of combination therapy with hyperhydration and one cycle of monotherapy. To determine if there is a possible time- or sequence effect, five patients will be sampled at an extra cycle of monotherapy.

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