A pharmacokinetic comparison of intravenous versus intra-arterial folinic acid

Abstract

Summary Recent clinical trials have suggested that a combination of folinic acid and 5-fluorouracil (5-FU) may improve response rates and survival in patients with advanced colorectal cancer. However, this regimen has been complicated by potentially life threatening toxicity. Regional delivery of folinic acid via a hepatic artery catheter might be expected to reduce systemic exposure and subsequent adverse effects.The present study compared the pharmacokinetic profiles of intravenous and intra-hepatic arterial infusions of folinic acid in patients with colorectal liver metastases (n = 6) who were being treated with weekly regional infusions of 5-FU. The mean area under the plasma concentration -time curve, the peak plasma concentration and the steady state volume of distribution were 163 jig ml-' h-' (SD 41), 18.5 jg ml-' (SD 1.2) and 7.41 m-2 (SD 0.44) respectively following intravenous administration of folinic acid compared with 142jigml-h-' (SD45), 14.8tjgml-' (SD2.4) and 11.21m2 (SD 1.22) following intra-hepatic arterial administration (P <0.05). Regional folinic acid was therefore associated with a statistically significant reduction in systemic exposure compared with the intravenous route.The outlook for patients with colorectal liver metastases remains depressing; the mean survival for patients in the West of Scotland is approximately 3 months (Wood et al., 1976). The results of systemic chemotherapy have been disappointing. Average response rates of only 10-15% have been reported following treatment with 5-FU and response has not been accompanied by increased survival (Kemeny, 1983). These reports have lead to a third of surgeons in England and Wales opting not to actively treat patients with nonresectable colorectal liver metastases (Karanjia et al., 1990) and trials in the UK continue to include 'no active treatment' control arms (Hunt et al., 1990).Recent studies, however, have suggested that the addition of folinic acid may significantly improve survival amongst advanced colorectal cancer patients receiving 5-FU (Erlichman, 1988, Poon et al., 1989Kerr, 1989). Briefly, folinic acid enhances 5-FU activity by stabilising the binding of the 5-FU metabolite, fluorodeoxyuridine monophosphate, to the enzyme thymidylate synthase. Unfortunately, therapy has been complicated by systemic toxicity which can be occasionally life-threatening.The rationale for regional chemotherapy is the delivery of high drug concentrations to the compartment harbouring the tumour with relatively less drug escaping into the systemic vascular compartment. There is a large literature on intrahepatic arterial administration of 5-FU and FUdR to patients with hepatic metastases from colorectal primary cancers. In summary, the data are suggestive that tumour response rates are higher comparing regional with systemic administration, but there is no convincing evidence that intra-arterial chemotherapy significantly prolongs survival.The aim of the present study was to compare the pharmacokinetic profiles of intravenous and intra-hepatic ...

IN VIVO KINETICS OF FOLATE METABOLISM

“…Short-term folate kinetics often have been examined using a single folate dose administered orally or intravenously followed by serial measurement of either total folate or individual folate forms in serum or plasma (e.g., 1,10,48,53,66,90). The need for relatively large doses to induce a consistently measurable change in plasma folate concentration is a limitation of protocols involving short-term plasma response (3,63), although such studies have relevance to clinical therapies.…”

Hepatic arterial chemotherapy for metastatic colorectal carcinoma

“…Further evidence suggests that modulation of regional 5-FU administration with folinic acid might confer significant therapeutic advantage (Anderson et al, 1991). Unfortunately, regional administration of folinic acid precipitated hepatic artery occlusion in some patients, while in previous studies with regional FUDR (Kemeny et al, 1989b), it had been shown to potentiate the risk of biliary sclerosis.…”

“…The recommended dose of hepatic arterial 5-FU as a 24h infusion when given in combination with a fixed dose of intravenous folinic acid (400 mg M-2) once per week (Anderson et al, 1992) was found to be 1.5 gm 2 week-'. At this dosage, neither myelosuppression nor hepatoxicity was apparent, while dose escalation to 2.0 g m2 week-' 5-FU was associated with WHO grade 3/4 diarrhoea and vomiting.…”

A phase I study of regional 5-fluorouracil and systemic folinic acid for patients with colorectal liver metastases

“…In vitro studies have suggested that a minimum extracellular L-folate concentration of 10 Ismol 1-' is required to maximise modulation of 5-FU thymidylate synthase inhibition (Evans et al, 1981). A 2 h intravenous infusion of 200 mg m-2 would be expected to provide such a satisfactory plasma folinic acid concentration (Anderson et al, 1991). However, 24h intravenous infusions of 500mgm-2 folinic acid fail to provide adequate plasma concentrations of folinic acid (Rustum, 1989).…”

“…We have shown in a series of previous pharmacokinetically guided studies that 24 h intraarterial infusion of 5-FU confers a significant pharmacological advantage relative to intravenous infusions or intra-arterial bolus administration (Goldberg et al, 1990). Regional administration of folinic acid is also associated with a statistically significant reduction in systemic exposure compared with the intravenous route but this apparent pharmacokinetic advantage has been offset by the potential for hepatic artery catheter thrombosis with this drug (Anderson et al, 1991).…”