The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified 'Modified de Gramont' (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m 72 ), then ambulatory 46-h fluorouracil infusion (2000 -3600 mg m 72 , cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m 72 . Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m 72 bolus + 2800 mg m 72 46-h infusion. A lower dose of 400 mg m 72 bolus + 2400 mg m 72 infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC 0 -48 h ) at this lower dose is equivalent to dG. With OxMdG, grade 3 -4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea 51% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. 1988). It was compared with the Mayo Clinic 5-day bolus FU/LV regimen in a 448-patient randomised trial, and showed a better response rate (32.6% vs 14.4%; P=0.0004), and median progression-free survival (27.6 vs 22 weeks; P50.0012) with significantly reduced rates of diarrhoea, mucositis and neutropenia; however, overall survival was not significantly improved (de Gramont et al, 1997). Following this trial dG was adopted as a standard therapy option by many oncologists, especially in France and the UK.Its low toxicity profile makes dG a good basis for combination chemotherapy. Pivotal trials of the design 'dG+new agent' have been performed in first-line therapy of metastatic colorectal cancer using oxaliplatin or irinotecan (Douillard et al, 2000), in each case producing a high response rate and good safety profile. Similar trials are now ongoing in the adjuvant setting.Although dG can be administered on an ambulatory, out-patient basis, many units find it more convenient to admit patients. This, together with the high dose of LV, and a labour-intensive administration schedule, place high demands on healthcare resources (Ross et al, 1998). Furthermore, repeated hospital visits or admissions during dG may detract from the benefits of its low toxicity profile.Along with others (see Discussion), we reasoned that it would be possible to modify the dG regimen, reducing its ...

Aims To investigate the pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) in healthy volunteers after the administration of morphine by subcutaneous bolus injection (s.c.b.) and subcutaneous infusion (s.c.i.) over 4 h, and to compare the results with the intravenous bolus (i.v.) administration of morphine. Methods Six healthy volunteers each received 5 mg morphine sulphate by i.v., s.c.b. and short s.c.i. over 4 h, on three separate occasions, in random order, each separated by at least 1 week. Plasma samples were assayed for morphine, M6G and M3G. Results After i.v. morphine, the concentrations of morphine, M6G and M3G and their pharmacokinetic parameters were similar to those we have observed previously, in other healthy volunteers (when standardized to nmol l x 1 , for a 10 mg dose to a 70 kg subject). After s.c.b. morphine, similar results were obtained except that the median t max values for morphine and M3G were signi®cantly longer than after i.v. morphine (P<0.001 and P<0.05, respectively), with a trend to a longer t max for M6G (P =0.09). The appearance half-lives after s.c.b. morphine for M6G and M3G were also signi®cantly longer than after i.v. morphine (P =0.03 and P<0.05, respectively). Comparison of log-transformed AUC values indicated that i.v. and s.c.b. administration of morphine were bioequivalent with respect to morphine, M6G and M3G. In comparison with i.v. morphine, morphine by s.c.i. was associated with signi®cantly longer median t max values for morphine (P<0.001), M6G (P<0.001) and M3G (P<0.05), and the mean standardized C max values signi®cantly lower than after both i.v. and s.c.b. morphine (morphine P<0.001, M6G P<0.001 and M3G P<0.01 for each comparison). Comparison of log-transformed AUC values after i.v. and s.c.i. morphine indicated that the two routes were not bioequivalent for morphine (logtransformed AUC ratio 0.78, 90% CI 0.66±0.93), M6G (0.72, 90% CI 0.63±0.82), or M3G (0.65, 90% CI 0.54±0.78). A small stability study indicated no evidence of adsorptive losses from morphine infused over 4 h using the infusion devices from the study. Conclusions Although bioequivalence was demonstrated between the s.c.b. and i.v. routes of morphine administration, the bioavailabilities of morphine, M6G and M3G after s.c.i. were signi®cantly lower than after i.v. administration. However, despite this, the study demonstrates that the subcutaneous route is an effective method for the parenteral administration of morphine.

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Etoposide demonstrates incomplete and variable bioavailability after oral dosing, which may be due to its concentration and pH-dependent stability in artificial gastric and intestinal fluids. The use of agents that may influence etoposide stability and, thereby, bioavailability, was investigated in a number of clinical studies. Drugs that influence the rate of gastric emptying, while modulating the time of drug absorption, did not significantly alter the etoposide area under the concentration-time curve (AUC) or bioavailability. Specifically, metoclopramide had little effect on the etoposide absorption profile and did not significantly alter the AUC (AUC with etoposide alone, 68.4 +/- 20.3 micrograms ml-1 h, versus 74.3 +/- 25.9 micrograms ml-1 h with metoclopramide), suggesting that in most patients the drug is already emptied rapidly from the stomach. In contrast, propantheline produced a dramatic effect on etoposide absorption, delaying the time of maximal concentration tmax from 1.1 to 3.5 h (P < 0.01), but again without a significant improvement in drug AUC or bioavailability across the 24-h study period (AUC with etoposide alone 78.3 +/- 19.1 micrograms ml-1 h, versus 88.1 +/- 23.6 micrograms ml-1 h with propantheline). The effect of these drugs on the absorption of oral paracetamol, a drug included in the study as a marker of gastric emptying, was exactly the same as that found for etoposide, with no change in AUC being observed after metoclopramide or propantheline administration but a significant delay in tmax being seen on co-administration with etoposide and propantheline. The co-administration of ethanol or bile salts (agents that significantly improved the stability of etoposide in artificial intestinal fluid) with oral etoposide similarly had no effect on improving the etoposide AUC or reducing the variability in AUC, suggesting that drug stability in vivo was not affected by these agents. In the third study the co-administration of cimetidine had no effect on the pharmacokinetics of oral or i.v. etoposide, despite the previous observation that etoposide stability was markedly improved at pH 3-5 as compared with pH 1 in artificial gastric fluid. This series of studies, designed to investigate factors that improved etoposide stability in laboratory studies, failed to demonstrate any potentially useful improvement in AUC or bioavailability in the clinical setting.

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