Pharmacokinetic studies in lung cancer patients

Piazza, E.; Cattaneo, María Teresa; Varini, M.

doi:10.1002/1097-0142(19840915)54:1+<1187::aid-cncr2820541316>3.0.co;2-r

Cited by 14 publications

(7 citation statements)

References 33 publications

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“….u 1 nl (Bryant et al, 1980a;Cerny et al, 1986;McNeil & Morgan, 1981;Nelson etal., 1976;Piazza et al, 1984). The terminal elimination half-life of ifosfamide at this dose was similar to that for low dose cyclophosphamide (5.1 h) (Graham et al, 1983).…”

supporting

confidence: 60%

“…The plasma decay of unchanged ifosfamide at this dose was best fitted by a monoexponential function, as shown by others (Creaven et al, 1976;Nelson et al, 1976 Our findings are similar to that of Lind et al (1989) using 1.5 g m2 ifosfamide intravenously daily for 5 days who found an increase in ifosfamide clearance from a median of 69.19 ml min -1 on day 1 to a median of 123.19 ml min -1 on day 5 without a change in ifosfamide distribution. Thus, the initial suggestions from small studies Piazza et al, 1984) of timedependent metabolism for ifosfamide are confirmed. A similar phenomenon has been observed with cyclophosphamide (D'Incalci et al, 1979;Graham et al, 1983).…”

mentioning

confidence: 69%

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Fractionated ifosfamide therapy produces a time‐dependent increase in ifosfamide metabolism.

Lewis

Fitzgerald

Harper

et al. 1990

Brit J Clinical Pharma

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1 Fifteen patients received 1.5 g m-2 of ifosfamide intravenously over 0.5 h every day for 5 days. Twenty-one courses of treatment were studied. Plasma was assayed for ifosfamide by gas liquid chromatography and plasma alkylating activity was measured using the nitrobenzylpyridine (NBP) reaction. 2 A pharmacokinetic analysis revealed a significant decrease in the median (range) elimination half-life of ifosfamide from 7.2 (2.8-14.2) h on day 1 to 4.6 (2.3-7.7) h on day 5 (P < 0.001, Wilcoxon's test) with a concomitant significant increase in the median (range) clearance from 66 (31-148) ml min-1 on day 1 to 115 (52-381) ml min-' on day 5 (P < 0.001). There was no significant change in the volume of distribution on day 5 compared with day 1.3 There was a highly significant 223% increase in the median (range) plasma nitrobenzylpyridine alkylating activity area under the curve on day 1 from 16 (0.6-105) nmol nor nitrogen mustard equivalents ml-' h to 52 (13-238) nmol nor nitrogen mustard equivalents ml-' h on day 5. 4 During five courses of treatment (in five patients in the group) 24 h urine samples were collected on days 1 and 5. The median (range) renal clearance of ifosfamide on day 1 was 6.8 (1.3-16.2) ml min-1 compared with 5.7 (1.3-15.3) ml min-1 on day 5. This difference was not significant. The median (range) metabolic clearance of ifosfamide in these five patients on day 1 was 78.6 (39.9-141.2) ml min-1 and 132.6 (54.6-149.5) ml min on day 5. This difference in metabolic clearance did not reach statistical significance. 5 These data indicate that after 5 days fractionated intravenous ifosfamide at 1.5 g m daily produces a time-dependent increase in ifosfamide metabolism.

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confidence: 60%

mentioning

confidence: 69%

Fractionated ifosfamide therapy produces a time‐dependent increase in ifosfamide metabolism.

Lewis

Fitzgerald

Harper

et al. 1990

Brit J Clinical Pharma

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“…Ifosfamide is converted to its active intermediate by the cytochrome P450 enzymes (Connors et al, 1974). There is evidence for enzyme induction by repeated administration (Nelson et al, 1976;Piazza et al, 1984;Wagner & Drings, 1986;Lind et al, 1989;Lewis et al, 1990), and this may alter the proportions of metabolites formed. Toxicity is common and may be severe.…”

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confidence: 99%

Metabolism of ifosfamide during a 3 day infusion

Hartley

Hansen²,

Harland³

et al. 1994

Br J Cancer

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Summary Urinary drug metabolites were measured in 21 patients receiving ifosfamide by continuous infusion over 3 days. Mean values for the proportion of drug excreted as parent compound, 2-dechloroethylifosfamide (2-DC), 3-dechloroethylifosfamide (3-DC), carboxyifosfamide (CX) and ifosforamide mustard (IPM) were 19, 6, 10, 7 and 8% of dose respectively. The proportion of urinary drug products in the form of ifosfamide fell considerably over the course of the 3 days. This was mirrored by an increase in the proportion of 2-DC, 3 al., 1974;Sladek, 1988) (see Figure 1 for a summary of the metabolic pathways). Ifosfamide is converted to its active intermediate (4-OH-IFOS) by the cytochrome P450 enzymes (Connors et al., 1974). There is evidence for enzyme induction by repeated administration (Nelson et al., 1976;Piazza et al., 1984;Wagner & Drings, 1986;Lind et al., 1989;Lewis et al., 1990), and this may alter the proportions of metabolites formed. Toxicity is common and may be severe. Whereas some sideeffects -myelosuppression and alopecia -are related to the tumoricidal metabolite ifosforamide mustard, other toxicities appear to be due to other products. Bladder toxicity and nephrotoxicity are almost certainly caused by acrolein (Brock et al., 1981), formed in equimolar amounts with ifosforamide mustard (Alarcon et al., 1972). The cause of the neurotoxicity seen following ifosfamide therapy is less certain, but it may be related to chloroacetaldehyde formed during the loss of the chloroethyl moieties (Norpoth, 1976;Goren et al., 1986). This compound could also contribute to renal damage (Skinner et al., 1993). The co-products of these pathways are 2-dechloro-and 3-dechloroifosfamide. Clearly, the efficacy and toxicity of ifosfamide will relate to the activity of the products of not only the above pathways, but also other inactivating pathways, notably 4-keto ifosfamide and carboxyifosfamide.Despite its importance, there are very few quantitative data on ifosfamide metabolism. The purpose of the present study was to determine the patterns of excretion and amounts of urinary metabolites during IFOS therapy both during single treatment cycles and in the same patients undergoing repetitive treatments. Materials and methodsThe parent drug, ifosfamide (IFOS), and its metabolites (2-chloroethyl)-2-amino-tetrahydro-2-oxide-2H-1,3,2-oxazaphosphorine, (2 dechloroethylifosfamide, 2DC), 2-(2-chloroethyl)-amino-tetrahydro-2-oxide-2H-1,3,2-oxazaphosphorine, (3-dechloroethylifosfamide 3DC), 3-[N,N'-bis(2-chloroethylamino)phosphinyloxy] propanic acid (carboxyifosfamide, CX) and N,N'-bis(2-chloroethyl)phosphorodiamidic acid (isophosphoramide mustard, IPM) were all prepared, authenticated and kindly given by Asta Medica (Frankfurt, Germany). The keto metabolite, when seen in patients' urine, was present in amounts near the limit of detection and so these are not reported here.Sodium acetate, potassium hydroxide and 4-(4-nitrobenzyl)pyridine (NBP) were all obtained from Sigma. Methanol and acetone for development of the NBP reagent w...

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“…Bonferroni P<0.024) an increase of 99.7% from baseline. In Cycle II despite the mean (n=4) day 5 ifosfamide Piazza et al [29] reported plasma concentration-time data on ten patients treated for three cycles of fractionnon-renal clearance being 95.2% above the baseline day 1 value (88.8 ml min−1 vs 45.5 ml min−1 respectively) ated ifosfamide suggesting the plasma ifosfamide concentrations were similar in each cycle (but without comment the difference in these means was not statistically significant (99.8% CIs−8.6 +95.6; Bonferroni P= on which days of the cycle the data were obtained and without pharmacokinetic or statistical analysis). Nelson 0.43).…”

Section: Introductionmentioning

confidence: 95%

A study of 5 day fractionated ifosfamide pharmacokinetics in consecutive treatment cycles

Lewis

1996

Brit J Clinical Pharma

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1 Ifosfamide demonstrates increased clearance with time when administered daily for 5 days. The objectives of this study were to define whether the increased ifosfamide clearance was sustained between treatment cycles and whether it was reproducible in consecutive treatment cycles. 2 Seven patients with inoperable cancer received 1.5 g m−2 ifosfamide infused intravenously over 0.5 h, each day for 5 days, for two consecutive cycles. Urine and appropriately timed blood samples were collected for up to 24 h post ifosfamide infusion on day 1 and day 5. Plasma ifosfamide concentrations were assayed by gas liquid chromatography and pharmacokinetic parameters were imputed using non-compartmental analysis. 3 The difference in the mean (n=7) total ifosfamide plasma clearance between day 5 and day 1 of Cycle I was an increase of 56.8 ml min−1 (99.8% CIs +22.6 +91.4). The difference in the mean (n=7) total ifosfamide plasma clearance between day 1 of Cycle II and day 5 was a decrease of 61.9 ml min−1 ( 99.8% CIs−111.2 −12.6). The magnitude of the mean increase in total ifosfamide plasma clearance in Cycle II and Cycle I was similar because the difference between these means ( 0.9 ml min−1; 99.8% CIs−63.7 +65.3) was not statistically significant. There was no change in the apparent volume of distribution of ifosfamide between the two study days in either of Cycle I or II, or between cycles. 4 The difference in the mean (n=7) ifosfamide renal clearance between day 5 and day 1 of Cycle I was minus 0.4 ml min−1 (99.8% CIs−8.5 +8.6); the means±s.d. were 6.3±2.6 ml min−1 and 6.7±3.2 ml min−1 respectively. The difference in the mean (n=4) ifosfamide renal clearance between day 5 and day 1 of Cycle II was −0.2 ml min−1 (99.8% CIs −5.7 +5.2); the means±s.d. were 7.8±6.1 ml min−1 and 8.0±6.2 ml min−1 respectively. 5 These data suggest that the increase in total ifosfamide plasma clearance with time in a 5 day fractionated regimen was due to an increase in ifosfamide metabolism which was not sustained over the 21 days between cycles, but was reproducible and of a similar magnitude in the two consecutive treatment cycles studied.

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Pharmacokinetic studies in lung cancer patients

Cited by 14 publications

References 33 publications

Fractionated ifosfamide therapy produces a time‐dependent increase in ifosfamide metabolism.

Fractionated ifosfamide therapy produces a time‐dependent increase in ifosfamide metabolism.

Metabolism of ifosfamide during a 3 day infusion

A study of 5 day fractionated ifosfamide pharmacokinetics in consecutive treatment cycles

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