Ifosfamide pharmacokinetics

Lokiec F, Santoni J, WeiU S, Tubiana-Hulin M. Phenobarbital administration does not affect high-dose ifosfamide pharmacokinetics inhumans.z4 tica c erDrM s (199 7, 893-6. 

Brain EGC, Yu LJ, Gustafsson K, Drewes P, Waxman DJ. Modulation of P450-dependent ifosfamide pharmacokinetics a better understanding of drug activation in vivo. BrJ Cancer (1998) 77,1768-76. 

Pharmacokinetics Unlike most of the alkylating agents, cyclophosphamide and ifosfamide are preferentially administered by the oral route. Minimal amounts of the parent drug are excreted into the feces (after biliary transport), or into the urine by glomerular filtration. 

It has been thought that the metabolism of ifosfamide to chloroacetaldehyde is the mechanism whereby ifosfamide causes renal damage. However, this was not confirmed in a study of repeated doses of 6-9 g/m in 15 children, in whom there was no correlation between the pharmacokinetics of ifosfamide or its metabolites and either acute renal toxicity or chronic renal toxicity at either 1 or 6 months after treatment (8). However, there were changes in the metabolism of ifosfamide with time, particularly a reduction in dechloroethylation, which correlated with the risk of chronic nephrotoxicity. 

Lind MJ, Margison JM, Cerny T, Thatcher N, Wilkinson PM. Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma. Cancer Res 1989 49(3) 753-7. 

The effect of ketoconazole on the CYP-mediated metabolism of ifosfamide to 4-hydroxjdfosfamide and the ultimate cytotoxic ifosforamide mustard, and its deactivation to 2- and 3-dechloroethyhfosfamide has been studied in a randomized, crossover study in 16 patients, who received intravenous ifosfamide 3 g/m /day, either alone or in combination with ketoconazole 200 mg bd 1 day before treatment and during 3 days of concomitant administration (46). Ketoconazole did not affect the fraction metabolized or exposure to the dechloroethylated metabolites and thus did not alter the pharmacokinetics of ifosfamide or its metabolism. 

Kaijser G, Bejnen J, Bult A, and Underberg W. Ifosfamide metabolism and pharmacokinetics. Anticancer Res 14 517-532,1994... 

Ifosfamide usually is administered in a short infusion in. 1% dextrose or normal. saline. Use within 8 hours of reconstitution is recommended. Pharmacokinetic studies indicate that it is handled in the same way as cyelophusphainide. except that metabolism is less extensive. There is an appareiil half-life trf 7 hours und a urinary recovery of 13%. 

Dechant KL, Brodgden RN, Pilkington T, Faulds D (1991) Ifosfamide/mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs 42 428-467... 

Aleksa K, Ito S, Koren G (2004) Renal-tubule metabolism of ifosfamide to the nephrotoxic chloroacetaldehyde pharmacokinetic modeling for estimation of intracellular levels. J Lab Clin Med 143 159-162... 

Chen N, Aleska K, Woodland C, Rieder MJ, Koren G (2007) Prevention of ifosfamide nephrotoxicity by N-acetylcysteine clinical pharmacokinetic considerations. Can J Clin Pharmacol 14 e246-e250... 

Hanly LN, Chen N, Aleksa K et al (2011) N-acetylcysteine as a Novel Prophylactic Treatment for Ifosfamide-induced Nephrotoxicity in Children Translational Pharmacokinetics. J Clin Pharmacol 52(l) 55-64... 

T. Kerbusch, J. de Kraker, R. A. Mathjt, and J. H. Beijne, Population pharmacokinetics of ifosfamide and its dechloroethylated and hydroxilated metabolites in children with malignant disease a sparse sampling approach. Clin Pharmacokinet 40 615-625 (2001). 

T. Kerbusch, R. A. Mathot, H. J. Keizer, G. P. Kaijser, J. H. ScheUens, and J. FI. Beijnen, Influence of dose and infusion duration on pharmacokinetics of ifosfamide and metabolites. Drug Metab Dispos 29 967-975 (2001). 

Schmidt, R., Baumann, F., Hanschmann, H., Geissler, F., and Preiss, R. (2001) Gender difference in ifosfamide metabolism by human liver microsomes. Eur. J. Drug Metab. Pharmacokinet. 26, 193-200. 

Kaijser G, Bejnen J, Bull A, Underberg W. Ifosfamide metabolism and pharmacokinetics. Anticancer Res 1994 14 517-532. Boos J, Welslau U, Ritter J, Blaschke G, Schellong G. Urinary excretion of the enantiomers of Ifosfamide and its inactive metabolites in children. Cancer Chemother Pharmacol 1991 28 455-460. 

Allen LM, Creaven PJ, Nelson RL. Studies on the human pharmacokinetics of Ifosfamide (NSC-109724). Cancer Treat Rep 1976 60 451-458. 

Ifosfamide has a plasma elimination t of 15 hours after doses of 3.8-5 g/rrf and a somewhat shorter t at lower doses, although its pharmacokinetics are highly variable due to variable rates... 

Granvil, C.P. Ducharme, J. Leyland-Jones, B. Trudeau, M. Wainer, I.W. Stereoselective pharmacokinetics of ifosfamide and its 2- and 3-N-dechlor-oethylated metabolites in female cancer patients. Cancer Chemother. Pharmacol. 1996, 37, 451-456. 

Corlett, S.A. Parker, D. Chrystyn, H. Pharmacokinetics of ifosfamide and its enantiomers following a single 1 h intravenous infusion of the racemate in patients with small cell lung earcinoma. Br. J. Clin. Pharmacol. 1995, 59, 452 55. 

Prasad, V.K. Corlett, S.A. Abaasi, K. Heney, D. Lewis, I. Chrystyn, H. Ifosfamide enantiomers pharmacokinetics in children. Cancer Chemother. Pharmacol 1994, 54, 447 49. 

Aprepitant had no effect on the pharmacokinetics of a single dose of docetaxeL The activation of cyclophosphamide and thiotepa was slightly lower in patients receiving aprepitant, but this was not clinically relevant. However, because of the possibility of increased toxicity the manufacturer recommends caution with antineoplastics principally metabolised by the cytochrome P450 isoenzyme CYP3A4, particularly irinotecan, and also etoposide, vinorelbine, paclitaxel, ifosfamide, imatinib, vinblastine and vincristine, although there appears to be some limited evidence of safe concurrent use. 

The UK manufacturer of aprepitant recommends caution when it is used with antineoplastics that are metabolised by CYP3A4, particularly irinotecan, because of the possibility of increased toxicity with this drug. They also mention that etoposide, vinoreibine, docetaxel, paclitaxel, ifosfamide, imatinib, vinblastine and vincristine, were given without dosage adjustment for potential interactions, but as this was not a formal interaction study they recommend caution. However, with intravenous docetaxel, it appears that no important changes in pharmacokinetics occur, and therefore dosage adjustments are unlikely to be needed for this drug,... 

Animal studies suggest that the benzodiazepines may possibly increase the metabolic activation and the toxicity of high doses of cyclophosphamide and ifosfamide. However, diazepam did not alter the pharmacokinetics of high-dose cyclophosphamide in a clinical study. Note also that lorazepam is widely used for chemotherapy-induced nausea and vomiting. 

The clearance of ifosfamide is higher when it is given after do-cetaxel. This results in less toxicity, but the effect on efficacy is unknown. Ifosfamide did not aiter the pharmacokinetics of docetaxel. The sequence of ifosfamide followed by paclitaxel was antagonistic in vitro. 

The AUCs of ifosfamide and its metabolites were lower when ifosfamide was given immediately after docetaxel than when it was given 24 hours before docetaxel, due to increased clearance. Docetaxel pharmacokinetics were unaltered by ifosfamide. This supports the evidence that the maximum tolerated dose is greater when ifosfamide is given after docetaxel. The mechanism is unknown, but it has been suggested that docetaxel may competitively inhibit the activation of ifosfamide by the cytochrome P450 isoenzyme CYP3A4. These results showthat the toxicity, and possibly efficacy, of the combination are schedule dependent. More study is needed. Cyclophosphamide does not appear to alter doeetaxel pharmacokinetics. For full details see also Taxanes + Cyclophosphamide , p.661. 

Schrijvers D, Pronk L, Highley H Bruno R, Locci-Tonelli D, De Bruijn E, Van Oosterom AT, Verweij J. Pharmacokinetics of ifosfamide are changed by combination widi docetaxel. AmJ Clin Oncol (2000) 23, 358-63,... 

The pharmacokinetics of docetaxel were not altered by pretreatment with an intravenous bolus dose of cyclophosphamide in a phase I study. For a report that the pharmacokinetics of docetaxel are not affected by ifosfa-mide, see Cyclophosphamide or Ifosfamide + Taxanes , p.628. 

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