Pharmacokinetics cyclophosphamide

Yule SM, Boddy AV, Cole M, Price L,WyllieR, Tasso MJ, Pearson ADJ, Idle JR. Cyclophosphamide pharmacokinetics in children. BrJ Clin Pharmacol 996)A, 13-19. 

Despite the fact that alkylating agents exhibit a common mechanism of action, their clinical use varies depending on differences in pharmacokinetics, metabolism, hpid solubility, ability to penetrate membranes, and toxicity. They can be classified as nitrogen-containing mustard derivatives (mechorethamine, chlorambucil, melfalan, cyclophosphamide, ifos-famide), derivatives of ethylenimine (thiotepa), nitrosoureas (carmustine, lomustine, strep-tozocin), alkylsulfonates (busulfan), and derivatives of platinum (cwplatin, carboplatin). 

Herceptin with cisplatin, doxorubicin or epirubicin plus cyclophosphamide, or paclitaxel. A comparison of serum levels of trastuzumab given in combination with various chemotherapeutic agents did not suggest the possibility of any pharmacokinetic interactions except in combination with paclitaxel. Although not statistically signihcant, mean serum trough concentrations of trastuzumab were consistently elevated, about 1.5-fold, when Herceptin was administered in combination with paclitaxel. However, trastuzumab and paclitaxel were used concurrently in clinical trials with positive outcome results. The concurrent administration of anthracyclines, cyclophosphamide, and trastuzumab increased the incidence and severity of cardiac dysfunction during clinical trials. 

Cyclophosphamide s major active metabolite is phosphoramide mustard, which cross-links DNA to prevent cell replication. It suppresses T-cell and -cell function by 30-40% T-cell suppression correlates with clinical response in the rheumatic diseases. Its pharmacokinetics and toxicities are discussed in Chapter 54. 

Belfayol-Pisante L, Guillevin L, Tod M, Fauvelle F. Possible influence of prednisone on the pharmacokinetics of cyclophosphamide in systemic vasculitis. Clin Drug Invest 1999 18 225-31. 

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. 

Spielmann H, Habenicht U, Eibs HG, et al. 1981. Investigations on the mechanism of action and on the pharmacokinetics of cyclophosphamide treatment during the preimplantation period in the mouse. Cult Tech 5th Symp Prenatal Dev, 435-445. 

The clinical significance of the aforementioned findings is unknown. A report by Khakoo et al. (62) did not demonstrate a pharmacokinetic interaction between IFNa2i) and ribavirin or an additive effect of the combination therapy on safety assessments. In another study, administration of IFNa prior to the administration of cyclophosphamide significantly impaired the metabolism of cyclophosphamide and 4 hydrox-ycyclophosphamide. In contrast, the administration of IFNa after cyclophosphamide resulted in higher 4-hydroxy cyclophosphamide concentrations and produced a significant decrease in leukocyte count (63). 

Hassan M, Nilsson C, Olsson H, Lundin J, Osterborg A. The influence of interferon-alpha on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite in patients with multiple myeloma. Eur J Haematol 1999 63 163-70. 

Xie, H. Broberg, U. Griskevicius, L. Lundgren, S. Carlens, S. Meurling, L. Paul, C. Rane, A. Hassan, M. Alteration of pharmacokinetics of cyclophosphamide and suppression of the cytochrome p450 genes by ciprofloxacin. Bone Marrow Transplant. 2003, 31, 197-203. 

In 66 patients who received busulfan in combination with cyclophosphamide, etoposide, and/or cytarabine in preparation for bone marrow transplantation, there was a higher incidence of veno-occlusive disease of the liver (sinusoidal obstruction syndrome) in those who received busulfan + cyclophosphamide (four of 10) than in those who received busulfan + cyclophosphamide + cytarabine (one of 18) or busulfan + cyclophosphamide + etoposide (seven of 38) (24). The risk of veno-occlusive disease was higher in those whose busulfan AUC was over 1500 minute.pmol/l (relative risk = 11). Other pharmacokinetic parameters, age, sex, type of bone marrow transplantation, previous therapy, or pretransplant liver function tests were not predictive of veno-occlusive disease. 

Hassan M, Ljungman P, Ringden O, Hassan Z, Oberg G, Nilsson C, Bekassy A, Bielenstein M, Abdel-Rehim M, Georen S, Astner L. The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant 2000 25(9) 915-24. 

Honjo I, Suou T, Hirayama C. Hepatotoxicity of cyclophosphamide in man pharmacokinetic analysis. Res Commun Chem Pathol Pharmacol 1988 61(2) 149-65. 

Depending on the timing of exposure, interferon alfa may adversely affect the pharmacokinetic and hematological effects of cyclophosphamide. In 10 patients with multiple myeloma, interferon alfa given 2 hours before cyclophosphamide infusion significantly reduced cyclophosphamide clearance and produced less exposure to its metabolite 4-hydroxycyclophosphamide compared with interferon administration 24 hours after cyclophosphamide (406). This resulted in a significantly greater fall in white blood cell count in patients who received interferon alfa after cyclophosphamide. 

Juma FD, Rogers HJ, Trounce JR. Pharmacokinetics of cyclophosphamide and alkylating activity in man after intravenous and oral administration. BrJ Clin Pharmacol. 8 209-217,1979... 

Mouridsen HT, and Jacobsen E. Pharmacokinetics of cyclophosphamide in renal failure. Acta Pharmacol Toxicol 86 409-414, 1975... 

Fung LK, Ewend MG, AiUs A, Sipos EP, Thompson R, Watts M, Colvin OM, Brem H, Saltzman WM (1998) Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxy-cyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res 58 672-684. 

M. Hassan, U. S. Svensson, P. Ljungman, B. Bjorkstrand, H. Olsson, M. Bielentein, M. Abdel-Rehim, C. Nilsson, M Johansson, and M. O. Karlsson, A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients. Br J Clin Pharmacol 48 669-677 (1999). 

Trastuzumab has dose-dependent pharmacokinetics with a mean t of 5.8 days at the 2-mg/kg maintenance dose. Steady-state levels were achieved between the 16th and the 32nd weeks. The infusion effects of trastuzumab are typical of other monoclonal antibodies and include fever, chills, nausea, dyspnea, and rashes. Allergic reactions also may be observed. Cardiac dysfunction is an unexpected and potentially serious side effect that was observed in the pivotal trial of trastuzumab chemotherapy. Left ventricular dysfunction was seen most commonly in those patients who received doxorubicin and cyclophosphamide. 

Pharmacokinetics Hepatic cytochrome P450-mediated biotransformation of cyclophosphamide is needed for antitumor activity. One of the breakdown products is acrolein. 

Holm, K.A. Kindberg, C.G. Stobaugh, J.F. Slavik, M. Riley, C.M. Stereoselective pharmacokinetics and metabolism of the enantiomers of cyclophosphamide. Preliminary results in humans and rabbits. Biochem. Pharmacol. 1990, 39, 1375-1384. 

A pharmacokinetic study in patients with non-Hodgkin s lymphoma receiving CHOP (cyclophosphamide, vincristine, prednisone and doxorubicin 37.5 to 50 mg/m ) found that the addition of tamoxifen 480 mg daily for 5 days had no significant effect on the AUC or total clearance of doxorubicin. For the possible additive thromboembolic effect of doxorubicin and tamoxifen, see Antineoplastics + Tamoxifen , p.616. 

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. 

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