Pharmacokinetics cisplatin

Three hours after receiving intravenous cisplatin 70 mg/m a patient experienced severe nausea and vomiting and his blood pressure rose from 150/90 to 248/140 mmHg. This was managed with furosemide 40 mg intravenously, hydralazine 10 mg intramuscularly, diazoxide 300 mg intravenously and propranolol 20 mg orally twice daily for 2 days. Nine days later the patient showed evidence of renal impairment (creatinine raised from about 88 micromol/L to 283 micromol/L), which resolved within 3 weeks. The patient was subsequently similarly treated on two occasions with cisplatin and again developed hypertension, but no treatment was given and there was no evidence of renal impairment. The reasons for the renal impairment are not known, but a study in rats indicate that kidney damage may possibly be related to the concentrations of cisplatin, and that furosemide can increase cisplatin levels in the kidney. However, another study in patients found that there was no difference in the toxicity or pharmacokinetics of cisplatin when furosemide was used to induce diuresis, compared with mannitol. Two other studies have also found that furosemide does not alter cisplatin pharmacokinetics. Another study showed that sodium chloride solution with or without furosemide was associated with less cisplatin nephrotoxicity than sodium chloride solution with mannitol. ... 

The combination of a platinum derivative and fluorouracil is widely used, but the optimum schedule to improve activity and reduce toxicity is not firmly established. In one study of bolus cisplatin and continuous infusion fluorouracil, modifying the dose of fluorouracil based on AUC reduced toxicity while still maintaining response rates. In another study, cisplatin pharmacokinetics were said to be optimum when it was given as a continuous infusion with a continuous infusion of fluorouracil. Further study is needed. 

While carboplatin has the same mechanism of action as cisplatin, it has a much less toxic side-effect profile than cisplatin. The pharmacokinetics of carboplatin are best described by a two-compartment model, with an a half-life of 90 minutes and a terminal half-life of 180 minutes. Carboplatin is eliminated almost entirely by the kidney by glomerular filtration and tubular secretion. Many chemotherapy regimens dose carboplatin based on an area under the curve (AUC), which is referred to... 

The serendipitous discovery of the antitumor activity of cisplatin opened a huge field of research, leading to significant advances and successes in cancer chemotherapy [181]. Cisplatin and its analogues are reactive complexes that exhibit pharmacokinetic, pharmacodynamic, and toxicological behaviors so closely interdependent as to be all but impossible to untangle. Our focus here is and remains metabolism, but some considerations regarding activity and toxicity are also addressed. 

K. Hanada, K. Ninomiya, H. Ogata, Pharmacokinetics and Toxicodynamics of Cisplatin and Its Metabolites in Rats Relationship between Renal Handling and Nephrotoxicity of Cisplatin , J. Pharm. Pharmacol. 2000, 52, 1345 - 1353. 

Han, J. Y., Lim, H. S., Shin, E. S., et al. (2006) Comprehensive analysis of UGTIA polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-ceU lung cancer treated with irinotecan and cisplatin. J. Clin. Oncol. 24, 2237-2244. 

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. 

Ajani JA, Faust J, Ikeda K et al. Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. J Clin Oncol 2005 23 6957-6965. 

ICP-MS has been employed, as discussed in Section 9.5, for the determination of platinum originating from cisplatin, carboplatin and oxaliplatin in human plasma ultrafiltrate. The method developed was successfully used to support pharmacokinetic studies in cancer patients treated with cisplatin, carboplatin or oxaliplatin.5 Counterfeit products on the drug market, which have important implications for pharmaceutical companies and human health, can be clarified by mass spectrometric isotope ratio measurements. For example, precise and accurate sulfur isotope measurements (a 54S) by MC-ICP-MS, were employed to study the isotope variation of pharmaceuticals and to detect to the origin of counterfeits by Clough el al.6... 

Goel, R., Andrews, P.A., Pfeifle, C.E., Abramson, I.S., Kirmani, S. and Howell, S.B. (1990) Comparison of the pharmacokinetics of ultrafilterable cisplatin species detectable by derivatization with diethylelithiocarbamate or atomic absorption spectroscopy. Eur. J. Cancer, 26, 21-27. 

Goss G et al (2009) A phase I and pharmacokinetic study of daily oral cediranib, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with cisplatin and gemcitabine in patients with advanced non-small cell lung cancer a study of the national cancer institute of Canada clinical trials group. Eur J Cancer 45 782-788... 

Following construction, characterization, and scale-up of trastuzumab, phase I testing of the humanized mAh was carried out in patients with HER2-overexpressing metastatic breast cancer. The initial phase I study evaluated the safety and pharmacokinetics of a single, escalating (10-500 mg) intravenous dose of trastuzumab. A subsequent phase I study evaluated the safety and pharmacokinetics of multiple-dose administration, with weekly intravenous doses and similar dose escalation by cohort (10-500 mg). Both studies of 32 patients overall demonstrated that trastuzumab monotherapy was very well tolerated, with no serious adverse events attributable to mAh treatment. A third phase I study included trastuzumab, again via weekly intravenous administration of 10-500 mg, in combination with cisplatin chemotherapy at 50 or 100 mg/m2 per 4-week cycle. Toxicities in this trial were those commonly seen with cisplatin. 

Interpretation of pharmacokinetic data is also complicated by biotransformation processes. Cisplatin is metabolized to various aquated species and in the low-chloride intracellular environment these predominate. Plati-num(IV) compounds are converted rapidly to platinum(II) derivatives in plasma, and multiple distinct circulating molecular species may be produced [223], While some HPLC assays may distinguish among metabolites, sensitivity often limits resolution of the various molecular species. Pharmacokinetic data should be interpreted accordingly. Recently it has been possible... 

Conversely, in another experiment using oral doses of 20, 50, 100 and 200 mg/kg to Balb C mice, broadly linear pharmacokinetics were observed. The maximum platinum levels in plasma were observed between 30 and 120 min and were delayed with increasing dose. Platinum unbound to proteins was detectable up to 7 hpost dosing. Elimination of total platinum was biphasic with a terminal half-life of 30 h. The half-life for ultrafilterable free platinum ranged from 87 to 135 min which is considerably longer than the 10 min reported for cisplatin or 25 min reported for carboplatin [25],... 

At the preclinical level, oral antitumor activity has been observed with two other classes of platinum compound, the PtIV monocarboxylate, C(5)-OHP-C1, and the first Ptn complex to exhibit oral activity, the sterically hindered AMD473. Now licenced to Zeneca, AMD473 exhibited promising circumvention of acquired cisplatin resistance against both in vitro and in vivo preclinical models. Together with the drug s favourable pharmacokinetic and toxicology profile in rodents (myelosuppression was dose-limit-... 

Cisplatin [SIS pla tin] is a member of the platinum coordination complex class of anticancer drugs. Because of cisplatin s severe toxicity, carboplatin [KAR bow pla tin] was developed. The therapeutic effectiveness of the two drugs is similar but their pharmacokinetics, patterns of distribution and dose-limiting toxicities differ. Cisplatin has synergistic cytotoxicity with radiation and other chemotherapeutic agents. 

Pharmacokinetics Cisplatin and carboplatin are administered IV in saline solution they can also be given intraperitoneally for ovarian cancer. Over 90% of cisplatin is bound to serum proteins. Highest concentrations are found in liver, kidney, intestinal, testicular and ovarian cells, but little penetrates into the cerebral spinal fluid (CSF). The renal route is the main avenue for excretion. 

Kaneda Y, Liu D, Brooks A et al. (2001) Toxicity and pharmacokinetics of isolated lung perfusion with cisplatin in rat. Jpn J Thorac Cardiovasc Surg 49 443-448 Newton JFJ, Hook JB (1981) Isolated perfused rat kidney. Methods Enzymol 77 94-105... 

To develop platinum drugs with improved properties compared to cisplatin, a plethora of cisplatin analogs have been designed with appended additional ftmctionalities. The rationale is that these incorporated moieties could lead to a host of favorable pharmacokinetic properties, such as targeting to cancer cells, improved transport into the cell, and increased affinity for DNA. Furthermore, to overcome the problem of resistance, pendant DNA interacting moieties have been... 

Brequinar was synergistic with cisplatin in preclinical models. However, co-administration of brequinar with cisplatin does not affect the pharmacokinetics of either drug (5). 

Burris HA 3rd, Raymond E, Awada A, Kuhn JG, O Rourke TJ, Brentzel J, Lynch W, King SY, Brown TD, Von Hoff DD. Pharmacokinetic and phase I studies of brequinar (DUP 785 NSC 368390) in combination with cisplatin in patients with advanced malignancies. Invest New Drugs 1998 16(l) 19-27. 

---