Carboplatin pharmacokinetics

Underlying risk factors, which predispose patients to more severe forms of myelosuppression, include lower initial blood cell counts, renal impairment, poor performance status, extensive prior chemotherapy, and advanced age. There is a strong correlation between carboplatin pharmacokinetics and the severity of myelo-suppressive adverse effects an AUC-adapted dosage of carboplatin is therefore highly recommended during conventional dose chemotherapy (22,23,155). 

Obasaju CK, Johnson SW, Rogatko A, Kilpatrick D, Brennan JM, Hamilton TC, Ozols RF, O Dwyer PJ, Gallo JM, Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel, Clin Cancer Res (1996) 2,549-52,... 

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... 

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). 

Stevenson JP, Gallagher M, Sun W, et al. Phase I clinical and pharmacokinetic study of the taxanes analog BMS-184476 administered as a 1-hour iv infusion in combination with carboplatin every 21 days. Proc Am Assoc Cancer Res 2000 41 608 (abstract 3871). 

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... 

Detailed pharmacokinetic studies were performed on transscleral iontophoresis of various drugs [38-40,42,75-78]. Each drug resulted in different patterns of distribution in the vitreous. Carboplatin distribution in the vitreous after iontophoretic delivery demonstrated heightened levels in a controlled manner from 1 to 6 h after treatment [39], Foscarnet iontophoresis demonstrated a very low elimination rate, thus therapeutic levels in the vitreous were maintained for up to 60 h [78]. Methylprednisolone obtained a relatively low peak concentration 2 h after treatment [38], and gentamicin showed a peak concentration 16 h after the transscleral iontophoresis [42]. 

Hayden, B.C., et al. 2004. Pharmacokinetics of systemic versus focal carboplatin chemotherapy in the rabbit eye Possible implication in the treatment of retinoblastoma. Invest Ophthalmol Vis Sci 45 3644. 

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],... 

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. 

The present drug of choice for this purpose is cis-platin [cis-diamminedichloroplatinum (II)], or its analog carboplatin. As will be discussed in Chapter 30, early compartmental models predicted a substantial pharmacokinetic advantage of intraperitoneal over intravenous delivery (8). A later Phase III trial (7) confirmed that a comparative survival advantage... 

In 21 patients with advanced non-small cell lung cancer carboplatin had no effect on the pharmacokinetics of paclitaxel 135-200 mg/m as a 24-hour intravenous infusion (58). Peripheral neuropathy occurred in 13 of 37 patients treated with paclitaxel 175 mg/m and carboplatin (59). The authors concluded that clinically important neurotoxicity increases with every cycle of chemotherapy. The peripheral neuropathy mainly affected sensory fibers without involving motor nerves. The same paclitaxeP carboplatin chemotherapy in 28 women caused no signs of acute central neurotoxicity or neuropsychological deterioration however, 11 patients had a peripheral neuropathy (60). 

Kearns CM, Belani CP, Erkmen K, Zuhowski M, Hiponia D, Zacharski D, Engstrom C, Ramanathan R, Trenn MR, Aisner J, et al. Pharmacokinetics of paclitaxel and carboplatin in combination. Semin Oncol 1995 22(5 Suppl 12) l-4 discussion 5-7. 

There are significant pharmacokinetic differences among cisplatin, carboplatin, and oxahplatin. Cisplatin is the most highly protein-bound (>90%), followed by oxaliplatin (85%) and carboplatin (24—50%). 

Pharmacokinetic-pharmacodynamic correlations between AUC, response rates, and the extent of myelosuppression have been examined retrospectively in patients with advanced ovarian carcinoma (21,24). AUC values below 4 minutes/mg/ml and exceeding 7 minutes/mg/ml cannot be recommended the former is associated with low response rates and the latter is associated with more pronounced neutropenia and thrombocytopenia without higher response rates. Doses of carboplatin are generally calculated by the Calvert formula (26) ... 

Lee EJ, Egorin MJ, Van Echo DA, Cohen AE, Tait N, Schiffer CA. Phase I and pharmacokinetic trial of carboplatin in refractory adult leukemia. J Natl Cancer Inst 1988 80(2) 131-5. 

Harland SJ, Newell DR, SiddikZH, Chadwick R,Calvert AH, Harrap KR. Pharmacokinetics of cis-diammine-1,1-cyclobutane dicarboxylate platinum[ll] in patients with normal and impaired renal function. Cancer Res. 1984 Apr 44[4] 1693-7 Koeller JM,Trump DE,Tutsch KD, Earhart RH, DavisTE,Tormey DC. Phase I clinical trial and pharmacokinetics of carboplatin [NSC 241240] by single monthly 30-minute infusion. Cancer. 1986 Jan 15 57[2] 222-5... 

Canetta R, Rozencweig M, Carter SK. Carboplatin the clinical spectrum to date. CancerTreat Rev. 1985 Sep 12 SuppI A 125-36 Egorin MJ,Van Echo DA,Tipping SJ, Olman EA, Whitacre MY,Thompson BW, Aisner J. Pharmacokinetics and dosage reduction of cis-diammine[1,1-cyclobutanedicarboxylato]platinum in patients with impaired renal function. Cancer Res. 1984 Nov 44[11] 5432-8... 

Several phase I and II studies have been completed in humans (24-26). Daily oral administration with doses ranging from 50 mg to 700 mg on 14 of 28 consecutive days or continuous administration for 28 days was examined. With intermittent repeated daily dosing, a median half-life was estimated at 46-49 h allowing for once daily dosing (24, 25), with a mean Cmax of 0.1-2.2 ng/ml (24). In combination with paclitaxel and carboplatin (27), 500 mg per day of ZD 1839 was found to be safe with no change in the pharmacokinetics of either. ZD 1839 resulted in partial responses in NSCLC and prostate cancer, and stable disease (>4 months) in several patients with various tumor types (24-26). Five of 23 Japanese patients... 

Morikawa N, Mori T, Abe T, Kawashima H, Takeyama M, Hori S (1999) Pharmacokinetics of etoposide and carboplatin in cerebrospinal fluid and plasma during hyperosmotic disruption of the blood brain barrier and intraarterial combination chemotherapy. Biol Pharm Bull 22 428-431. 

E. Chatelut, A. V. Boody, B. Peng, et al.. Population pharmacokinetics of carboplatin in children. Clin Pharmacol Ther 59 436-443 (1996). 

Shen, M., Schilder, R.J., Obasaju, C., and Gallo, J.M. Population pharmacokinetic and limited sampling models for carboplatin administered in high dose combination regimens with peripheral blood stem cell support. Cancer Chemotherapy and Pharmacology 2002 50 243-250. 

---