Carboplatin

Typical dose/schedule lOOmgm i.v. q 3-4 weeks or 20 mg m daily for 5 days, q 3-4 weeks 400mgm i.v. q 3-4 weeks 

Major toxicities Nephrotoxicity Severe nausea and vomiting Neurotoxicity (peripheral neuropathy) Ototoxicity (tinnitus/hearing loss) M yelosuppression (mainly thrombocytopaenia) 

Numerous clinical trials have demonstrated that carboplatin is substantially less toxic (especially in terms of nephrotoxicity and gastrointestinal effects see Table 1) than is cisplatin. Overview analyses of randomised studies comparing the activity of cisplatin versus that of carboplatin (mainly in ovarian and testicular cancers) have concluded that the two are broadly comparable in terms of response rates and disease-free intervals. However, it also appears that the two drugs are effective against the same population of tumours and thus share cross-resistance with one another. Notably, however, secondary responses to 

While some have advocated replacing cisplatin with the less toxic carboplatin as first-line treatment for all patients with ovarian tumours, this issue remains contentious, both with respect to cost and because many of the randomised studies of cisplatin versus carboplatin are still, in the context of clinical trials, in relatively early stages without long-term follow up. 

The three major conclusions from these clinical trials are  

The role of metal speciation in bleomycin uptake and cytotoxicity has been studied extensively. The relatively high amounts of copper in the blood, however,suggest that exogenous or endogenous metals in the blood do not markedly alter the uptake or activity of bleomycin. Nonetheless, a number of other metals can bind to bleomycin including indium and cobalt, and formulating bleomycin with these ex vivo can significantly reduce the cytotoxicity of bleomycin (Lyman et al. 1986). Complexes of this type have been used, however, to examine tumor cell uptake of bleomycin compounds. 

Doxorubicin and other anthracyclines, such as daunorubicin, are believed to exhibit their antineoplastic activity through inhibition of topoisomerase II activity. This appears to occur in the absence of significant metal binding by the anthracyclines. Doxorubicin can, however, bind with iron(III) and this results in the formation of a redox-active complex that may cause untoward effects (Myers et al. 1986). Doxorubicin-iron(III) complexes have been shown to oxidatively damage membranes and inactivate protein kinase C, but the biological signficance of this is not well understood (Hannun et al. 1989). 

Cisplatin and a new analog carboplatin are coordinated complexes of platinum, which exhibit significant clinical antitumor activity as single agents and 

---

A.n log ue Synthesis. Two notable examples, in which analogues have greater therapeutic indexes than the parent dmgs, have been identified in Phase I trials. These are carboplatin (29) and ado2elesin (37) (35). Carboplatin s approval was based on its comparable efficacy to cis-platinum (28) and its more favorable toxicity profile, ie, reduced and delayed episodes of emesis, reduced ototoxicity, etc. On the other hand, ado2elesin, a totally synthetic analogue of natural product CC1065, has demonstrated a similar potency and antitumor activity profile as its natural prototype but is devoid of the delayed death UabiUty associated with the parent dmg in animals (36). 

Carboplatin (96) is significantly less toxic in the clinic than cisplatin. Most particularly, it is much less nephrotoxic. Use of a bidentate ligand also ensures formation of a ds complex. Its synthesis begins with cis-diammine platinum diiodide (94) which is reacted with silver sulfate to give cis-diaquodiam mine platinum sulfate (95). This is reacted with the barium salt of 1,1-cyclo-butanedicarboxylic acid to yield carboplatin [23],... 

The platinum(IV) compound that has shown most promise is carboplatin (paraplatin), which received FDA approval in 1990. Features to note in its structure are the use of hydroxy and carboxylate groups to improve water solubility. As noted above, the ammine ligand has been found to need at least one hydrogen, possibly for hydrogen-bonding to phosphate groups in the DNA (Figure 3.116). 

Carboplatin displays less nephro-, oto- and neurotoxicity. However, myelosuppression is more frequent, and as the drug is exclusively cleared through the kidney, adjustment of dose for creatinine clearance must be accomplished. 

Other subgroups of alkylating agents are the nitrosoureas (examples carmustine, BCNU lomustine, CCNXJ) and the triazenes (example dacarbazine, DTIC). Platinum derivatives (cisplatin, carboplatin, oxaliplatin) have an action that is analogous to that of alkylating agents (formation of crosslinks) and therefore are appended to this class, as well. 

Bis(dicyclohexylammonium) bis(2,6-pyridinedicarboxylato)dibutylstannate is concluded to have sevenfold coordination at the Sn on the basis of its Sn CP/ MAS NMR chemical shift ((5 = —424.9 ppm). The assignment has been corroborated by crystal structure determination of its monohydrate, in which the Sn atom has frflMS-C2SnN04 PBP geometry (Sn-C = 204.0,206.7pm, C-Sn-C = 168.9°). One 2,6-pyiidinedicarboxylato group chelates to the Sn atom (Sn-O = 223.4,226.0 pm Sn-N = 227.9 pm), whereas the other binds through only one carboxyl end (Sn-O = 241.6, 244.1pm). The anhydrous compound displays higher in vitro antitumor activity than those of cisplatin and carboplatin (Table 7). ... 

Cl2H(,N2Pt 15663-27-1) see Carboplatin Nedaplatin ds-3,3,5-trimethylcyclohexyl ( )-mandelate (C,7H240i) see Micinicate citric acid... 

Platinum is used therapeutically as ds-platin, carboplatin and iproplatin against tumors (Konig and Schuster 1994). Determination of Pt in serum must be carried out after enrichment procedures followed by GF-AAS. 

A. Pampel, R. Reszka, D. Michel 2002, (Pulsed field gradient MAS NMR studies of the mobility of carboplatin in cubic liquid crystalline phases), Chem. Phys. Lett. 357, 131-136. 

Aminoglycosides, amphotericin B, carboplatin, cisplatin, foscamet, and intravenous contrast dyes... 

Other drugs that are commonly implicated in causing ARF include acyclovir, adefovir, carboplatin, cidofovir, cisplatin, foscarnet, ganciclovir, indinavir, methotrexate, pentamidine, ritonavir, sulfinpyrazone, and tenofovir.45... 

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... 

JP is receiving a highly myelosuppressive chemotherapy regimen for the next 3 days for his lymphoma. The chemotherapy orders specify ifosfamide, carboplatin, and etoposide. The goal of this cycle of chemotherapy is to put the cancer into remission so that his lymphoma can be cured with a bone marrow transplant. 

Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage Prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989 7( 11) 1748-1756. 

Non-Small Cell Raclitaxel-carboplatin- Diarrhea, fever, headache, hypertension, hemoptysis, infection, High (day 1 only)... 

CAV, cyclophosphamide, doxorubicin, vincristine EC, etoposide carboplatin EP, etoposide cisplatin IC, irinotecan, cisplatin. See Table 87M for doses and schedules. 

---