Dose-toxicity relationship of carboplatin in combination with cyclophosphamide in ovarian cancer patients

Sørensen, Betina Bang; Strömgren, Annette S; Jakobsen, Preben; Jakobsen, Anders

doi:10.1007/bf00685696

Cited by 40 publications

(13 citation statements)

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“…The Calvert formula was designed to accurately predict the carboplatin AUC based on renal function and has demonstrated good correlation with the measured plasma carboplatin AUC in some, 17,14 but not in all studies. 29,30 The…”

Section: Discussionmentioning

confidence: 99%

“…6,[9][10][11] The relatively simple pharmacokinetics of carboplatin suggest that drug exposure measured by the area under the plasma concentration vs time curve (AUC) correlates closely with renal function, 8,[12][13][14] and that toxicities may be more accurately predicted when the dose is determined not on the patient's body surface area (BSA), but by achieving a specific carboplatin AUC. 5,8,15,16 A dosing equation based on pre-treatment renal function as assessed by glomerular filtration rate (GFR) has been designed by Calvert and colleagues13 where the carboplatin dose (mg) = AUC (mg/ml Ϫ1 min) ϫ (GFR (ml/min) + 25).…”

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confidence: 99%

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High-dose carboplatin and regimen-related toxicity following autologous bone marrow transplant

Colby

Koziol

McAfee

et al. 2002

Bone Marrow Transplant

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Summary:Pharmacokinetic analysis of carboplatin dosing suggests a more accurate prediction of toxicity when the dose is based on the area under the plasma concentration vs time curve (AUC) instead of body surface area (BSA). We retrospectively calculated the carboplatin AUC of 117 patients who received an autologous stem cell transplant following a conditioning regimen consisting of carboplatin 1800 mg/m 2 and cyclophosphamide 6000 mg/m 2 to identify whether higher carboplatin exposure resulted in an increase in regimen-related non-hematologic toxicities. The most common non-hematologic toxicities were gastrointestinal and hepatic. Twenty (17%) patients experienced additional уgrade 2 toxicity, specifically, renal toxicity significantly associated with a higher median AUC of 10.2 mg/ml ؊1 min (P = 0.001). Prior platinum therapy was also significantly associated with toxicity (P = 0.052). While carboplatin dose based on BSA varied minimally (median 990 (range 450-1340) mg, the calculated AUC showed a near four-fold range of exposure (median 7.8 (range 3.6 to 13.8) mg/ml ؊1 min). These data suggest a relationship between nonhematologic adverse events and the estimated AUC. Prospective trials will be necessary to identify the target carboplatin AUC which optimizes outcome and minimizes toxicity in the autologous transplant setting.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

High-dose carboplatin and regimen-related toxicity following autologous bone marrow transplant

Colby

Koziol

McAfee

et al. 2002

Bone Marrow Transplant

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“…The activity and toxicity of cisplatin and carboplatin depend upon both pharmacokinetic and pharmacodynamic factors. A number of clinical pharmacokineticpharmacodynamic relationships have been described for cisplatin (Campbell et al, 1983; Reece et al, 1987;Thomas et al, 1994) and carboplatin (Egorin et al, 1984;Newell et al, 1987Newell et al, , 1993Harland et al, 1991;Horwich et al, 1991;Sorensen et al, 1991;Jodrell et al, 1992), and interpatient variability in tumour response to and/or tolerance of platinum (Pt)-complex therapy may relate to plasma levels more closely than to dose. Therefore optimum treatment with Pt drugs may necessitate adjustment for interindividual pharmacokinetic differences.…”

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confidence: 99%

Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

Peng

Tilby²,

English³

et al. 1997

Br J Cancer

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Summary Platinum (Pt)-DNA adducts were measured in peripheral blood leucocytes (PBLs) from 24 children with solid tumours after standard cisplatin and/or carboplatin treatment. The relationship between Pt-DNA adduct levels and pharmacokinetics of cisplatin and carboplatin was investigated. Adduct measurements were performed by competitive enzyme-linked immunosorbent assay (ELISA) and plasma unbound Pt concentrations were measured by atomic absorption spectrophotometry (AAS). There was considerable interindividual variation in Pt-DNA adduct level that was weakly correlated (r 2 = 0.32) with the area under the unbound drug concentration vs time curve (AUC) at 6 h after the start of cisplatin infusion, indicating that the variation in Pt-DNA adduct levels was primarily determined by factors other than AUC. No clear relationship between AUC and adduct levels was seen at 24 and 48 h after cisplatin or at 6, 24 or 48 h after carboplatin. Carboplatin produced lower levels of immunoreactive adducts than did cisplatin (1.3±0.6 nmol Pt g-1 DNA vs 3.2 ± 1.7 nmol Pt g-' DNA), despite a 20-fold higher unbound drug AUC for carboplatin (8.0 ± 3.5 mg ml-' min vs 0.4 ± 0.2 mg ml-' min). This study demonstrates that, after cisplatin and carboplatin treatment the drug-target interaction is determined by both pharmacokinetic and, predominantly, cellular factors. Intrinsic differences between the two complexes, primarily reactivity, probably explain the lower adduct levels observed after carboplatin treatment.Keywords: cisplatin; carboplatin; Pt-DNA adduct; pharmacokinetics; child cancer Cisplatin and carboplatin are widely used in the treatment of solid tumours in childhood (Pinkerton et al, 1986;Pearson et al, 1992;Doz and Pinkerton, 1994). The activity and toxicity of cisplatin and carboplatin depend upon both pharmacokinetic and pharmacodynamic factors. A number of clinical pharmacokineticpharmacodynamic relationships have been described for cisplatin (Campbell et al, 1983;Reece et al, 1987;Thomas et al, 1994) and carboplatin (Egorin et al, 1984;Newell et al, 1987Newell et al, , 1993Harland et al, 1991;Horwich et al, 1991;Sorensen et al, 1991;Jodrell et al, 1992), and interpatient variability in tumour response to and/or tolerance of platinum (Pt)-complex therapy may relate to plasma levels more closely than to dose. Therefore optimum treatment with Pt drugs may necessitate adjustment for interindividual pharmacokinetic differences. Renal function-based dosing formulae have been developed for carboplatin administration to children (Marina et al, 1993;Newell et al, 1993;Chatelut et al, 1996) because carboplatin is cleared primarily by glomerular filtration.Although pharmacokinetics is one determinant of the clinical efficacy of Pt complexes, intracellular factors are certain to play an additional role. Pt complexes exert their anti-tumour effect by reacting with DNA (Roberts and Thomson, 1979;Sherman and Lippard, 1987;Fichtinger-Schepman et al, 1995 (Poirier et al, 1982;Fichtinger-Schepman et al, 1985;Terheggen et al, 1988; Tilby...

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“…v Usefulness regardless of previous or concurrent therapy [25], and v High association between target AUC values and manageable thrombocytopenia [4,17,20,23,26].…”

Section: Individualized Dosingmentioning

confidence: 99%

New Perspectives on an Old Friend: Optimizing Carboplatin for the Treatment of Solid Tumors

Alberts

Dorr

1998

The Oncologist

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Background. Since its clinical introduction in 1981, carboplatin has proved a feasible alternative to cisplatin for the treatment of many solid tumors, especially ovarian cancer. Because the pharmacokinetics and, ultimately, the pharmacodynamics of carboplatin are highly dependent on the status of renal function, fixed dosing based on body surface area has led to carboplatin overdosing or, especially, underdosing. This has resulted in less than optimal treatment results compared with cisplatin in a variety of solid tumor types. Only in the past few years has the optimal dosing method for carboplatin—individualizing the dose (area under the concentration‐versus‐time curve [AUC]) rather than conventional use of body surface area—been adopted by clinical oncologists. Methods. An extensive review of the oncology literature has been performed to update both carboplatin dosing guidelines as well as its present role in solid tumor chemotherapy. Initial efforts to devise a dosing formula for carboplatin focused on reducing myelotoxicity (especially thrombocytopenia). Subsequently, a simple formula was developed to adjust the carboplatin dose according to renal function. By targeting a carboplatin AUC rather than empirically dosing according to body surface area, doses of carboplatin can be individualized to fall within the drug's therapeutic index. Results. The use of carboplatin dosing guidelines based on renal function has led to optimization of its pharmacodynamic effects both with respect to its safety profile and its ultimate impact on solid tumor response and patient survival. Since carboplatin has little neurotoxicity, it has become the platinum agent of choice in combination with paclitaxel for therapy of previously untreated ovarian cancer. Carboplatin plus etoposide and carboplatin plus paclitaxel have been studied in phase II and III trials, with the latter combination demonstrating improved activity against advanced non‐small cell lung cancer. Additional trials in patients with other solid tumors have shown that carboplatin is more cost‐effective and less toxic than cisplatin. Conclusions. Dosing based on renal function and a targeted serum AUC, rather than on body surface area, has resulted in the optimal utilization of carboplatin in cancer chemotherapy. Its predictable toxicity and clinical efficacy equivalent to cisplatin make carboplatin the drug of choice for selected tumor types.

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Dose-toxicity relationship of carboplatin in combination with cyclophosphamide in ovarian cancer patients

Cited by 40 publications

References 8 publications

High-dose carboplatin and regimen-related toxicity following autologous bone marrow transplant

High-dose carboplatin and regimen-related toxicity following autologous bone marrow transplant

Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

New Perspectives on an Old Friend: Optimizing Carboplatin for the Treatment of Solid Tumors

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