Gene Ther Mol Biol Vol 16, 227-233, 2014

Gene Ther Mol Biol Vol 16, 227-233, 2014

Gene Therapy and Molecular Biology Vol: 16, page 1

Gene TherMolBiolVol 17, 42-41, 2015

Pharmacokinetic analysis of carboplatin in two patients receiving hemodialysis

Case report

Loeffler M.1*, Wehrli S.2, Rippin SJ.2, Widmer S.3, Fischer N.1

1Department of Medical Oncology, Kantonsspital Winterthur, Switzerland

2Department of Nephrology, Kantonsspital, Winterthur, Switzerland

3Hospital Pharmacy, Kantonsspital Winterthur, Switzerland

**Correspondence:Loeffler M., MD, Departement of Oncology/Hematology, Kantonsspital Aarau, Switzerland, Telephone: +41 (0)62 838 6053, Fax: +41 (0)62 838 6052, Email: 7809

Keywords:lung cancer, carboplatin, hemodialysis, pharmacokinetics

Received: 8 January 2015; Revised: 27 January 2015

Accepted: 20 March 2015; electronically published: 13 May 2015


Platinum-based chemotherapy in patients with end-stage renal disease managed with hemodialysis is still challenging and the evidence base in the literature is limited. We investigated the pharmacokinetics of Carboplatin during hemodialysis in two patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD) and diagnosed with lung cancer; small-cell in one case and non-small cell in the other. In case 1 small cell lung cancer was treated with a dose of 250mg/m2 followed by a dose of 280mg/m2 of Carboplatin in combination with 50mg/m2 of Etoposide. In case 2 stage III B NSCLC was treated in curative intent with a dose of 280mg/m2 followed by a dose of 225 mg/m2 with concurrent radiotherapy with 60 Gy. HD was initiated 60 minutes after Carboplatin administration and continued for a period of 4 h. Pharmacokinetic assessments were carried out at the end of the Carboplatin infusion and then every hour until 1 hour after the end of HD, as well as at the beginning and the end of the two following dialysis treatments on days 3 and 5. The respective areas under the curve (AUC) were 4.8 mgmin/ml and 6.6 mgmin/ml (patient 1) and 6.2 mgmin/ml and 6.4 mgmin/ml (patient 2). Hematological- and non-hematological adverse events were moderate. In summary, the safety and efficacy of Carboplatin-based chemotherapy in patients with ESRD undergoing HD were demonstrated. Carboplatin-based chemotherapy can therefore be regarded as a therapeutic option for the treatment of chemosensitive malignant tumors in patients with end-stage renal disease.


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I. Introduction:

The incidence and prevalence of end-stage renal disease (ESRD) requiring dialysis continues to rise around the world. In comparison to the general population, the risk of cancer in patients with ESRD is increased (Maisonneuve et al, 1999). Both the prognosis of patients with ESRD on dialysis and oncological treatment options are continually improving. Carboplatin is used in oncology to treat a variety of malignancies. Compared to Cisplatin, it has a better toxicity profile without dose limiting nephro-, neuro- and ototoxicity, at the expense of increased hematological toxicity.

Carboplatin has a linear pharmacological profile with extensive renal filtration and tubular secretion but no tubular reabsorption (Duffull S, Robinson B, 1997). The dose can be calculated based on renal function by means of the Calvert formula. Thus Carboplatin can be used in patients with chronic kidney disease and ESRD. Due to the low initial binding rate to plasma proteins, Carboplatin can be removed by hemodialysis during the early period after dosing (Go RS., Adjei AA, 1999). To improve our knowledge of the pharmacokinetics and tolerability of Carboplatin in this situation we analyzed the area under the curve (AUC) of Carboplatin and side effects of treatment in two consecutive patients with lung cancer and ESRD on hemodialysis (HD).

II. I. Patients and methods

II.A. Patients

Two patients with ESRD undergoing HD three times a week were treated with Carboplatin-based chemotherapy. The dose of Carboplatin and the timing of HD were selected on the basis of previous reports (Inoue et al, 2004, Yanagawa et al, 1996, Haraguchi et al, 2005, Takezawa et al, 2008). Patient 1 received Carboplatin in combination with Etoposide, patient 2 in combination with radiotherapy. Carboplatin was administered intravenously over 30 minutes in 250 ml of a 5% glucose solution. HD was started 60 minutes after the end of Carboplatin administration.

II.B. Hemodialysis

Nikkiso DBB-05 machines and a highfluxpolynephronTM dialyzer (ELISIOTM-19H, surface area 1.9 m2, NIPRO Medical Corporation, Osaka, Japan) were used. The hemodiafiltration option was not activated. Blood flow was set individually between 400 und 450 ml/min. Dialysate flow was set between 500 and 600 ml/min. HD was applied for four hours three times per week. Fluid removal was programmed individually for each patient according to the desired dry weight. Low molecular weight heparin was used as anticoagulant. The administration of darbepoetin alpha for renal anemia was continued throughout the chemotherapy.

II.C. Pharmacokinetic analysis

Serial blood samples were collected for pharmacokinetic analysis during the first two cycles of chemotherapy in both patients, starting at the end of the Carboplatin infusion and then every hour until 1 hour after the end of HD. Further Carboplatin measurements were taken at the beginning and the end of the two following


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dialysis treatments on day 3 and 5 (patient 1: cycle 2, patient 2: both cycles). The blood samples were centrifuged at 3000 rpm for 10 minutes und analyzed for total platinum concentration by inductive coupled plasma mass spectroscopy.


Gene Therapy and Molecular Biology Vol: 16, page 1

III. Results

III.A. Case 1

A 69 year old patient, with ESRD due to chronic glomerulonephritis, requiring chronic HD since 2008, presented with a FDG positive mass in the left upper lobe, mediastinal and supraclavicular lymph node metastases as well as an ipsilateral pleural FDG-positive satellite metastasis (cT3cN3M1, stage IV). Histopathological analysis of the supraclavicular lymph node revealed small cell lung cancer (SCLC). The patient was treated with four cycles of combination chemotherapy with Carboplatin on day 1 and Etoposide on day 1-3 every 21 days. The initial dose of Carboplatin in the first cycle was 250mg/m2 und the dose of Etoposide 50mg/m2, based on the recommendations of previous studies (Inoue et al, 2004, Yanagawa et al, 1996, Haraguchi et al, 2005, Takezawa et al, 2008).

Based on the results of the Carboplatin measurements, the dose was increased to 280mg/m2 in the second cycle. The patient had to be hospitalized in the first cycle due to bilateral pneumonia without neutropenia. In addition, WHO grade 2 anemia und grade 2 alopecia occurred. Pretreatment and nadir blood counts are shown in table 1. Neither erythrocyte, platelet transfusions, nor G-CSF treatment were necessary at any time. Complete remission (CR) was demonstrated after two cycles of chemotherapy. Four cycles were administered in total, followed by prophylactic whole brain radiotherapy. 17 months after the initiation of chemotherapy the patient’s tumor remains in complete remission.

III.B. Case 2

Whilst evaluating a respiratory tract infection, a mass was detected in a 73-year old woman with ESRD due to secondary focal and segmental glomerulosclerosis, requiring chronic HD since 2012. PET-CT revealed a tumor in the right upper lobe with bilateral mediastinal lymphadenopathy, as well as a pathological lymph node in the right supraclavicular region. Cytological analysis showed adenocarcinoma with an EGFR mutation in Exon 18 (p.G724S). This stage IIIB non-small cell lung cancer (NSCLC) was treated with curative intent with combined radiochemotherapy with 60 Gy and concurrent Carboplatin (two cycles q3w). On the basis of the results of the Carboplatin measurements in Case 1, in whom the intended AUC 5-6 could only be reached after increasing the dose from carboplatin 250 mg/m² to 280 mg/m², the starting dose of Carboplatin in the first cycle was set to 280mg/m2. Due to grade 2 thrombocytopenia, the second cycle was given at a reduced dose of 225 mg/m2 (80% of the starting dose).

Non-hematological toxicity was mild. A minimal response of the primary tumor and mediastinal lymphadenopathy was achieved. Four weeks after the last administration of chemotherapy the patient had to be hospitalized due to pneumonia. No pathogen was identified. Two months after the end of radiochemotherapy, bilateral pulmonary dissemination was found and palliative therapy was initiated with Erlotinib. Due to poor drug tolerance, particularly gastrointestinal side effects, the dose had to be gradually reduced. After two months progressive disease was found. The patient died five months later.

III.C. Pharmacokinetic data

The total platinum concentrations (Cmax) in the plasma at the end of Carboplatin administration was 14-22 mg/l and 11-12 mg/l at the initiation of HD. Figure 1 shows the total plasma concentration of Carboplatin for each patient. In the first cycle, the area under the curve (AUC) was 4.8 mgmin/ml and 6.2 mgmin/ml for patients 1 and 2 respectively. After increasing the dose from 250 mg/m2 to 280mg/m2 in cycle 2 for patient 1, the AUC was found to be 6.6 mgmin/ml. After dose reduction, the AUC for patient 2 was 6.4 mgmin/ml.

IV. Discussion

Management of patients on HD poses very difficult problems if they require cytotoxic chemotherapy. It is currently not clear how best, if at all, to choose the dose of Carboplatin in these patients. So far the evidence is restricted to several case reports. The majority of these case reports have been conducted with Asian patients and also with significantly lower doses of Carboplatin (100- 115mg/m², 100-125mg total) (Motzer et al, 1990; Oguri et al, 2010; Fong et al, 2013) compared to patients with normal renal function. In some case reports a higher Carboplatin dose of 250-300mg/m² was administered, but HD was started earlier, at 0.5-1h after the end of the carboplatin administration (Inoue et al, 2004, Yanagawa et al, 1996, Haraguchi et al, 2005, Takezawa et al, 2008). In these cases the overall toxicity was moderate (Takezawa et al, 2008; Yangawa et al, 1996). Except in the report of Inoue two thirds of the patients suffered grade 3 or 4 hematotoxicity with an initial dose of Carboplatin 300 mg/m2, after subsequent dose reduction of Carboplatin from 300 mg/ m² to 250mg/m2 hematotoxicity was only moderate. In addition, information on the resulting AUC is, up to now, only limited (Takezawa et al, 2008). Carboplatin is not avidly protein bound initially, but it becomes largely protein bound by 24 hours (Egorin et al, 1984). This affects the amount of Carboplatin that is cleared by HD, given that protein bound Carboplatin is not easily dialyzable (Achuta et al, 2014). Due to the kinetics of Carboplatin protein binding we decided to initiate HD one hour after completion of Carboplatin administration and, given the good tolerance and absence of severe hematological side effects reported with 250 mg/ m² of Carboplatin in previous case reports, to start with 250 mg/ m² of Carboplatin. Because of the subtherapeutic AUC of 4.8 mgmin/ml with 250 mg/m2 of Carboplatin in cycle 1, with a target of AUC of 5-6 mgmin/ml, the dosage for patient 1 in cycle 2 was increased and the initial dose for patient 2 in cycle 1 was adjusted as well.

With the doses of Carboplatin chosen for our patients, 225mg/m² and 280 mg/m² respectively, an AUC of 4.8-6.6 mgmin/ml was achieved. This AUC is within the range of the designated dose for patients with normal renal function. The overall toxicity, and especially the resulting myelotoxicity, was moderate.

In patient 1 the increased dose in cycle 2 resulted in a corresponding increase of the AUC. However, in patient 2, despite a dose reduction to 225mg/m² in the 2nd cycle, a higher AUC was observed than in the previous cycle. The cause for this increase is not completely clear. Although the duration of HD was not modified, the blood flow was inadvertently set at only 200 ml/min for approximately the first 45 minutes of treatment. It is possible that the lower blood flow contributed to the higher AUC in spite of the dose reduction. Comedication was not different during the second cycle.

A pharmacokinetic analysis of the measured plasma concentration over the whole time was performed. On the one hand, the calculated t1/2 of free platinum in different phases after infusion were compared to t1/2 values in renal healthy people (table 2). The t1/2 before the first dialysis is longer in patient 1 than in renal healthy people resp. in patient 2 similar to values in renal healthy people. During the first dialysis we have a t1/2 of 1.12-1.13 hours (patient 1) and 1.2-1.4 hours (patient 2), respectively, which is shorter than in renal healthy people (t1/2 of approximately 3 hours (ArzneimittelkompendiumSchweiz, 2015)). After the first dialysis we found a t1/2 of 3.3-7.2 days. This is in a similar range to the t1/2 of protein-bound platinum in renal healthy people. On the other hand, a logarithmic plasma concentration curve was compared to the curve of a renal healthy people (Mulder et al, 1990). Our two patients reach a plateau (5 hours after infusion) after the first dialysis session. Renal healthy people reach a similar plateau, but at some hours later (Mulder et al, 1990). The total clearance of platinum is in the range of 34-52 ml/(min*m2). Compared to the clearance of free platinum 79 ± 23 ml/(min*m2) in the study of Mulder et al. in renal healthy people, we achieved a somewhat lower clearance values of platinum. The decrease in plasma concentration in the period of the first dialysis is a little bit faster than in renal healthy people. According to the clinical efficacy and the side effects of the therapy, we conclude that we chose an appropriate strategy. To further evaluate the pharmacokinetic data and especially calculate the dialysis clearance of carboplatin more blood samples and measurement of the eliminated platinum in the dialysis solution would have been necessary. Unfortunately these data have not been collected which is a weakness of this report.

Etoposide is metabolized in the liver and excreted via feces, bile and 44-60% through the kidney as unchanged drug and metabolites (BC Cancer Agency (BC)). Due to high plasma protein binding, removal of Etoposide by HD is very unlikely. For this reason, a measurement of the Etoposide plasma level was not carried out (English et al, 1998). In compliance with recommendations the dose was reduced by about 50% to 50mg/m² (BC).

In summary, the safety and efficacy of Carboplatin-based chemotherapy in patients with ESRD undergoing HD were demonstrated. Carboplatin-based chemotherapy can therefore be regarded as a therapeutic option in the treatment of chemosensitive malignant tumors, in patients with ESRD – a patient group which is otherwise often not treated at all, or only insufficiently because of the ESRD.


We are grateful Labor Limbach Heidelberg, Germany for measurement of Carboplatin concentrations and to Dr. Jonathan Rippin and Prof. MiklosPless for proofreading the manuscript.

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