Laurence J. C. van Warmerdam

Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ringopened hydroxy acid, is essential for this activity. The open form predominates at physiological pH. We performed a pharmacokinetic, study as part of a phase I study in patients with various types of solid tumors, where topotecan was administered in a 30-min infusion daily on 5 consecutive days every 3 weeks. The plasma kinetics of topotecan could be described best using an open two-compartment model with t1/2(α) and t1/2(β) of 8.1 (range 0.3 to 40.7) min and 132 (range 49 to 286) min, respectively. The plasma concentration-time profiles of the metabolite, however, could be described using a one-compartment model with t1/2(formation) of 29.0 (range 5.6–99.5) min and t1/2 (elimination of 123.2 (range 32–265) min, respectively. The lactone was the predominate form during the first hour from the start of infusion, but was rapidly converted into its ring-opened structure. The elimination rate of topotecan was independent of the dose. There were linear relationships between the dose (mg m−2 day−1), the area under the plasma concentration versus time curve (AUC) of topotecan and its metabolite, the total AUC, peak plasma lactone concentrations, and the time period that the topotecan concentrations remained above 10 nM. Different models were used to correlate pharmacokinetic and pharmacodynamic parameters. The percentage decrease in absolute neutrophil count (ANC) was related to these parameters and plots were well fitted by linear and sigmoidal Emax models.

Evaluation of formulas using the serum creatinine level to calculate the optimal dosage of carboplatin.

Carboplatin is a chemotherapeutic agent frequently used in the treatment of various malignancies. An individual dosing strategy has been recommended to yield the most optimal exposure, expressed as the area under the concentration-time curve (AUC). The formula developed by Calvert et al. (dose = target-AUC × [GFR+25]) can be used to achieve this. However, due to the inconvenient [51Cr]-ethylenediaminetetraacetic acid ([51Cr]-EDTA)-based measurement of the glomerular filtration rate (GFR), its application in the clinic has thus far been limited. Chatelut and coworkers have recently proposed a formula to estimate carboplatin clearance using the serum creatinine concentration. We retrospectively tested the Chatelut equation and the Calvert formula using either the creatinine clearance based on 24-h urine collection or the creatinine clearance based on the formula of Cockcroft and Gault. The latter equations were shown to predict the carboplatin clearance reasonably well, although systematic overprediction and underprediction occurred. However, the formula proposed by Chatelut and co-workers had no significant bias and was precise. It is proposed that this formula be used to calculate the optimal carboplatin dosage after prospective validation has been performed.

Bioequivalence of Liposome-Entrapped Paclitaxel Easy-To-Use (LEP-ETU) formulation and paclitaxel in polyethoxylated castor oil: a randomized, two-period crossover study in patients with advanced cancer.

BACKGROUND Preclinical studies comparing paclitaxel formulated with polyethoxylated castor oil with the sonicated formulation of liposome-entrapped paclitaxel (LEP) have demonstrated that LEP was associated with reduced toxicity while maintaining similar efficacy. Preliminary studies on the pharmacokinetics in patients support earlier preclinical data, which suggested that the LEP Easy-to-Use (LEP-ETU) formulation and paclitaxel formulated with castor oil may have comparable pharmacokinetic properties. OBJECTIVES Our objectives were: (1) to determine bioequivalence of paclitaxel pharmaceutically formulated as LEP-ETU (test) and paclitaxel formulated with castor oil (reference); and (2) to assess the tolerability of LEP-ETU following intravenous administration. METHODS Patients with advanced cancer were studied in a randomized, 2-period crossover bioequivalence study. Patients received paclitaxel 175 mg/m(2) administered as an intravenous infusion over 180 minutes, either as a single-treatment cycle of the test formulation followed by a single-treatment cycle of the reference formulation, or vice versa. RESULTS Thirty-two of 58 patients were evaluable and were included in the analysis for bioequivalence. Mean total paclitaxel Cmax values for the test and reference formulations were 4955.0 and 5108.8 ng/mL, respectively. Corresponding AUC0-∞ values were 15,853.8 and 18,550.8 ng·h/mL, respectively. Treatment ratios of the geometric means were 97% (90% CI, 91%-103%) for Cmax and 84% (90% CI, 80%-90%) for AUC0-∞. These results met the required 80% to 125% bioequivalence criteria. The most frequently reported adverse events after LEP-ETU administration were fatigue, alopecia, and myalgia. CONCLUSION At the studied dose regimen, LEP-ETU showed bioequivalence with paclitaxel formulated with polyethoxylated castor oil.

Validation of a limited sampling model for carboplatin in a high-dose chemotherapy combination

A limited sampling model for the estimation of the carboplatin area under the concentration versus time curve (AUC), as developed by Sørensen et al., was validated prospectively for the use in a high-dose combination chemotherapy schedule. The model allows an estimation of the AUC on the basis of only one timed plasma drug concentration, sampled at exactly 2.75 h after a 1-h carboplatin infusion. Pharmacokinetic curves were obtained from nine patients receiving carboplatin (400 mg/m2 per day) combined with cyclophosphamide (1500 mg/m2 per day), thiotepa (120 mg/m2 per day), and mesna (3 g/day) for 4 consecutive days. Peripheral blood stem-cell transplantation (PBSCT) was performed 3 days later to restore hematopoiesis. Using this combination of high doses, the model proved to be unbiased (MPE −3.40%; SE, 1.22%) and highly precise [root mean squared prediction error (RMSE), 5.15%; SE, 0.17%] for estimation of the AUC during 4 consecutive days. The validated limited sampling model provides a starting point for future pharmacokinetic studies in a larger population of patients, which might lead to more insight into the relationships with the pharmacodynamic outcome of carboplatin and may help in achieving more rational dosing of patients on the basis of an AUC determination.

A single 24-hour plasma sample does not predict the carboplatin AUC from carboplatin-paclitaxel combinations or from a high-dose carboplatin-thiotepa-cyclophosphamide regimen

Purpose: It has been observed that the area under the free carboplatin concentration in plasma ultrafiltrate versus time curve (AUC) is related to toxicity and tumour response. For this reason, it can be important to measure the carboplatin AUC and subsequently adjust the dose to achieve a predefined target AUC. The use of limited sampling strategies enables relatively simple measurement and calculation of actual carboplatin AUCs. Methods: We studied the performance of a limited sampling model, based on a single 24-h sample (the Ghazal-Aswad model), in 52 patients who received carboplatin in two different chemotherapy regimens (a carboplatin-paclitaxel combination and a high-dose carboplatin-thiotepa-cyclophosphamide combination). Results: The measured mean AUC in our population was 4.1 min · mg/ml (median 3.9, range 1.9–6.3, SD 1.0 min · mg/ml). With the limited sampling model, the predicted mean AUC was 4.4 min · mg/ml (median 4.2, range 2.4–8.4, SD 1.2 min · mg/ml). Statistical analysis revealed that the model was slightly biased (MPE%, 6.5%), but imprecise (RMSE%, 20.6%) in our study population. Conclusion: Although easy and attractive to use, the Ghazal-Aswad formula is not precise enough to predict the carboplatin AUC, and needs to be evaluated prospectively in other patient populations.

A limited-sampling model for the pharmacokinetics of carboplatin administered in combination with paclitaxel

Purpose: Carboplatin doses are often determined by using modified Calvert formulas. It has been observed that the area under the concentration versus time curve (AUC) for free carboplatin is lower than expected when modified formulas are used for carboplatin/paclitaxel chemotherapy combination regimens. By using limited-sampling models, the carboplatin AUC actually reached can easily be verified, and the dose adjusted accordingly. Methods: In this report, we describe the development and validation of a limited-sampling model for carboplatin from 77 pharmacokinetic curves, when carboplatin is used in combination with paclitaxel. Results: The following single-point model was selected as optimal: AUC carboplatin (min mg−1 ml−1) = 418 · c2.5 h(mg/ml) + 0.43 (min mg−1 ml−1), where c2.5 h is the concentration (mg/ml) of carboplatin 2.5 h after the start of a 30-min infusion. This model proved to be unbiased (mean prediction error = 3.4 ± 1.6%) and precise (root mean square error = 10.1 ± 1.5%). Conclusions: The proposed model can be very useful for ongoing and future carboplatin/paclitaxel studies aimed to optimise and individualise treatment.

Carboplatin Dosage Formulae Can Generate Inaccurate Predictions of Carboplatin Exposure in Carboplatin/Paclitaxel Combination Regimens

SummaryCarboplatin is a frequently used antitumour agent recommended to be administered according to the Calvert formula: dose = AUC × (GFR+25), where GFR is the glomerular filtration rate as measured by 51Cr-EDTA clearance and AUC is the targeted area under the carboplatin concentration versus time curve. In several modified Calvert formulae, the GFR is estimated on the basis of serum creatinine levels. We compared AUCs of carboplatin that were predicted by modified Calvert formulae with actual measured AUCs in 75 courses in patients with non-small cell lung cancer or ovarian cancer who were treated with the combination of carboplatin-paclitaxel. Predictions were made using two modified Calvert formulae, in which the GFR was calculated by serum creatinine level-based equations, according to Jelliffe (Eq. 1) and Cockroft-Gault (Eq. 2). We also studied the performance of a formula for the clearance of carboplatin, as proposed by Chatelut (Eq. 3). The actual measured mean AUC was 4.6 mg/ml·min (range 1.9 to 10.4 mg/ml·min, SD 1.7). Equation 1 overestimated the AUC by 32.9% with an imprecision of 43.0%, and equation 2 overestimated the AUC by 27.6% with an imprecision of 33.4%. For equation 3, an AUC overestimation of only 10.2%, but with an imprecision of 25.3%, was observed. In conclusion, all three equations overestimated the carboplatin AUCs and had poor precisions. We concluded that the real carboplatin AUCs were lower than calculated, using the three tested formulae. This may have important consequences for ongoing and future phase II and III studies with carboplatin-paclitaxel combinations, utilising these formulae to calculate the carboplatin dose. Thus far, the original Calvert dosage formula remains the ‘golden standard’.

Capecitabine-Induced Pancreatitis

Capecitabine is an oral pro-drug of fluorouracil, which is a commonly used cytotoxic drug in the treatment of colorectal carcinoma. Many adverse effects are known to occur with capecitabine including diarrhea, palmar-planter erythrodysesthesia and nausea. We report a case of capecitabine-induced pancreatitis, also occurring with re-challenge. J Oncol Pharm Practice (2010) 16: 133—134.

Extravasation of topotecan, a report of two cases:

Objective. Extravasations of anticancer agents may give serious complications and specific therapy might be needed. Topotecan is a new cytotoxic drug and is used in many clinical studies. In our clinic two extravasations of topotecan occurred, and the clinical consequences are discussed. Clinical Features. The extravasations oc curred in two patients who were receiving topo tecan intravenously because of ovarian carcinoma stage III. The patients experienced some discom fort caused by the expansion of soft tissue. How ever, no serious complications were observed. Case Progress and Outcome. Both patients received all further courses of topotecan without any negative effects. Conclusion. In conclusion, besides stopping the injection, trying to aspirate the fluid, keeping the arm high, and cooling the swelling, we advise no specific measures to be taken after extravasa tion of topotecan.