Anders Jakobsen

A limited sampling method for estimation of the carboplatin area under the curve.

SummaryA limited sampling method for estimation of the carboplatin area under the curve (AUC) from one or two plasma concentration determination is presented. The model was conceived and developed using 43 pharmacokinetic studies in 15 patients with ovarian cancer (model data set) who received carboplatin in combination with cyclophosphamide. Linear regression analyses comparing the AUC and the drug concentration at a single time point (0.25–10 h after the end of the infusion) as calculated from the fitted exponential equations gave correlation coefficients as high as 0.97, with maximal correlations falling within the interval of 2–3.25 h. The model was validated prospectively in 9 patients with ovarian cancer (validation data set) who received the same treatment as did the model data set (21 pharmacokinetic studies), testing the equation AUC=0.52×C2.75h+0.92. Observed and estimated AUCs were correlated in the validation data set (r=0.91). The mean predictive error (MPE%±SE) was −4.4%±3.1% and the root mean squared error (RMSE%) was 13.9%. Multiple regression analysis revealed that adding a second sample drawn at 0.25 h (AUC=0.053×C0.25h+0.401×C2.75h+0.628) improved the MPE% to −2.2%±2.1% and the RMSE% to 9.4% (r=0.96). We conclude that the carboplatin AUC can be estimated from a single plasma sample at 2.75 h or, more precisely, from two plasma samples at 0.25 and 2.75 h. The methods described may prove to be a handy tool for the calculation of approximate AUCs in trials of a size that would discourage detailed pharmacokinetic studies.

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

SummaryA study was undertaken to examine the relationships between carboplatins pharmacokinetic parameters and the myelotoxicity associated with its administration in combination with cyclophosphamide. An additional aim of the study was to test the applicability of the method proposed by Calvert et al. for calculation of the carboplatin dose to be used in the combination regimen. A total of 24 previously untreated ovarian cancer patients were given a combination of 250–500 mg/m2 carboplatin and 500 mg/m2 cyclophosphamide every 4 weeks for 4 months. The pharmacokinetics of carboplatin and the associated myelotoxicity were investigated in 64 courses. The results showed a significant correlation (r=0.89) between the AUC calculated for carboplatin and that predicted according to Calverts formula [carboplatin dose in milligrams=AUC (glomerular filtration rate +25)]. We conclude that the model is a useful guide in the calculation of the carboplatin dose to be given in combination with cyclophosphamide, and it enables a more precise prediction of the carboplatin exposure than does the conventional calculation, which is based on milligrams of drug per square meter of body surface. The AUC for carboplatin was a reliable predictor of the myelotoxicity as measured by the relative decrease in thrombocyte count. However, the relationship between AUC and myelotoxicity changed during the treatment because of increasing bone marrow toxicity. Despite this finding, dose calculation based on carboplatins AUC appears to provide an improvement in the clinical use of the drug, and the method also seems to be fully applicable in combination chemotherapy with cyclophosphamide.

Multiple-dose pharmacokinetics of epirubicin at four different dose levels : studies in patients with metastatic breast cancer

SummaryPharmacokinetic analysis of epirubicin and its metabolites epirubicinol and 7-deoxy-13-dihydro-epirubicinol aglycone during the first and the fourth courses of treatment was performed in 78 patients with metastatic breast cancer. The patients were treated every 3 weeks with epirubicin given as 10-min i.v. infusions at four different dose levels: 40, 60, 90 and 135 mg/m2. In most cases (76 of 78 cases), plasma concentration-time curves fitted to a three-compartmental pharmacokinetic model. The terminal half-life of epirubicin was independent of dose and duration of treatment. Large interindividual differences were demonstrated (meant1/2γ, 21.6±7.9 h; range, 10.6–69 h;n=110). In two subjects, extremely long half-lives and high serum bilirubin concentrations indicated impaired liver function. No correlation was found between the half-life and levels of liver alanine aminotransferase (ALAT) or serum creatinine. The metabolite epirubicinol appeared quickly after epirubicin administration and its half-lives were shorter than that of the parent compound (meant1/2γ, 18.1±4.8 h; range, 8.2–38.4 h;n=105).Formation of the aglycone metabolite was delayed and the half-life of this metabolite was shorter than that of epirubicin (meant1/2γ, 13±4.6 h; range, 2.7–29 h;n=104). The AUC of epirubicin and the total AUC (drug and metabolites) were linearly proportional to the dose, with the former value constituting two-thirds of the latter. A correlation was found between AUC and the plasma concentration of epirubicin at two time points (2 and 24 h after administration). The proposed model was AUC=9.44×c2+62.5×c24+157.7 (r=0.953).

DNA level and stereologic estimates of nuclear volume in squamous cell carcinomas of the uterine cervix. A comparative study with analysis of prognostic impact

Grading of malignancy in squamous cell carcinomas of the uterine cervix is based on qualitative, morphologic examination and suffers from poor reproducibility. Using modern stereology, unbiased estimates of the three‐dimensional, volume‐weighted mean nuclear volume (nuclear v̄Mv), were obtained in pretreatment biopsies from 51 patients treated for cervical cancer in clinical Stages I through III (mean age of 56 years, follow‐up period >5 years). In addition, conventional, two‐dimensional morphometric estimates of nuclear and mitotic features were obtained. DNA indices (DI) were estimated by flow cytometry. Finally, the semiquantitative malignancy grade score value (MGS) was determined according to previously published methods. Estimates of nuclear v̄Mv were on average increased in euploid lesions (2P = 0.01), but the overall relationship between nuclear v̄Mv and DI was poor. Different clinical stages of disease did not differ with regard to nuclear v̄Mv (2P = 0.99) and DI (2P = 0.56). No relationship was disclosed between MGS and nuclear v̄Mv (2P = 0.85). Single‐factor analysis showed prognostic impact of clinical stage of disease (2P = 0.0001) and DI (2P = 0.04), whereas estimates of nuclear v̄Mv were only of marginal prognostic significance (2P = 0.07). How‐ M ever, Cox multivariate regression analysis showed independent prognostic value of patient age and nuclear v̄Mv along with clinical stage and DI. All other investigated variables were rejected from the model. A prognostic index with highly distinguishing capacity between prognostically poor and favorable cases was constructed (2P = 1.9 × 10−7). It is concluded that realistic estimates of nuclear volume are independent of nuclear DNA content and are of prognostic value for objective malignancy grading in patients with squamous cell carcinoma of the uterine cervix.

Predictive value of CA 125 during early chemotherapy of advanced ovarian cancer

Abstract CA 125 was measured during early chemotherapy of 61 patients with epithelial ovarian carcinomas (FIGO stages III and IV) to determine if patients with a poor response to further treatment could be identified during early therapy. Blood samples were drawn before the start of chemotherapy and 1 month after the first, second, and third courses. Prior to therapy all patients had increased CA 125 levels, but 77% (4761) had normal antigen levels after the third course. Second-look laparotomy was performed 4–10 months after the third course; 24 patients had no evidence of disease (NED) and 37 had residual tumor (RT). After three courses of chemotherapy, NED patients all had normal CA 125 values, whereas 38% (1437) of the RT patients had increased antigen levels. In conclusion, increased CA 125 values after the third course of chemotherapy identified 38% of the patients who responded insufficiently to further therapy. Treatment in progress should here be stopped and replaced by palliative therapy if other curative regimens are considered nonexistent. Normal CA 125 values had no predictive value owing to the many (62%) false-negative antigen values.

New prognostic factors in squamous cell carcinoma of cervix uteri

The prognostic importance of a detailed histopathological grading system and the ploidy level as determined by flow cytometry were investigated in squamous cell carcinoma of the uterine cervix. The study included 79 patients, Stages Ib-III. A multiple regression analysis of different prognostic variables identified stage and size as highly correlated. Stage was a significant prognostic variable when size was excluded. The histopathological degree of differentiation held no significant prognostic information, but the ploidy level was highly significant in that respect and should be used for a rational planning of new treatment schedules.

Prognostic influence of ploidy level and histopathologic differentiation in cervical carcinoma stage Ib

Flow-cytometric DNA analysis and extended histopathologic grading were performed in specimens from 126 patients with squamous cell carcinoma of the uterine cervix stage Ib. Archival material was used for the measurements and the ploidy level was analysed according to the method described by Hedley with some modifications. The histopathologic grading was based on eight well-defined parameters all scored 1-3. The results showed that the ploidy level held significant prognostic information about the 10 year survival according to a division of DNA indices above and below 1.5. Further prognostic information appeared from a combination of DNA index and histopathologic score value. The combination held its prognostic importance in subgroups of patients with different tumour sizes. It is concluded that flow-cytometric analysis and histopathologic grading can identify subsets of patients who need more aggressive treatment.

A limited sampling method for estimation of the etoposide area under the curve

A limited sampling method for estimation of the etoposide area under the curve (AUC) is presented. The method was developed and validated in 23 patients (42 pharmacokinetic studies) with small-cell lung cancer (SCLC), limited disease. The patients received 100 mg/m2 etoposide as a 90-min intravenous infusion in combination with carboplatin, allowing for etoposide dose modification at a following course (25% increase or decrease) due to high or low nadir values for leukocytes or thrombocytes. Of the 42 pharmacokinetic studies, 27 were used in the model development and 15 were used in the model validation. Single regression analyses of the AUC versus the fitted concentrations for the model data set were performed at several time points. The analyses demonstrated high and essentially identical correlation coefficients in the interval between 2 and 21 h, with a maximal value of 0.96 being recorded at 4 h. Multiple regression analysis was then performed using fitted concentrations corresponding to 0.08–21 h. The best model for one sample was AUC =1.01x(dose level divided by 100 mg/m2)+799×C4 h, that for two samples was AUC=1.43x(dose level divided by 100 mg/m2)+544×C4 h+1756×C21 h, and that for three samples was AUC=0.07x(dose level divided by 100 mg/m2)+110×C5 min+474×C4 h+1759×C21 h. Not unexpectedly, the model validation revealed that the one-sample model was less precise than the two- or three-sample model [percentage of root mean squared error (RMSE%)=11.6%, 7.1%, and 5.4%, respectively]. All models proved to be unbiased in the validation [percentage of mean predictive error (MPE%) ±SE=4.2%±11.0%, 7.9%±6.1%, and 6.3%±5.3%, respectively]. The models were subsequently validated in 14 pharmacokinetic studies of patients with metastatic germ-cell tumours who were receiving combination chemotherapy with cisplain and bleomycin plus 100 mg/m2 etoposide as a 90-min infusion. The RMSE% was 13.4%, 10.8%, and 9.0% and the MPE%±SE was −1.0%±11.9%, 1.7%±10.5%, and 2.7%±7.9% for the one-, two-, and three-sample models, respectively. The limited sampling methods presented herein may prove to be a most valuable tool for therapeutic drug monitoring in regimens in which etoposide is given in combination with carboplatin or with cisplatin and bleomycin.

Pharmacokinetics of oral idarubicin in breast cancer patients with reference to antitumor activity and side effects.

The pharmacokinetics of orally administered idarubicin (22.5 mg/m2/week) and idarubicinol were studied for 12 weeks in 14 patients with breast cancer. Plasma concentrations were monitored for 72 hours after the first, fourth, and twelfth doses and trough concentrations after 1, 2, 3, 4, 5, 7, 11, and 12 weeks of treatment. The half‐lives of idarubicin and idarubicinol were 19 and 60 hours, respectively. No time‐dependent changes or cumulation were observed. The metabolic ratio showed little variation. The plasma AUCs of idarubicin and idarubicinol varied between patients but were fairly constant in individual patients. The sum of the plasma AUCs was lower in patients with rapid progression than in patients who responded to treatment. A correlation between this parameter and the relative decrease in the leukocyte counts was demonstrated (p < 0.05). No correlation was found between the pharmacokinetic parameters and the time to final progression.

Renal handling of carboplatin

SummaryThe mechanism for renal handling of carboplatin was studied in 17 ovarian cancer patients treated with a combination of carboplatin and cyclophosphamide. Carboplatin and [51Cr]-ethylenediaminetetraacetic acid (EDTA) renal clearances were measured simultaneously during short intervals of from 45 to 120 min. A total of 131 clearance intervals were analyzed during 35 chemotherapy courses. The carboplatin/[51Cr]-EDTA clearance ratio (R) served as an indicator of the net tubular reabsorption (R<1) or secretion (R>1). The R value was calculated for each sampling interval. No significant difference was found between interpatient and intertreatment variation. The intertreatment variation as tested against the variation in the short intervals by anF-test was highly significant. We calculated the average R value for each treatment and consequently based our results on a total of 35 observations. The mean R value was 0.77 (t-test for R=1;P<0.001). We conclude that the renal elimination of carboplatin takes place by glomerular filtration followed by tubular reabsorption.