Preben Jakobsen

Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group.

PURPOSE To test for possible correlations between dose of single-drug epirubicin and efficacy/toxicity in postmenopausal women with metastatic breast cancer. The study also included analysis of a correlation between pharmacokinetic and pharmacodynamic parameters. PATIENTS AND METHODS Two hundred eighty-seven women were randomized to receive either 40, 60, 90, or 135 mg/m2 of epirubicin intravenously (IV) every 3 weeks. Treatment consisted of first-line cytotoxic therapy for metastatic disease. In patients with early progressive disease after either 40 or 60 mg/m2, dose escalation to 135 mg/m2 was performed. A full pharmacokinetic analysis was performed in 78 patients. RESULTS Among 263 eligible patients, an increase in response rate and time to progression was found with an increase in dose from 40 to 90 mg/m2, while no increase in efficacy was found from 90 to 135 mg/m2. Multivariate analysis, using the Cox proportional hazards model with time to progression as the end point, confirmed that epirubicin dose more than 60 mg/m2 was an independent prognostic covariate. Furthermore, a significant association was established between randomized dose and both hematologic and nonhematologic toxicity. No association between pharmacokinetic parameters and efficacy parameters was demonstrated. On the other hand, a significant correlation between pharmacokinetic parameters and both hematologic and nonhematologic toxicity was found. CONCLUSION An increase in dose of epirubicin from 40 to 90 mg/m2 is accompanied by increased efficacy. Further increases in dose do not yield increased efficacy. A positive correlation between epirubicin dose and toxicity, as well as a correlation between pharmacokinetic parameters and toxicity, was also established.

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.

A randomized study of epirubicin at four different dose levels in advanced breast cancer. Feasibility of myelotoxicity prediction through single blood-sample measurement.

SummaryDetailed pharmacokinetic analysis and subsequent evaluation of myelotoxicity were performed in 55 patients who had been randomized to 4 different doses of epirubicin (40, 60, 90 or 135 mg/m2 given i.v. every 3 weeks). A significantly positive correlation was demonstrated between the AUC and the myelotoxicity of epirubicin. A similar correlation was observed when the metabolite epirubicinol was also considered. The decrease in leucocyte count as expressed by the logarithmic ratio between nadir WBC and initial WBC was linearly correlated with the AUC of either epirubicin alone (r=−0.55,P<0.001) or epirubicin and epirubicinol together (r=−0.63,P<0.001). As a relationship between the concentration of epirubicin in a single plasma sample taken at 6 h following i.v. administration and the AUC of the drug has been established, a log-linear relationship between the expected decrease in leucocytes and the concentration at 6 h after administration could be calculated. The proposed model is expressed as the equation: log WBCnadir=log WBCinitial−0.0073×c6 (ng/ml) −0.14.

Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac: pharmacokinetics, pharmacodynamics, formation of antibodies and influence on the coagulation system

Asparaginase comes from different biological sources and the various preparations have different pharmacokinetic properties, and their tendency to induce side‐effects is different. Erwinia asparaginase (ASNase) has a shorter half‐life than the Escherichia coli preparations, and it has been reported to be less immunogenic than the E. coli preparations and to induce fewer coagulation disorders. Children with newly diagnosed acute lymphoblastic leukaemia (ALL) were included in this study. Twenty‐seven patients were treated with Erwinia ASNase (induction therapy 30·000 IU/m2/d i.m. for 10 d, and re‐induction therapy 30·000 IU/m2 twice a week for 2 weeks) and 15 were treated with ASNase Medac (induction therapy 1·000 IU/m2/d i.m. for 10 d, and re‐induction therapy 5·000 IU/m2 i.m. twice a week for 2 weeks). Blood samples were drawn to determine enzyme activity, l‐asparagine, anti‐asparaginase antibodies, and coagulation parameters. After i.m. administration, Erwinia ASNase displayed a protracted absorption phase compared to ASNase Medac. The mean bioavailability after i.m. administration was 27% for Erwinia ASNase and 45% for ASNase Medac respectively. Mean trough enzyme activities during induction therapy were Erwinia ASNase 1748 IU/l and ASNase Medac 272 IU/l, and during re‐induction therapy Erwinia ASNase 83 IU/l and ASNase Medac 147 IU/l. We conclude that in this setting, therapy with ASNase Medac resulted in sufficient treatment during both phases of therapy, whereas treatment with Erwinia ASNase resulted in unnecessarily intense therapy during the induction phase and insufficient treatment during the re‐induction phase. There was no significant difference in the incidence of antibody formation, and therapy with Erwinia ASNase resulted in a more pronounced influence on the coagulation parameters than therapy with ASNase Medac.

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).

The pharmacokinetics of octreotide in cirrhosis and in healthy man

BACKGROUND/AIM The aim of the study was to evaluate the pharmacokinetics of octreotide in patients with cirrhosis compared to healthy volunteers. METHODS Seventeen patients with cirrhosis and nine normals received an intravenous bolus of octreotide (0.75 microgram/kg), followed by a continuous infusion of 0.75 microgram.kg-1.h-1 for 12 h. Eight patients were decompensated with ascites, while nine were without signs of decompensation. Serum octreotide levels were followed by blood sampling during the infusion period and for 24 h afterwards. RESULTS The average clearance (+/-SEM) was 151 +/- 15 ml/min in normals compared to 102 +/- 9 (p < 0.05) and 105 +/- 9 (p < 0.05) in patients with compensated and decompensated cirrhosis, respectively. The average area under the serum octreotide curve was significantly increased by 53% (p < 0.05) in decompensated and 46% (p < 0.05) in compensated cirrhosis compared to healthy volunteers, while no difference was observed between the groups with cirrhosis. This difference was also reflected by an increased maximum serum concentration during the infusion period of 9797 +/- 580 ng/l in the patients with cirrhosis compared to 7081 +/- 547 ng/l (p = 0.006) in normals. The serum half-life for the beta-phase (T1/2 beta) was 165 +/- 26 min in normals, 200 +/- 21 min in the compensated and 216 +/- 26 min in the decompensated group (NS). The volume of distribution (Vd beta) showed no difference between the three groups. Because of the slow equilibration between plasma and ascitic fluid in decompensated cirrhosis, the calculated clearance may have been overestimated and T1/2 beta and Vd beta underestimated in these patients. CONCLUSIONS The present study demonstrates that the pharmacokinetics of octreotide in cirrhosis is substantially different from that found in normals.

Pharmacokinetics and therapeutic efficacy of retinoids in skin diseases.

SummaryThe retinoids are a class of compounds that includes the natural forms and synthetic analogues of vitamin A. Isotretinoin, often referred to as a first generation retinoid, may be of considerable benefit to patients with severe, recalcitrant acne. Etretinate and acitretin, 2 aromatic compounds representing the second generation, have found their major success in the treatment of psoriasis, particularly in combination with more traditional therapies. Retinoid therapy is associated with a distinctive adverse effect profile typical of hypervitaminosis A; thus, it is especially important that fertile women undergoing retinoid therapy adhere to a contraceptive regimen. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. The terminal elimination half-lives of isotretinoin, etretinate and acitretin after long term treatment are up to 20h, 120 days and 48h, respectively. Because of lack of definite correlation between plasma concentration and desired pharmacological effects, in conjunction with the very pronounced inter- and intraindividual variation in systemic availability (15 to 90%) after oral administration of these drugs, initial dosages in individual patients can only be roughly judged on the basis of the general pharmacokinetics of the agents. Later dosage adjustments should be made on the basis of monitoring of both plasma drug (and possible metabolite) concentrations, and the efficacy and tolerability of the drugs.

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.

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.