Carlo Maurizio Camaggi

Epirubicin and doxorubicin comparative metabolism and pharmacokinetics

SummaryThe pharmacokinetics and metabolism of doxorubicin (DX) and epirubicin (epiDX) were investigated in eight cancer patients who received 60 mg/m2 of both drugs independently by intravenous (i.v.) bolus at 3-week intervals according to a balanced cross-over design. Unchanged DX and epiDX plasma levels followed a triexponential decay. Half-lives (t/2) of the three decay phases were longer for DX (t/2α: 4.8 vs. 3 min; t/2β 2.57 h vs. 1.09 h; t/2γ 48.4 vs. 31.2 h). According to a model-independent analysis, the different plasma disposition kinetics of the two compounds appears to be related to a higher plasma clearance (PlCl) and to a lower mean residence time (MRT) of epiDX (PlCl: 75.0 l/h, range: 35.6–133.4 l/h; MRT: 31.6 h, range: 7.0–41.5 h;) compared to DX (PlCl: 56.8 l/h, range: 24.4–119.5; MRT: 45.6 h, range: 26.0–83.1 h). No statistically significant differences could be detected for the volume of distribution at steady state (Vss) (epiDX, 31.8 l/kg; DX, 33.3 l/kg). Metabolites common to both compounds were detected in plasma: the 13-dihydro derivatives doxorubicinol (DXol) and epirubicinol (epiDXol), together with monor amounts of four aglycones (7-deoxy adriamycinone, adriamycinone, 7-deoxy 13-dihydro adriamycinone, and 13-dihydro adriamycinone). Following epiDX administration, two additional major metabolites were detected: the glucuronic acid conjugates of epiDX (4′-O-β-d-glucuronyl-4′-epiDX) and epiDXol (4′-O-β-d-glucuronyl 13-dihydro-4′-epiDX). This additional detoxication route appears to account for the more efficient and faster elimination of epiDX than of DX. In the urine collected in the 6 days after treatment, 12.2% of the DX and 11.9% of the epiDX dose was excreted as unchanged drug and fluorescent metabolites. A comparable renal clearance was calculated for DX (4.7 l/h, range 1.4–7.0 l/h) and epiDX (4.4 l/h, range 1.7–7.0 l/h). One patient with hepatic metastates and abnormal bilirubin serum level had percutaneous biliary drainage because of extrahepatic obstruction. The elimination of both drugs was significantly impaired in this patient; nevertheless, elimination of epiDX was still more efficient and faster than that of DX (PlCl: 35.6 vs. 24.4 l/h; MRT: 39.0 vs. 83.1 h; t/2γ: 47 vs. 74 h). This patients biliary excretion accounted for 35.4% of the epiDX dose and 18.2% of the DX dose.

Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study

SummaryThe pharmacokinetics and metabolism of 4-demethoxydaunorubicin (idarubicin, IDA) were studied in 21 patients with advanced cancer after i.v. (12 mg/m2) and oral (30–35 mg/m2) treatment according to a balanced crossover design. Patients were divided into four groups: subjects who showed normal liver and kidney function (group N), those who presented with normal kidney function and liver metastases (group L), those with kidney dysfunction (creatinine clearance, ≤60 l/h; group R), and those with both liver and kidney dysfunction (group LR). Five patients showed variations in liver or kidney function after the first treatment and were considered to be nonevaluable for the crossover study but evaluable for the liver/kidney function study; some of them appeared in different groups for the i.v. as opposed to p.o. treatments. After i.v. administration, IDA plasma levels followed a triphasic decay pattern. The main metabolite observed in all patients was the 13C-reduced compound (IDAol), which attained plasma levels 2–12 times higher than those of the parent compound. IDA pharmacokinetics was not dependent on the presence of liver metastases but was related to the integrity of kidney function. Analysis of variance indicated a significant correlation between IDA plasma clearance and creatinine clearance; it was also found that IDA plasma clearance was lower in patients whose creatinine clearance was <60 ml/min [group N, 122.8±44.0 l/h; group L, 104.4±27.7 l/h (P=0.58) vs group R, 83.4±18.3 l/h (P=0.037)]. The IDAol terminal half-life and mean residence time (MRT) were significantly increased in patients with impaired kidney function [MRT: group N, 63.6±10.8 h; group L, 69.9±10.2 h (P=0.27) vs group R, 83.2±10.9 h (P=0.025) andt1/2γ: group N, 41.3±10.1 h; group L, 47.0±7.4 h (P=0.31) vs group R, 55.8±8.2 h (P=0.025)]. After oral treatment, drug absorption occurred during in the first 2–4 h after IDA administration; a biphasic decay pattern was observed thereafter. The main metabolite observed in all patients was again IDAol. The AUC of IDAol was greater after oral administration than after i.v. treatment in proportion to the AUC of IDA (i.v.: AUC-IDAol/AUC-IDA, 2.4–18.9; p.o.: AUC-IDAol/AUC-IDA, 4.1–21.4). Following oral dosing, a substantial amount of 4-demethoxydaunomycinone (AG1) was found in 11/21 patients. No AG1 was detected after i.v. treatment, nor was the corresponding aglycone derived from IDAol found after p.o. or i.v. administration. IDA bioavailability, computed as the ratio of the dose-corrected AUC after p.o. and i.v. treatments in the same patient, was in the 25.2%–35.7% range for groups N, L, and R. Group LR showed a significantly reduced IDA bioavailability (15.7%±5.2%). However, a better description of the actual bioavailability was obtained by taking into account the AUCs of both IDA and IDAol after i.v. and p.o. administration and the relative potency of the two compounds.

Radical annulations with nitriles: Novel cascade reactions of cyano-substituted alkyl and sulfanyl radicals with isonitriles

Abstract New radical annulation reactions are described involving addition of cyano-substituted alkyl and sulfanyl radicals to aromatic isonitriles. The tandem cyclisation of the resulting imidoyl radicals onto the cyano group affords cyclopenta- and thienoquinoxalines, respectively. The intervention of the isonitriles in the aromatisation process of the cyclohexadienyl radicals is discussed, as well as the regiochemistry of the cyclisation of the iminyl radicals obtained by addition of the imidoyls to the nitrile moiety. The hypothesis of an exclusive 6-membered ring closure onto the aromatic ring is also supported by the results of semiempirical AM1 calculations.

Design and synthesis of novel 3,4-disubstituted pyrazoles for nanomedicine applications against malignant gliomas

A series of novel 3,4-disubstituted pyrazoles were synthesized. The cytotoxicity against U87MG glioma cell line have been investigated in vitro and three of these compounds showed promising inhibitory activity on cell growth with an IC50 lower than 90 microM. AutoDock molecular docking into type I TGF-beta receptor (TGF-beta-RI; PDB: 1py5) has been done for lead optimization of the mentioned compounds as potential TGF-beta-RI1 inhibitors. In particular, 3-aryl-4-amido pyrazole containing long omega-amino-aliphatic chain emerged as a good candidate for further optimization. Entrapment into targetable PEG-based micelles improved growth inhibition IC50 values up to 100 nM and this could lead to a novel drug delivery strategy for treating glioblastoma.

A phase-II clinical trial of 4'-epi-doxorubicin in advanced solid tumors.

SummarySixty-six patients with advanced solid tumors were treated with 4′-epi-doxorubicin at a dose of 90 mg/m2 by rapid IV injection every 21 days until the disease had progressed or to a maximum cumulative dose of 540 mg/m2. Myelosuppression, nausea and vomiting, and alopecia were the almost frequent side effects, but their incidence seemed lower than that after a comparable dosage of doxorubicin. After a cumulative dose of 540 mg/m2 a significant decrease of QRS complex deflection on the electrocardiogram was detected, but no case of congestive heart failure was observed. Partial remission and minor remission were achieved, respectively, in nine (15%) and five (9%) out of 59 evaluable patients for a median duration of 6 months. Partial remission occurred in anthracycline-sensitive tumors like breast cancer (4 of 13), lung cancer (1 of 17), head and neck cancer (1 of 8), gastric cancer (2 of 4), and ovarian cancer (1 of 1).

Medroxyprogesterone acetate (MAP) plasma levels after multiple high-dose administration in advanced cancer patients.

SummaryMedroxyprogesterone acetate plasma levels were measured in advanced cancer patients after multiple PO or IM administration (500, 1000, 2000, 3000, 4000, and 5000 mg/day PO and 500, 1000, 2000 mg/day IM for 30 days). After PO administration, the plasma concentration rises quickly and plateau level is reached in 4–10 days. Discontinuation of the treatment produces a fast decay (t1/2=62.4 h) of the drug levels. When medroxyprogesterone acetate is given IM plasma levels steadily increase and after drug discontinuation no noticeable decay is observed for at least 6 months; plateau plasma levels are about three times higher than after the corresponding PO treatment. Extremely high interpatient variation in bioavailability is present with both administration routes. These data may well rationalize the results of previous clinical trials and will help in planning treatment schedules.

High-performance liquid chromatographic analysis of idarubicin and fluorescent metabolites in biological fluids

SummaryA specific, sensitive, and reliable high-performance liquid chromatographic (HPLC) method for the determination of idarubicin (IDA) and its known fluorescent metabolites idarubicinol (IDAol) and 4-demethoxy-daunomycinone (AG1) in biological fluids (human plasma and urine) was developed and tested. Plasma samples were solid-phase-extracted (C18 bonded silica cartridges). Complete separation of unchanged drugs and metabolites was achieved on a Cyanopropyl chromatographic column (25 cm×4.6 mm inside diameter; particle size, 5 μm) using fluorescence detection (excitation wavelength, 470 nm; emission wavelength, 580 nm). Sensitivity was better than 0.2 ng/ml for all analytes; rates of recovery of unchanged drug and metabolites were better than 84.5% (IDA), 80.3% (IDAol), and 83.9% (AG1). The interassay coefficient of variation was 6.5% for IDA, 5.8% for IDAol, and 9.8% for AG1. Mean intra-assay precision was 4.6% for IDA, 5.9% for IDAol, and 5.0% for AG1 at sample concentrations of above 1 ng/ml and 12.1% for IDA, 10.8% for IDAol, and 14.1% for AG1 at sample concentrations of below 1 ng/ml.

Epirubicin metabolism and pharmacokinetics after conventional- and high-dose intravenous administration : a cross-over study

In a pharmacokinetics study, six patients were treated i.v. with epirubicin (EPI) at the two dose levels of 60 and 120 mg/m2, whereas a further six patients were treated at 75 and 150 mg/m2. Both groups were studied according to a balanced cross-over design; the aim of the study was to assess the pharmacokinetic linearity of epirubicin given at high doses. Both the absolute goodness of fit and the Akaike Information Criterion (AIC) point to a linear, tricompartmental open model as the choice framework for discussing EPI plasma disposition after 16/24 administrations, independent of the delivered dose. After 8 treatments, the minimal AIC value corresponded to a nonlinear tissue-binding model. However, even in these cases, second-order effects were present only during the early minutes following treatment. In a model-independent framework, mean EPI plasma clearance was identical at the two dose levels of 60 and 120 mg/m2 (65.4±8.0 vs 65.3±13.4 l/h,P=0.92). Both the mean residence time (MRT) and the volume of distribution at steady-state (Vss) were similar as well (MRT: 22.6±2.9 vs 24.2±3.7 h;P=0.46; Vss: 21.3±1.5 vs 22.6±6.5 l/kg,P=0.46). No statistically significant difference could be found in mean statistical-moment-theory parameters determined after 75- and 150-mg/m2 EPI doses (plasma clearance, PICI: 83.4±13.5 vs 68.5±12.8 l/h,P=0.12; MRT: 22.6±4.8 vs 21.9±3.9 h,P=0.60; Vss: 26.7±10.5 vs 21.2±7.0 l/kg,P=0.17). Analysis of variance also failed to reveal any significant correlation between dose and plasma clearance. However, when data relative to single patients were examined, a trend toward nonlinear drug distribution as well as a consequent increase in peripheral bioavailability could be observed in 4/6 patients of the 75-mg/m2 vs the 150-mg/m2 group. No significant dose-dependent variation was observed in the ratio between the molecular-weight-corrected areas under the concentration-time curve for the metabolites and those for EPI [60 vs 120 mg/m2: epirubicinol (EPIol), 0.23±0.10 vs 0.22±0.06,P=0.20; epirubicin glucoronide (G1), 0.46±0.14 vs 0.62±0.40,P=0.26; epirubicinol glucuronide (G2), 0.21±0.05 vs 0.30±0.16,P=0.06; and 75 vs 150 mg/m2: EPIol, 0.33±0.22 vs 0.32±0.19,P=0.42; G1, 0.51±0.23 vs 0.46±0.17,P=0.53; G2, 0.18±0.10 vs 0.22±0.10,P=0.34]. In conclusion, all the metabolic pathways seemed well preserved when the dose was doubled, and no evident sign of “saturation kinetics” could be found.

Low dose oral administration of 4-demethoxy-daunorubicin (idarubicin) in advanced cancer patients

SummaryData relating to 4-demethoxydaunorubicin (DMDR) pharmacokinetics after oral administration (10–15 mg/m2 per day for 3 days) were collected in a total of 12 patients with advanced breast cancer and melanoma.Drug absorption took place in the first 2–4 h after administration. Plasma levels of the reduced metabolite DMDRol were higher than those of the parent compound: Peak levels were 4–10 ng/ml for DMDR and 15–40 ng/ml for DMDRol. The dose-corrected area under the timeconcentration curve (AUC) was consequently higher for DMDRol (12.3–74.7, mean 32.6 vs 2.4–7.4, mean 4.6 ng/ml.mg for DMDR).Apparent plasma terminal half-lives after the last dose administered were in the range of 13–36 (mean 23.7) h for DMDR and 30–81 (mean 58.9) h for DMDRol.Drug and the reduced metabolite accumulated in the blood cells; the ratio of AUC (blood) to AUC (plasma) was 1.40–3.75 (mean 2.80) for DMDR and 1.29–3.50 (mean 2.16) for DMDRol.The biliary excretion of the drug and of the fluorescent metabolites was studied in two additional patients with extrahepatic obstruction and percutaneous biliary drainage. In the first 7 days of therapy, biliary excretion (DMDR + DMDRol) accounted for 3.7%–4% of the administered dose.In contrast to our observations with doxorubicin and epirubicin, urinary excretion seems very likely to be more important for this drug than biliary excretion. In these patients urinary excretions were 2.2, 2.9 times (for DMDR) and 1.2, 3.4 times (for DMDRol) the biliary excretion.

Serum albumin-bound proteomic signature for early detection and staging of hepatocarcinoma: sample variability and data classification.

Abstract Background: Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) proteomic signature might be of interest for the early detection and staging of hepatocellular carcinoma (HCC). However, published procedures have been criticized for the lack of data about analytical reproducibility, and the use of inadequate data processing. Methods: MALDI-TOF profiling of peptides bound to serum albumin (“albuminome”) was performed using 90 μL of serum from 45 study subjects (HCV-related cirrhosis, small, unifocal HCCs and advanced HCCs). To overcome the large intra-sample variability, a Quality Assurance protocol was implemented, and 4–8 samples for each subject were processed and analyzed. Overall, 522 subject samples and 299 quality-control spectra were analyzed. A machine-learning approach (Random Forest) was applied to analyze the data sets. Results: Mean intra-sample coefficient of variation (CV) of the analytical procedure was 17.6%–30.0%; inter-subject CV was in the range 48.8%–71.3% among the three study groups. The Random Forest procedure correctly classified 433/522 “patient samples” and 295/299 “reference samples”; 43/45 patients were correctly classified following this approach. Conclusions: Our data suggest that, notwithstanding the large analytical variability found, multiple proteomic profiles obtained from each subject can differentiate cirrhosis with and without HCC, and HCCs with and without vascular invasion, warranting further investigation in a prospective setting. Clin Chem Lab Med 2010;48:1319–26.