Standard (S2S) versus iterative-2 (IT2S) stage population analysis of daunorubicin (D1) and daunorubicinol (D2) pharmacokinetics

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Co-modelling of daunorubicin and daunorubicinol pharmacokinetics

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Human pharmacokinetics of esorubicin (4′ -deoxydoxorubicin)

The pharmacokinetics of esorubicin, a new anthracycline antibiotic, was investigated in conjunction with a phase I clinical trial. The drug was administered to 12 patients as an intravenous bolus at a dose of 20 to 40mg/m2. All patients had normal renal and hepatic functions and no third space fluid accumulation. Plasma and urine samples were assayed by HPLC. The peak plasma concentration of esorubicin was 0.74 ± 0.57 μM (mean ± SE). Esorubicin disappeared from plasma according to a tri-exponential pattern with a terminal half-life of 20.4 ± 7.3 hr. The area under the plasma concentration versus time curve was 0.64 ± 0.31 μMxhr. Total body plasma clearance was 45.5 ± 26.8 liter/min/m2 and the apparent volume of the central compartment, 41.0 ± 24.8 L. A single metabolite, 4′-deoxydoxorubicinol, was detected in plasma. This metabolite was observed in 5 patients only and its mean peak concentration was 0.029 ± 0.017 μM. The area under the plasma versus concentration time curve for 4′-deoxydoxorubicinol was 0.02 ± 0.014 μMxhr. The urinary excretion of total fluorescence within 5 days of therapy was 7.3 ± 1.3% of the administered dose. Esorubicin represented more than 80% of the excreted anthracyclines. As in plasma, 4′ -deoxydoxorubicinol was the only metabolite detectable in urine. No correlation between the various pharmacokinetic parameters and drug-induced toxicity was observed in this small group of patients. © 1985 Martinus Nijhoff Publishers.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Human pharmacokinetics of marcellomycin

In conjunction with two phase I clinical trials, we have investigated the pharmacokinetics of marcellomycin (MCM), a new class II anthracycline antibiotic, in nine patients with normal renal and hepatic functions and no third-space fluid accumulation. MCM was infused IV over 15 min at a dosage of 27.5, 40, or 50 mg/m2. Plasma and urine samples were collected up to 72 h. MCM and metabolites were assayed by thin-layer chromatography and quantified by specific fluorescence. The disappearance of total MCM-derived fluorescence from plasma followed first-order kinetics and lacked the rebound in total fluorescence that has been described for the structurally similar agent, aclacinomycin A. After 40-50 mg/m2, the peak MCM concentration in plasma was 1.67±0.61 μM; MCM disappeared from plasma in a triexponential fashion and was undetectabel by 48 h after infusion. The area under the plasma concentration-time plot (AUC), including the infusion time, was 1.11±0.39 μMxh; plasma clearance of MCM was 1.50±0.88 l/min/m2. Five other fluorescent compounds were consistently observed in plasma. M2 was a contaminant present in the parent drug. P1 and P2 were conjugates of MCM and M2, respectively. G1 and G2 were aglycones. The peak concentrations of the metabolites were 25% or less or the peak concentration for MCM, but their persistence resulted in higher AUCs than that for MCM. For the dosage of 27.5 mg/m2, fewer data were available; but the pharmacokinetics of MCM and metabolites appeared to be similar to that at higher dosage. Urinary excretion of total fluorescence amounted to 8.0%±1.6% of the total dose at 40-50 mg/m2, and to 7.0%±2.3% at 27.5 mg/m2. No correlation was detected among the various pharmacokinetic parameters and toxicities encountered in these patients. © 1985 Springer-Verlag.SCOPUS: ar.jinfo:eu-repo/semantics/publishe