Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmaco-therapeutic group: Antineoplastic agents, anthracyclines and related substances, ATC code: L01DB01

The active substance in Myocet is doxorubicin HCl. Doxorubicin may exert its antitumour and toxic effects by a number of mechanisms including inhibition of topoisomerase II, intercalation with DNA and RNA polymerases, free radical formation and membrane binding. Liposomal-encapsulated compared with conventional doxorubicin was not found more active in doxorubicin resistant cell lines in vitro. In animals, liposome-encapsulated doxorubicin reduced the distribution to heart and gastrointestinal mucosa compared with conventional doxorubicin, while antitumoural efficacy in experimental tumours was maintained.

Myocet (60 mg/m2) + CPA (600 mg/m2) was compared with conventional doxorubicin + CPA (at the same doses) and Myocet (75 mg/m2) + CPA (600 mg/m2) was compared to epirubicin + CPA (at the same doses). In a third trial, Myocet (75 mg/m2) monotherapy was compared with conventional doxorubicin monotherapy (at the same dose). Findings regarding response rate and progression-free survival are provided in Table 3.



Table 3
Antitumour efficacy summary for combination and single-agent studies

Myocet/CPA Dox 60/CPA Myocet/CPA             Epi/CPA       Myocet       Dox (60/600     (60/600   (75/600               (75/600     (75 mg/m2) (75 mg/m2) mg/m2)     mg/m2)     mg/m2)                mg/m2)       (n=108)    (n=116) (n=142)     (n=155)    (n=80)                (n=80)
Tumour response rate          43%             43%           46%          39%           26%         26% Relative Risk                         1.01                       1.19                       1.00 (95% C.I.)                        (0.78-1.31)                (0.83-1.72)                (0.64-1.56) Median PFS (months)a          5.1                 5.5        7.7             5.6        2.9         3.2 Risk Ratio                             1.03                       1.52                       0.87 (95% C.I.)                         (0.80-1.34)                (1.06-2.20)                (0.66-1.16) Abbreviations: PFS, progression-free survival; Dox, doxorubicin; Epi, epirubicin; Relative Risk, comparator taken as reference; Risk Ratio, Myocet taken as reference a
Secondary endpoint

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The plasma pharmacokinetics for total doxorubicin in patients receiving Myocet shows a high degree of inter-patient variability. In general however, the plasma levels of total doxorubicin are substantially higher with Myocet than with conventional doxorubicin, while the data indicate that peak plasma levels of free (not liposome-encapsulated) doxorubicin are lower with Myocet than with conventional doxorubicin. Available pharmacokinetic data preclude conclusions regarding the relationship between plasma levels of total/free doxorubicin and its influence on the efficacy/safety of Myocet. The clearance of total doxorubicin was 5.1 ± 4.8 l/h and the volume of distribution at steady state (Vd) was 56.6 ± 61.5 l whereas after conventional doxorubicin, clearance and Vd were 46.7 ± 9.6 l/h and 1,451 ± 258 l, respectively. The major circulating metabolite of doxorubicin, doxorubicinol, is formed via aldo-keto-reductase. The peak levels of doxorubicinol occur in the plasma later with Myocet than with conventional doxorubicin.

The pharmacokinetics of Myocet have not been specifically studied in patients with renal insufficiency. Doxorubicin is known to be eliminated in large part by the liver. A dose reduction of Myocet has been shown to be appropriate in patients with impaired hepatic function (see section 4.2 for dosage recommendations).

Substances that inhibit P-glycoprotein (P-Gp) have been shown to alter the disposition of doxorubicin and doxorubicinol (see also section 4.5).