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Idamycin

IDAMYCIN - HUMAN PHARMACOKINETICS

Table of Contents

Clinical Pharmacology

Pharmacokinetic evaluations of IDAMYCIN® include observations of 42 adult leukemia patients 19 pediatric leukemia patients, and 43 solid tumor patients. The leukemia studies required daily IV administration with or without Ara-C, for 3- to 5-day periods per course. Solid tumor studies employed single IV doses of IDAMYCIN.

Two pilot studies involving solid tumor patients determined initial estimates of kinetic parameters for IDAMYCIN and its metabolite, idarubicinol.[33,34] Following IV doses of 12.5 to 18 mg/m≤, plasma concentrations of IDAMYCIN, as a function of time, declined very rapidly. Displaying multiphasic decay characteristics, 2- or 3-compartment model appeared to best describe first order plasma decay.

Total body clearance and distribution volume estimates for IDAMYCIN indicate extensive metabolism and distribution. Extensive metabolism of IDAMYCIN is suggested by only 13% of the total dose (including metabolite) being recovered in the urine over 24 hours. These studies also indicated that the half-life of idarubicinol is much longer than its parent. Berman et al, reported higher levels of idarubicinol following oral dosing (50 mg/m≤ than following IV dosing (12.5 mg/m≤). Oral bioavailability was about 29%. These studies also reveal the minimal role of the renal pathway in the elimination of IDAMYCIN.[33,34] Table 9 shows some disposition parameters from these studies.

TABLE 9: DISPOSITION PARAMETERS FOR IDAMYCIN IN SOLID TUMOR PATIENTS FOLLOWING IV ADMINISTRATION OF 12.5-18 mg/m≤ DOSES[33 34]

STUDY

tΩ Lamdaz
(hr)

CLs
(L/hr/m≤)

AUCm/AUCp

Vd/Lamdaz
(L/m≤)

Kappa

6

-

-

-

Beta

10.5

61

1.7

1000

Abbreviations: tΩ Lamdaz mean half life; CLs, systemic body clearance; AUCm/AUCp, areas under metabolite (AUCm) to the parent (AUCp) concentration versus time curve; Vd/Lamdazdistribution volume.

Pharmacokinetic Evaluations In Adult Leukemia PATIENTS

Pharmacokinetics of IDAMYCIN® and idarubicinol were assessed in four adult leukemia studies at the Memorial Sloan-Kettering Cancer Center (MSKCC). Plasma samples were collected frequently following IDAMYCIN dosing on Day 1 and after the last dose on Day 3 or 4, with additional samples collected up to Day 7 or 8 This strategy allowed for a more rigorous analysis of data The extensive biologic fluid sampling, up to 96 and 120 hours in these studies, was intended to provide good estimates of pharmacokinetic parameters. Means of disposition parameters and their associated coefficient of variation (% CV) estimates are summarized in Table 10 [10,35,36].

TABLE 10: DISPOSITION PARAMETERS FOR IDAMYCIN IN ADULT LEUKEMIA PATIENTS FOLLOWING IV ADMINISTRATION OF 10 mg/m≤/d DAILY X 3 OR 4[10,35,36]
STUDY tΩ Lamdaz
(hr)
CLs
(L/hr/m≤)
Vss
(L/m≤)
AUCm/AUCp tΩ Lamdaz(IDR-OL)
BERMAN E*[35]

13
(22)

109
(23)

1837
(21)

4.8
(6)

49
(42)

DATA ON FILE[10] A

19
(51)

59
(75)

988
(125)

1.2
(100)

44
(52)

DATA ON FILE[10] B

24
(18)

33
(36)

749
(73)

2.1
(48)

38
(58)

DATA ON FILE[10] A

26
(40)

45
(27)

1325
(90)

2.6
(58)

63
(16)

DATA ON FILE[10] B

17
(59)

38
(46)

470
(59)

2.8
(75)

50
(34)

DAGHESTIANI AN[36]

22
(72)

43
(17)

910
(44)

2.7
(56)

54
(78)

Abbreviations: tΩ Lamdaz, mean half-life; CLs, systemic body clearance; Vss, steady-state distribution volume; AUCm/AUCp, areas under metabolite (AUCm) to the parent (AUCp) concentration versus time curve; tΩ Lamdaz(IDR-OL), idarubicino mean half-life.
*Previously untreated patients receiving Ara C Number in parenthesis is coefficient of variation (% CV)
A and B correspond to two schedules of Ara C dosing: A ( 1 hour before) and B (1 hour after) IDAMYC N dose A and B schedules for IDAMYCIN with Ara-C over Day 1-5 or 3-7, respectively. Previously treated patients who did not receive Ara-C.

The terminal half-life of IDAMYCIN® varied over a 13- to 26- hour range. The rapid disappearance of IDAMYCIN from plasma is characterized by a trioexponential function (3-compartment model).

The mean half-lives associated with the rapid (tΩ Lamda1) and the slow (tΩ Lamda2) distribution phases, suggest that postdistribution equilibrium following IDAMYCIN administered IV in adult leukemia patients is achieved in about 4 to 10 hours. This prolonged equilibration with some deep tissues has also been observed in rat tissue distribution studies.[32]

Two studies evaluating the effect of scheduling Ara-C have found that coadministration of these two agents does not alter disposition characteristics of IDAMYCIN[10,35] (See Table 10.) The similarity of AUCm/AUCp ratios further suggest that the formation and/or elimination of idarubicinol is not influenced by Ara-C, as shown in Table 10. This is also supported by the study in which patients received no Ara-C.[35]

Systemic clearance is apparently 2- to 3-fold higher than the hepatic plasma flow. High systemic plasma clearance (CLs) of IDAMYCIN is evident from all studies. Such a high CLs is indicative of an extremely efficient and extensive IDAMYCIN metabolism. IDAMYCIN is prone not only to hepatic, but extrahepatic metabolism. Aldoketoreductase, which converts IDAMYCIN to idarubicinol, is known to have extensive extravascular and intracellular distribution.

The observed CLs is reflective of the nonrenal component, with metabolic clearance (CLm) as its major component. Since hepatic metabolism of IDAMYCIN followed by biliary excretion into feces is its predominant route of elimination, hepatic clearance (CLh) is probably the most significant component of CLm. Estimates of the mean half-life (tΩ Lamdaz(IDR-OL)) of idarubicinol ranged from 38 to 63 hours. No difference was observed between previously treated or untreated, and those on Ara-C or not.

Peak IDAMYCIN levels at 5 minutes following in jection were approximately five times lower than peak daunorubicin levels.[37,38] The 13-OH metabolites, idarubicinol and daunorubicinol, were detected at the first sampling point, 5 minutes postin jection.

The concentrations of the metabolite exceeded the parent drug at appoximately 2 to 4 hours after in jection and increased at each consecutive administration. It is apparent that with an appropriate mean idarubicinol half-life of 45 hours, a 2-fold accumulation is likely over a 3-day regimen. Figure 2 illustrates the concentration-time curve of IDAMYCIN following rapid in jection on 3 consecutive days.

Long-term infusion (4-hour infusion on 3 consecutive days) is illustrated in Figure 3. This figure shows maximum plasma concentrations reached at 4 hours.

Prolonged half-life or slow clearance of idarubicinol leads quickly to plasma levels that exceed those of the parent and could potentially provide higher exposure to target tissues. This is also evident from the mean AUCm/AUCp ratios that average from about 2 to 3.

FIGURE 2

figure 2
Fig 2 - Concentration-time curve of IDAMYCIN® (black circles) and the metabolite idarubicinol (open circles) in plasma and in nucleatedcells (black squares, open squares). IDAMYCIN, 10 mg/m≤ was administered as a rapid injection on 3 consecutive days.


FIGURE 3

figure 3
Fig 3 - Concentration-time curve of IDAMYCIN® (black circles) and the metabolite idarubicinol (open circles) in plasma and in nucleated cells (black squares, open squares). IDAMYCIN. 10 mg/m" was administered as a 4-hour infusion and on 3 consecutive days.

Two kinetic studies in leukemia patients have provided additional information regarding the cellular uptake[37] and accumulation potential[39] of IDAMYCIN® following 10 mg/m≤/d. Extensive sampling used in these studies also allowed for a more accurate estimation of pharmacokinetic parameters. Mean estimates indicating significant cellular uptake are shown in Table 11 . In the study by Speth et al, a biphasic decay of drug was seen in both plasma and nucleated cells. The half-life and CLs of IDAMYCIN were 19 hr and 501/hr/m≤. Only 30% to 40% variation was seen in the estimates of CLs tΩ Lamdaz(IDR-OL) estimated from the plasma pool was 48 hours. Mean t Ω estimates of the parent and its metabolite in the nucleated blood cells were almost 100% and 35%, respectively, higher than those observed in plasma. A 4-fold lower cellular AUCm/AUCp ratio in nucleated blood cells, relative to plasma, indicates that idarubicinol may be a better substrate than IDAMYCIN for intracellular metabolism. The slow rate of intrinsic exchange of idarubicinol with tissues leads to a delayed peak of the plasma levels and long half-life.[37]

The high propensity of IDAMYCIN and its metabolite for nucleated hematopoietic cells is evident from cellular to plasma AUC ratio ranges shown in Table 11 . No ma jor differences due to varied dosing paradigms are seen. This indicates a lack of influence of drug input functions on IDAMYCIN disposition. High cellular levels of IDAMYCIN support earlier findings of relatively large distribution volumes in acute leukemia patients and preclinical studies (Vss and Vd Lambdaz)[32,40].

A slight autoinduction in IDAMYCIN disposition can be discerned from a study where the mean AUC0-24 following the last dose was found to be 50% lower than AUC0-inf after the first dose. The metabolite may be of particular interest due to its enhanced formation, higher levels than IDAMYCIN, slower clearance, and possible propensity to accumulate with dosing paradigms used in treating leukemia.

TABLE 11: RELATIVE CELLULAR UPTAKE OF IDAMYCIN IN LEUKEMIA PATIENTS FOLLOWING IV DOSING[37]

ESTIMATE

AUCm/AUCp

AUCm(c)/AUCp

AUC RATIO (CELLS/PLASMA)


IDAMYCIN

IDARUBICINOL

MEAN

3.2

0.8

293

99

RANGE

1.9 - 8.1

0.7 - 1.1

203 - 360

22 - 179

% CV

75

25

21

51

Subscripts m, p, and c represent the metabolite, the parent, and cellular.

Human Pharmacokinetics In Pediatric Patients

Several studies were used to evaluate the pharmacokinetics of IDAMYCIN® in pediatric patients with leukemia. A Phase I study[41] showed plasma IDAMYCIN concentration versus time profiles remarkably similar to those observed in adult patients[35,37,39] The half-lives associated with distribution and elimination of IDAMYCIN showed no pattern of dose dependence. Mean CLs and the AUCm/AUCp were slightly lower than observed in adults. As in the adult studies, idarubicinol was the only metabolite detected in the plasma of pediatric patients[41] Its possible that CLs and subsequent levels of idarubicinol could be dependent upon age and may relate to the efficacy or toxicity of IDAMYCIN. Both the Phase I and Phase l/ll studies (as well as adult studies) show the disposition characteristics of IDAMYCIN clearly described by a 3-compartment model.[41] The observation that the renal pathway plays a minor role in the elimination of IDAMYCIN was consistent with adult studies.[10,35,36]

One study identified idarubicinol in the cerebrospinal fluid (CSF) of 19/21 children, 18 to 30 hours postdose. The mean CSF concentration was 0.29 ng/mL and the range was 0.14 to 1.05 ng/mL[42] The clinical relevance of these findings are being evaluated; see full prescribing information.

Results show that IDAMYCIN binding to human plasma is 97% and concentration independent over a range observed with the doses generally used in leukemia studies in adult and pediatric patients. Variability in the plasma levels is not expected to influence the biodisposition of IDAMYCIN in pediatric or adult leukemic patients following IV dosing.[10]

Human Pharmacokinetics In Patients With Solid Tumors

The chemotherapeutic regimens for treating solid tumors provide a more conventional dosing and kinetic sampling environment for the description of drug kinetics. These studies involve single doses of IDAMYCIN every 2 to 3 weeks.

The kinetic parameters in these studies are supportive of an extensive metabolism and distribution of IDAMYCIN, except for the estimates in one study.[10,43]

The Smith et al study[43] involved breast cancer patients. One reason for the higher distribution volume and lower CLs may be the purported 4- to 8-fold higher sensitivity of the analytical method used in this study compared to others.[10,43] Another explanation may be that the high distribution volumes in these elderly cancer patients are due to a slightly altered IDAMYCIN distribution due to age, or the underlying disease. Mean CLs in patients with solid tumors appears to be 2- to 5-fold higher than the expected Qp (hepatic plasma flow). This observation supports the adult leukemia studies and demonstrates significant hepatic and extrahepatic metabolism of IDAMYCIN.[10,35,36]

Disposition of IDAMYCIN has also been assessed in patients with solid tumors following single IV administration. The results from the analysis of data collected from these studies show that the mean terminal elimination half-life ranges between 12 to 30 hours. This is consistent with that seen in leukemia patients. The estimated distribution volume, postequilibration, appears to be slightly larger than that estimated in leukemia patients. The half-life estimates for idarubicinol were similar to those previously mentioned (52 to 72 hours).

In general, no significant differences are apparent in the disposition characteristics of IDAMYCIN studied in patients with leukemia or solid tumor disease.

Summary

Based on studies carried out on adult and pediatric leukemia patients, and solid tumor patients, clinical pharmacokinetic evaluations with IDAMYCINÆ revealed the results that follow.

IDAMYCIN disposition following IV dosing can be described by a multiphasic decaying function. A 3-exponential or 3-compartment model has been found adequate in the analysis of most of the plasma IDAMYCIN concentration versus time data, when extensive sampling was done during the first 1 to 2 hours.

IDAMYCIN may be classified as a "semi-restrictively" cleared compound. It is expected that the CLs of IDAMYCIN, a moderately extracted drug, will not be affected by small changes in Qh or due to other influential factors such as: heart disease, liver dysfunction, or administration of drugs that affect the cardiovascular system performance.

Extensive tissue binding, reflected by the large distribution volumes observed in preclinical[32,40] and clinical studies)[10,34,36-39] may influence IDAMYCIN disposition.Since renal clearance of IDAMYCIN makes a minor contribution to the total plasma CLs, renal dysfunction should not alter its basic disposition profile. The plasma clearance of the metabolite, idarubicinol, is slower than for the parent. Its prolonged presence in the vascular system may contribute to the cytotoxic exposure to the host.

Given the daily x 3 regimen used in leukemia, the extent of accumulation for IDAMYCIN and idarubicinol can be expected to be of lower than steady-state estimates of 1.8 and 3.5 fold, respectively, assuming an average tΩ, Lambdaz(IDA) of 20 hours and tΩ, Lambdaz(IDR-OL) of 50 hours.

The stability of the anthracyclines in an acidic environment and the high lipophilicity of IDAMYCIN[33] suggest that absorption from the Gl tract is probably complete.

High CLs and Vsspresent the two most salient kinetic features that overall best describe IDAMYCIN.

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