A randomized, multiple-dose parallel study to compare the pharmacokinetic parameters of synthetic conjugated estrogens, A, administered as oral tablet or vaginal cream.

OBJECTIVE: A randomized, parallel-design study was conducted to determine the pharmacokinetic profile of synthetic conjugated estrogens A (SCE-A) vaginal cream (0.625 mg SCE-A/g) when administered at intervals (1 g once daily for 7 d, then twice weekly) over a 27-day period as compared with the pharmacokinetic profile of 0.3 mg SCE-A tablets administered once daily orally for 27 days. METHODS: Blood samples were collected 48 hours before initial dosing for baseline levels and at multiple occasions during the study until 48 hours after final study dosing (day 29). Maximum plasma concentration, time to maximum plasma concentration (Tmax), and area under the curve from 0 to 24 hours were calculated at days 1, 7, and 27; in addition, area under the curve from 0 to 48 hours was calculated at days 7 and 27, and area under the curve weekly (AUCweekly) values were calculated for both groups. For purposes of comparison, ratios of AUCweekly values for vaginal cream and oral tablets were analyzed. RESULTS: Compared with an oral daily dose of 0.3 mg SCE-A, the steady-state systemic exposure from vaginal cream application was considerably less, with the cream-to-oral ratio being 0.45 for baseline-adjusted (BA) unconjugated estradiol, 0.30 for BA unconjugated estrone, and 0.04 for unconjugated equilin (AUCweekly). At steady-state, the systemic blood levels of BA unconjugated estrone, BA unconjugated estradiol and unconjugated equilin were significantly lower in women who received biweekly application of 1 gm vaginal cream compared to women who took an oral daily dose of 0.3 mg SCE-A tablet. CONCLUSIONS: After intravaginal application of SCE-A vaginal cream, absorption of estrogens was lower compared with absorption after oral administration. At steady state, the systemic exposure of equilin, estradiol, and estrone was significantly lower after twice-weekly administration of 1 g SCE-A vaginal cream compared with that achieved with an oral daily dose of a 0.3 mg SCE-A tablet.

Pharmacokinetics of a modified-release estrogen tablet.

OBJECTIVE: To determine steady-state plasma concentrations and the pharmacokinetic profile of the essential components of synthetic conjugated estrogens, B (SCE-B), particularly total estrone and delta8,9-dehydroestrone (DHE), after oral administration of a modified-released tablet. STUDY DESIGN: A randomized, multiple-dose, pharmacokinetic study of 28 healthy, postmenopausal women randomly assigned to receive two SCE-B 0.3-mg tablets or one 1.25-mg tablet daily for 14 days. Blood samples were obtained before and after dosing at designated times. Total (conjugated and free) and unconjugated estrogens, namely estrone, equilin, and delta8,9-DHE, were determined, and pharmacokinetic analysis was performed. RESULTS: Steady-state plasma levels of total estrone and total delta8,9-DHE measured on day 14 over a 24-hour period showed minor fluctuations and a similar time to maximum concentration (Tmax): mean Tmax of total estrone = 7.94 and 8.36 hours for 0.3-mg and 1.25-mg tablets, respectively; mean Tmax of total delta8,9-DHE = 7.08 and 8.36 hours for 0.3-mg and 1.25-mg tablets, respectively. Consistency in pharmacokinetic parameters was seen between the two doses of SCE-B. CONCLUSION: SCE-B 0.3-mg and SCE-B 1.25-mg tablets achieved consistent pharmacokinetic parameters and steady-state levels when administered to healthy postmenopausal women. Achieving smooth, predictable levels of component estrogens may result in more consistent relief of menopausal symptoms.

Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study.

PURPOSE: Liposomal encapsulation of doxorubicin is designed to increase safety and tolerability by decreasing cardiac and gastrointestinal toxicity through decreased exposure of these tissues to doxorubicin, while effectively delivering drug to the tumor. We conducted an open-label phase I study to determine the pharmacokinetic profile of a single dose of liposome-encapsulated doxorubicin (Myocet) in patients with various solid tumors. Safety and tolerability were monitored. EXPERIMENTAL DESIGN: Patients received a single intravenous infusion of Myocet 75 mg/m2. Plasma samples were analyzed for concentration of liposome-encapsulated doxorubicin, total doxorubicin, and doxorubicinol. RESULTS: A total of 18 patients aged 20-73 years (median 60 years) participated; 17 were evaluable for pharmacokinetic analysis. The most common primary tumor was soft tissue sarcoma (22%). Total body clearance for total doxorubicin was 5.6 l/h/m2 while the volume (Vss) was 82 l/m2. The terminal half-life was 52.6 h. Based on the AUC and Cmax values for total doxorubicin and encapsulated doxorubicin, an estimated 85% of circulating doxorubicin was encapsulated. Doxorubicinol was detected in all patients; the mean AUC was 2.03+/-1.10 micromol/l/h. The mean 48-h urinary excretion of doxorubicin was 6.44% of the dose. The most common adverse events were nausea (94%), fatigue (78%) and vomiting (67%). Cardiotoxicity (measured as ten-point fall in LVEF to <50%) was observed in one patient. Pharmacokinetic values did not correlate with hematological, laboratory or demographic variables. CONCLUSIONS: The pharmacokinetic profile of Myocet suggests that the liposomal formulation results in a longer half-life with less free drug available for tissue distribution than conventional doxorubicin, consistent with the enhanced therapeutic index observed in clinical studies.

Activity, pharmacokinetics and tissue distribution of TLC ELL-12 (liposomal antitumor ether lipid) in rats with transplantable, s.c. methylnitrosourea-induced tumors.

TLC ELL-12 is a liposomal formulation of the novel antineoplastic compound 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (L-ET-18-OCH(3)). The purpose of these studies was to evaluate the activity and tissue distribution of L-ET-18-OCH(3) when administered i.v. as TLC ELL-12 to rats bearing solid tumors. Growth-inhibitory activity of L-ET-18-OCH(3) and TLC ELL-12 against methylnitrosourea (MNU)-induced tumors grown in vitro was evaluated. Female Buffalo rats were injected s.c. with transplantable MNU-induced tumor cells. Four days later, animals were treated i.v. with L-ET-18-OCH(3) administered as TLC ELL-12 once daily for 5 consecutive days. Another group of MNU-tumor bearing rats was given a single 12.5 mg/kg dose of TLC ELL-12 containing [14C]L-ET-18-OCH(3) by i.v. injection into a tail vein. The 50% growth inhibitory concentration for TLC ELL-12 against MNU tumor cells in vitro was 63 microM (about 30 microg/ml). Tumor growth was significantly inhibited in ELL-12-treated rats versus controls. After a single dose, whole blood L-ET-18-OCH(3) concentrations declined in a multiphasic fashion with C(max) and terminal half-life values of approximately 91.1 microg L-ET-18-OCH(3)/ml and 13.1 h, respectively. Tumor L-ET-18-OCH(3) levels increased through the first 16-24 h post-dosing to about 23 microg/g and remained elevated at the terminal time point with little evidence of metabolism. Concentration-time profiles for selected tissues indicate rapid distribution of L-ET-18-OCH(3) from the circulation into tissues with highest concentrations in spleen, liver, lungs, kidneys and gastrointestinal tract. L-ET-18-OCH(3) as TLC ELL-12 shows both in vitro and in vivo activity against the MNU tumor line. When i.v. administered, L-ET-18-OCH(3) from ELL-12 is well distributed and slowly eliminated by metabolism in tissues.

Toxicity and disposition of TLC ELL-12 (liposomal antitumor ether lipid) in Sprague-Dawley rats.

TLC ELL-12 is a liposomal formulation of the antineoplastic L-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine [L-ET-18-OCH3 (EL)]. The purpose of these studies was to characterize the toxicity and disposition of [N-methyl-14C] L-ET-18-OCH3 administered as TLC ELL-12. Rats received TLC ELL-12 by i.v. infusion into a tail vein as a single 12.5 or 62.5 mg/kg dose or as five daily doses at 12.5 mg/kg (cumulative dose of 62.5 mg/kg). Whole blood and tissue samples were collected over 24 h, and assayed for total and EL-specific radioactivity. The amounts of radioactivity in urine, bile, injection site and carcass were determined for up to 48 h. TLC ELL-12 was well tolerated in male and female rats in single doses up to 37.5 mg/kg. The minimum lethal dose was 112.5 mg/kg. Doses of 12.5 mg/kg (no observed adverse effects) and 62.5 mg/kg (approximate maximum tolerated dose) were chosen for further study. The pharmacokinetics of EL given as TLC ELL-12 were non-linear with a disproportionate increase in AUC at the higher dose. Daily dosing at 12.5 mg/kg did not result in accumulation in the blood. The highest concentrations of EL at 24 h after dosing were in the spleen and liver. Virtually no radioactivity was recovered in the urine or bile of rats, most remaining in the carcass and injection site (tail). After a 12.5 mg/kg dose of TLC ELL-12, the levels of EL in the blood and most tissues examined were well above the levels that inhibit tumor growth and may therefore be therapeutically active.

Pharmacokinetics of doxorubicin administered i.v. as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventional doxorubicin when given in combination with cyclophosphamide in patients with metastatic breast cancer.

Myocet (TLC D-99) is a liposomal formulation of the anti-neoplastic drug doxorubicin with an improved therapeutic index compared with conventional doxorubicin. The objective of this study was to assess the plasma disposition of doxorubicin when administered i.v. as TLC D-99 and to compare this to conventional drug. Metabolite (doxorubicinol) plasma levels were also quantitated in both treatment groups. Plasma was collected during the first course of treatment from 10 patients receiving TLC D-99 60 mg/m and 10 receiving conventional doxorubicin 60 mg/m2, each with cyclophosphamide 600 mg/m2. Samples were assayed for total doxorubicin (all doxorubicin regardless of whether it is encapsulated or not), encapsulated doxorubicin (TLC D-99 group only) and doxorubicinol using high-performance liquid chromatography. Plasma concentrations of total doxorubicin were higher in patients receiving TLC D-99 than in patients receiving conventional doxorubicin. The clearance of total doxorubicin after administration of TLC D-99 was lower (approximately 9-fold) and the volume of distribution at steady state was less (25-fold) than that of doxorubicin after conventional drug. Doxorubicinol was detected in the plasma of all patients in both treatment groups. The mean AUC(0-infinity) of doxorubicinol for patients receiving TLC D-99 (1.5+/-0.4 M x h) was not statistically different than that in patients receiving conventional doxorubicin (1.8+/-0.4 M x h), although the appearance of the peak doxorubicinol concentration occurred later and was lower in patients receiving TLC D-99. There was a correlation between the plasma AUC(0-infinity) of total doxorubicin and the degree of myelosuppression in patients receiving conventional doxorubicin, but this correlation was not found in patients receiving TLC D-99.