The effect of dacomitinib (PF-00299804) on CYP2D6 activity in healthy volunteers who are extensive or intermediate metabolizers

Purpose  

This study evaluated the effect of a single 45-mg dose of dacomitinib (PF-00299804), an irreversible small-molecule inhibitor of human epidermal growth factor receptors-1, -2, and -4, on CYP2D6 activity in healthy volunteers (HV) using dextromethorphan (DM), a selective CYP2D6 probe.     

A phase I study of monohydroxyethylrutoside in healthy volunteers

The flavonol monohydroxyethylrutoside (monoHER) has demonstrated protection against doxorubicin-induced cardiotoxicity in in vitro and in vivo studies without affecting the antitumor effect. In the present phase I study, the possible side effects and the pharmacokinetics of monoHER were evaluated in healthy volunteers with the aim to develop a safe and feasible dose to be evaluated in cancer patients treated with doxorubicin. The study was performed as a single blind, randomized trial in healthy volunteers (age between 19 and 56 years). At each dose level, six subjects received monoHER and three placebo. MonoHER was solubilized in 100 ml dextrose 5% and administered as an i.v. infusion in 10 min. The placebo consisted of 100 ml dextrose 5%. The starting dose of monoHER was 100 mg/m². Dose escalation by 100% of the preceding dose took place after finishing each dose level until the protecting pharmacokinetic values for C _max and AUC^∞ (as observed in mice after 500 mg/kg monoHER i.p.) were reached and/or serious side effects were observed. The dose was escalated up to 1,500 mg/m². The mean values of C _max and AUC^∞ were 360±69.3 μM and 6.8±2.1 μmol min/ml, respectively. These values were comparable to the C _max and AUC^∞ observed under the protecting conditions in mice. No serious side effects occurred during the entire study. Thus, 1,500 mg/m² is a feasible and safe dose to be evaluated in a phase II study to investigate the protective properties of monoHER against doxorubicin-induced cardiotoxicity in cancer patients. Preliminary results of this study have been presented as a poster at AACR (Proc. AACR 43 (2002) 2751).     

Assessment of the absorption, metabolism and excretion of [14C]pasireotide in healthy volunteers using accelerator mass spectrometry

Purpose

Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog designed to have a broader somatostatin receptor binding profile than other currently available somatostatin analogs. The purpose of this study was to evaluate the absorption, metabolism and excretion of pasireotide in healthy male subjects (N = 4) following a single, subcutaneous (sc), 600 μg dose of [¹⁴C]pasireotide.

Methods

Blood, plasma, urine and feces were collected for 240 h post-dose and analyzed for total ¹⁴C and metabolite profile by accelerator mass spectrometry (AMS) or high-performance liquid chromatography–AMS. Parent drug levels were analyzed by radioimmunoassay.

Results

[¹⁴C]pasireotide was rapidly absorbed, with a mean peak plasma ¹⁴C concentration of 16.6 ± 5.28 ngEq/mL at 0.5 h in plasma. The parent drug to total ¹⁴C AUC_0–24h ratio was 1.08, indicating that little metabolite was present in plasma up to 24 h post-dose. In pooled plasma samples (0–12 h), only unchanged [¹⁴C]pasireotide was detected. Unchanged [¹⁴C]pasireotide accounted for approximately 84 % of total excretion (feces and urine). Approximately 56 % of the administered radioactive dose was recovered within 240 h, eliminated primarily in feces (48.3 ± 8.16 %) and minimally in urine (7.63 ± 2.03 %). No serious adverse events were reported.

Conclusions

A single dose of [¹⁴C]pasireotide 600 μg sc administered to healthy male subjects was rapidly absorbed and excreted in its unchanged form primarily via the hepatic route.     

A first-in-man phase I tolerability and pharmacokinetic study of the cyclin-dependent kinase-inhibitor AZD5438 in healthy male volunteers

AZD5438 is a novel cyclin-dependent kinase inhibitor with preclinical pharmacodynamic (PD) activity against a range of human tumour xenografts. A first-in-man tolerability and pharmacokinetic (PK) study involving single ascending doses of AZD5438 was conducted in healthy male volunteers. Single oral doses ranging from 5 to 160 mg were studied in 23 subjects. Dose-limiting nausea and vomiting occurred at 160 mg in the absence of prophylactic anti-emetics. The maximum tolerated dose (the dose at which no dose limiting toxicities occurred) was 80 mg, and the maximum well-tolerated dose was deemed to be 60 mg, which was associated with grade1 nausea but no vomiting. T _max occurred between 0.5–3.0 hours with a relatively short plasma half-life of 1–3 h. The coefficient of variation of exposures within a dose level ranged from 22–71% (AUC) to 16–63% (C _max), and exposure increased with increasing dose across the doses studied. <1% of the parent compound was excreted in the urine, suggesting metabolism as the major clearance mechanism. The maximum well-tolerated dose and a number of doses below this level will be taken forward into a PD study using normal tissue biomarkers in humans to determine proof of AZD5438’s action on the cell cycle. The pharmacokinetic profile of AZD5438 determined within this study will be used to guide the time-points for PD analysis within the planned PD study.     

Pharmacokinetics,metabolism and excretion of [14C]-lenalidomide following oral administration in healthy male subjects

Purpose  

Assessment of the absorption, metabolism and excretion of [¹⁴C]-lenalidomide in healthy male subjects following a single oral dose.     

First-in-human,phase I dose-escalation study of single and multiple doses of a first-in-class enhancer of fluoropyrimidines,a dUTPase inhibitor (TAS-114) in healthy male volunteers

Purpose

TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor, which acts as a modulator of the pyrimidine nucleotide metabolic pathway. This was a first-in-human, phase 1 study that investigated the pharmacokinetics (PK) and safety of single-agent TAS-114 when it was given at single and multiple doses.

Methods

For the single-dose cohort (n = 25), healthy male volunteers received a single dose of TAS-114 at 6, 18, 60, 150, and 300 mg. The magnitude of dihydropyrimidine dehydrogenase (DPD) inhibition and the food effect on TAS-114 PK were also investigated. For the multiple-dose cohort (n = 10), subjects received TAS-114 for 14 days consecutively.

Results

In the dose-escalating single-dose cohort, the disposition of TAS-114 followed linear kinetics. The elimination half-life was approximately 2 h. The urine excretion rate and food effect were minimal. A significant increase in uracil C_max was observed at administered doses of 150 mg or higher of TAS-114, suggesting that significant inhibition of DPD occurred at these doses. No apparent CYP3A4 auto-induction was observed in the multiple-dose cohort. No significant safety concerns at these dose levels were noted after single and multiple dosing.

Conclusions

TAS-114 has shown both a favorable safety and pharmacokinetic profile after single and repeated doses. TAS-114 was considered to possess a moderate DPD inhibitory effect. These findings will facilitate clinical studies of the combination chemotherapies in cancer patients and may reduce the safety risk in the frail cancer patients.     

Disposition and metabolism of [14-14C] 4-demethoxydaunorubicin HCl (idarubicin) and [14-14C]daunorubicin HCl in the rat

Summary The disposition of [14-¹⁴C]4-demethoxydaunorubicin HCl ([14-¹⁴C]idarubicin HCl, [¹⁴C]IDR) and of [14-¹⁴C]daunorubicin HCl ([¹⁴C]DNR) was studied in male Sprague Dawley rats. [¹⁴C]IDR was administered either IV at 0.25 mg/kg body weight or PO at 1 mg/kg body weight, whereas [¹⁴C]DNR was dosed IV at 1 mg/kg body weight. The main elimination route for both compounds was the bile, fecal excretion representing 0.75–0.8 times the total dose at 72 h. Radioactivity due to [¹⁴C]IDR-derived species is released by the tissues at a slower rate than activity derived from [¹⁴C]DNR. After IV treatment comparable plasma levels are obtained, but tissue radioactivity is markedly lower with [¹⁴C]IDR, in keeping with the lower dosage. The ratio of plasma to tissue radioactivity is even higher in animals treated PO with [¹⁴C]IDR, because of the more extensive metabolism after this route of administration. The 13-dihydro derivatives of both [¹⁴C]IDR and [¹⁴C]DNR are the main metabolites in tissues, but in the case of the former, products of phase II reactions become more important at later times in liver and kidney and in excreta.     

A phase I study investigation of metabolism,and disposition of [ 14 C]-anlotinib after an oral administration in patients with advanced refractory solid tumors

Anlotinib is a novel oral multi-targeted receptor tyrosine kinase inhibitor, which selectively inhibits VEGFR2/3, FGFR1-4, PDGFR α/β, c-kit, and Ret. It shows antitumor effect in patients with advanced refractory solid tumors. The detailed absorption, metabolism, and excretion pathways of anlotinib have not yet been fully investigated. Six male patients were enrolled and divided into two groups. Group A (containing two patients) received 14.15 mg/80 µCi/subject [14C]-anlotinib hydrochloride. Group B (containing four patients) received 14.15 mg/120 µCi/subject [14C]-anlotinib hydrochloride. The blood, urine, and feces of all the six patients after orally administration of [14C]-anlotinib were collected. The absorption, metabolism, and excretion of [14C]-anlotinib were investigated, and the efficacy and safety of anlotinib were evaluated. In plasma, the average time to peak concentration (Tmax) of total radioactivity was 4.42 h and the average peak concentration (Cmax) of total radioactivity was 18.80 ng Eq./g. The average values of AUC0-last, AUC0-∞, and MRT0-t were 4071 h.ng Eq./g, 13,555 h.ng Eq./g, and 125 h, respectively. The average recovery of total radioactivity (TRA) in urine and feces was 62.03%, accounting for 48.52% and 13.51% in feces and urine of the total dosage, respectively. The parent drug, a carboxylic metabolite (M30), and mono-oxidation products (M46/M66) were major drug-related components in human plasma. Oxidative metabolism played the major role in drug clearance in human. The major metabolic pathways include oxidative deamination to M2, mono-oxidation to M1, and the formation of M30. Adverse events occurred in five patients and severe adverse events (SAE) occurred in one. Tumor response were evaluated as stable disease (SD) in three, partial response (PR) in one, and progressive disease (PD) in one of the patients, respectively. Anlotinib had a good pharmacokinetic profile with rapid absorption, long half-life, and extensive hepatic metabolism. The adverse events and efficacy were as expected.     

Mass balance,excretion and metabolism of [<Superscript>14</Superscript>C] ASA404 in cancer patients in a phase I trial

Purpose  

To determine the mass balance, excretion and metabolism of the small molecule flavonoid tumour vascular disrupting agent ASA404 in patients with advanced cancer.     

A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in cancer patients.

PURPOSE: Breast cancer resistance protein (ABCG2) substantially limits the oral bioavailability of topotecan. Coadministration with elacridar, an inhibitor of breast cancer resistance protein-mediated drug transport, increases the bioavailability of topotecan. The aim of this study was to establish the lowest effective dose of elacridar to obtain maximum oral bioavailability of topotecan and to determine the optimal schedule of coadministration of oral topotecan and elacridar. In the second part of this study, dose-limiting toxicities and maximum tolerated dose of oral topotecan coadministered with elacridar, at a daily times five regimen administered every 21 days, were established. EXPERIMENTAL DESIGN: In part I, 20 patients were randomized to receive 100, 300, 500, 700, or 1,000 mg of elacridar on days 1 and 8 1 h before or simultaneously with 2.0 mg oral topotecan, which was also randomized. On day 15, all patients were treated with 1.5 mg/m(2) i.v. topotecan. In part II of the study, patients were treated daily with oral topotecan and with the lowest effective dose of elacridar following from part I. The maximum tolerated dose and dose-limiting toxicity were determined in cohorts of three patients. Blood samples were taken on days 1, 8, and 15 of part I and on day 1 of cycles 1 and 2 of part II. RESULTS: Complete apparent oral bioavailability of topotecan (102 +/- 7%) for all treatment arms with elacridar in both schedules was seen in part I. In the topotecan dose escalation part, two dose-limiting toxicities were seen at the 2.5 mg topotecan dose level. CONCLUSION: The recommended schedule is 2.0 mg oral topotecan plus 100 mg elacridar administered concomitantly daily times five every 21 days.     

The effect of modulated electro-hyperthermia on the pharmacokinetic properties of nefopam in healthy volunteers: A randomised,single-dose,crossover open-label study

Abstract

Purpose: Nefopam is a widely available analgesic for the management of pain. The aim of this study was to reveal the effect of regional hyperthermia of the abdominal area on the pharmacokinetics of nefopam. Materials and methods: A randomised, single-dose, crossover, open-label study was conducted to reveal the effect of hyperthermia using modulated electro-hyperthermia on the pharmacokinetics of nefopam. The pharmacokinetics of orally administered nefopam without hyperthermia was studied in 12 healthy volunteers and then 7 days later they were treated with nefopam plus modulated electro-hyperthermia to the abdominal area for 1?h. Blood samples were collected up to 24?h after the drug administration. From the blood concentration-time curve, the maxinum plasma concentration (C_max), time to C_max (T_max) and the area under the curve (AUC) were obtained. The safety and tolerability of these treatments were also assessed. Results: The geometric mean ratios (GMRs) ((nefopam?+?modulated electro-hyperthermia)/nefopam) and the associated 90% confidence intervals (CIs) for C_max, AUC_last and AUC_inf were 1.2804 (1.1155～1.4696), 1.0512 (0.9555～1.1566) and 1.0612 (0.9528～1.1819), respectively. The increase in C_max was statistically significant, and T_max was significantly shortened. Conclusions: The significant increase in C_max and decrease in T_max indicated that modulated electro-hyperthermia increased the absorption of the orally administered nefopam, thereby transitionally increasing the blood concentration of the drug. The AUC is an important parameter that contributes to the therapeutic effect of drugs. The lack of significant change in AUC suggests that modulated electro-hyperthermia may increases the absorption of orally administered drugs without increasing the systemic adverse effect of the drugs.     

A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects

Purpose  

Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, is in clinical development for the treatment of patients with chronic myelogenous leukemia (CML). To support clinical development, we conducted a dose-escalation and food-effect evaluation of safety, tolerability, and pharmacokinetics (PK) of bosutinib in healthy adults.     

A phase I study of DWA2114R]

Phase I study of DWA2114R, a new platinum analogue, was conducted in 39 patients with various tumor types by a group of 13 institutions. Of the 39 patients entered in this study, 35 were evaluable. The starting dose was 40 mg/m2 (1N) and the drug was administered i.v. for 20-30 min, escalating stepwisely up to 1,000 mg/m2 (25 N). The dose limiting factor (DLF) was leukocytopenia, especially neutrocytopenia, and the maximum tolerated dose (MTD) was more than 1,000 mg/m2. Major clinical toxicity was gastrointestinal. Hepatotoxicity and nephrotoxicity were mild. Following administration of the drug, plasma concentrations of total and filterable platinum (Pt) showed a triphasic and biphasic decays. Excretion into urine within 24 hours was in the range of 54.2% to 92.2% of the administered platinum. The recommended dose of phase II study was 800-1,000 mg/m2, repeating every 3-4 weeks.     

Autoradiography of [14C]N-nitrosodiethanolamine in Sprague-Dawley rats

Whole-body autoradiography in Sprague-Dawley rats injected i.v. with [14C]N-nitrosodiethanolamine ([14C]NDELA) showed a localization of tissue-bound radioactivity in the liver and the nasal olfactory mucosa. Microautoradiography of the nasal olfactory mucosa showed the highest labelling over the subepithelial glands (Bowman's glands) in the lamina propria mucosae. Experiments in vitro showed a capacity of the liver and the nasal mucosa to form 14CO2 from the [14C]NDELA. Most of the injected [14C]NDELA was recovered in the urine in a non-metabolized form. A small proportion of the dose was exhaled as 14CO2. The target tissues for the NDELA carcinogenesis in Sprague-Dawley rats are the liver and the nasal mucosa. Our results indicate that a bioactivation of the NDELA will take place in the nasal mucosa, as well as in the liver.     

Carminomycin (NSC-180024): A phase I study

Carminomycin is a new anthracycline derivative. In this phase I trial, the drug was given i.v. every 3–4 weeks to 19 patients with solid tumors. Thirty-five courses of therapy were given. Leucopenia was dose-related and dose-limiting with a steep dose-effect relationship. Leucopenia appeared to be exacerbated in patients with low performance status and massive liver involvement. Thrombocytopenia was negligible. Mild to moderate alopecia was encountered in less than one-half of the patients. Vomiting and stomatitis were not seen. Transient electrocardiographic changes could be documented in two patients. Drug-induced congestive heart failure was not observed but full evaluation of the cardiac effect of carminomycin requires more prolonged treatments and larger accrual of patients.Doses of 20 mg/m²² repeated every 3 weeks can be recommended for phase II trials with carminomycin in good-risk patients. Relative to leucopenia, other acute toxic manifestations appear to be of minor clinical significance which makes this new anthracycline attractive for further investigation.