Ajit K. Shah

Pharmacokinetic and Safety Evaluation of Palonosetron, a 5‐Hydroxytryptamine‐3 Receptor Antagonist, in U.S. and Japanese Healthy Subjects

Palonosetron (Aloxi™, Onicit®) is a selective 5‐HT3 receptor antagonist recently approved by the Food and Drug Administration for the prevention of acute and delayed chemotherapy‐induced nausea and vomiting. This study was performed to determine the pharmacokinetics and assess the safety and tolerability of intravenous (IV) palonosetron in healthy U.S. and Japanese subjects. Subjects were administered a single IV dose of palonosetron, ranging from 0.3 to 90 μg/kg in either of two randomized, double‐blind, placebo‐controlled, ascending‐dose studies (n = 80 and n = 32, respectively). Serial blood samples were obtained in both studies to evaluate the pharmacokinetics of palonosetron and its N‐oxide metabolite, M9. Intravenous palonosetron was well tolerated across a wide range of doses in both studies. The incidence and severity of adverse events (AEs) were similar between subjects receiving palonosetron and those receiving placebo, with no dose‐dependent incidences. The most frequently reported AEs were headache, transient elevation of liver enzymes, and constipation. Systemic exposure (AUC and Cmax) for palonosetron generally increased with increasing dose. Mean total body clearance, elimination half‐life, and apparent volume of distribution ranged from 1.11 to 3.90 mL/min/kg, 33.7 to 54.1 hours, and 3.85 to 12.6 L/kg, respectively, in U.S. subjects and from 2.58 to 3.50 mL/min/kg, 30.8 to 36.8 hours, and 6.96 to 9.85 L/kg, respectively, in Japanese subjects. The pharmacokinetics of palonosetron appeared to be independent of dose, with no dose adjustment required in Japanese subjects. The plasma concentration profile of palonosetron, as represented by a half‐life of approximately 40 hours, may provide a clinical advantage over other 5‐HT3 antagonists.

Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers.

ABSTRACT Background: Palonosetron is a second-generation 5-HT3 receptor antagonist with a prolonged duration of action and higher receptor binding affinity than first-generation agents (ondansetron, granisetron, and dolasetron). Aprepitant is a selective antagonist of substance P/neurokinin 1 that augments the benefit of 5-HT3 receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting. Methods: This randomized, open-label, two-way, crossover trial was designed to evaluate the effect of oral aprepitant on the pharmacokinetics and safety of a single intravenous (IV) dose of palonosetron in 12 healthy subjects. Treatment A consisted of a single IV bolus dose of palonosetron 0.25 mg on day 1. Treatment B added oral aprepitant 125 mg on day 1 (30 minutes prior to palonosetron) and 80 mg on days 2 and 3. Blood for pharmacokinetic evaluations was collected through 168 hours after palonosetron administration on days 1 and 15; safety was monitored through day 22. Results: Mean plasma concentration-time plots for palonosetron were virtually identical for palonosetron administered alone or with concomitant aprepitant. The ratio of geometric least-square mean values (with:without aprepitant) for Cmax was 98.6% (90% confidence interval [CI]: 61.8–157%), and for AUC0–∞ the ratio was 101% (90% CI: 85.6–119%). With and without aprepitant coadministration, respectively, mean plasma elimination half-life was 40 hours and 43 hours (difference: –3.0 hours; p = 0.348), mean total body clearance was 130 mL/min and 136 mL/min (difference: –5.6 mL/min; p = 0.735), and mean volume of distribution at steady-state was 410.9 L and 442.3 L (difference: –31.4 L; p = 0.463). Palonosetron alone and the palonosetron/aprepitant regimen were well tolerated. Conclusion: These results indicate no significant differences in pharmacokinetic parameters for palonosetron between the two treatments, and suggest that palonosetron can be safely coadministered with aprepitant with no alterations in the expected safety profile and no dosage adjustment necessary.

A Double‐Blind, Placebo‐Controlled, Dose‐Ranging Safety Evaluation of Single‐Dose Intravenous Dolasetron in Healthy Male Volunteers

The safety and tolerability of dolasetron mesylate, a potent and selective 5‐HT3 receptor antagonist, were evaluated after single intravenous doses in healthy male volunteers. In this double‐blind, placebo‐controlled, randomized, phase I study, 80 subjects received either placebo or dolasetron in escalating doses (0.6 to 5.0 mg/k). Subjects were monitored for adverse events, vital sign and laboratory alterations, and changes in electrocardiographic (ECG) intervals and electroencephalographs (EEG) patterns. Overall, the percentage of subjects reporting adverse events was similar in those receiving dolasetron (44/64; 68.8%) or placebo (10/16; 62.5%); most adverse events were mild in severity. Subjects receiving dolasetron reported a higher incidence of central nervous system (headache and dizziness/lightheadedness), gastrointestinal (increased appetite and nausea), and visual adverse events and taste alterations. No clinically significant changes in laboratory variables were observed. Transient and asymptomatic ECG changes (small mean increases in PR interval and QRS complex duration versus baseline) were noted in several subjects at 1 to 2 hours after infusion at doses ≥ 3.0 mg/kg. Transient, mild blood pressure decreases were observed in five subjects, including one on placebo. Dolasetron mesylate was well tolerated in single intravenous doses up to 5.0 mg/kg in healthy male volunteers. Clinical studies of the drug are ongoing for antiemetic indications.

Evaluation of Safety and Pharmacokinetics of Consecutive Multiple‐Day Dosing of Palonosetron in Healthy Subjects

This study evaluated the safety and pharmacokinetics of consecutive multiple‐day dosing of palonosetron. Sixteen healthy subjects received an intravenous bolus dose of palonosetron 0.25 mg (n = 12) or placebo (n = 4) daily for 3 consecutive days. Safety was evaluated throughout the study. Serial plasma samples were collected on days 1 and 3 for pharmacokinetic determinations. Three days of dosing with palonosetron 0.25 mg was safe and well tolerated. There were no clinically significant changes from baseline in laboratory values, vital signs, physical examinations, or electrocardiogram intervals. Plasma palonosetron concentrations declined in a biphasic manner, measurable up to 168 hours after dosing on day 3. Mean terminal phase elimination half‐life after day 3 dosing was 42.8 hours. The 2.1‐fold accumulation of palonosetron in plasma following 3 daily doses was predictable based on elimination half‐life of approximately 40 hours, and the maximum plasma concentration remained below the maximum plasma concentration previously observed after a single, well‐tolerated 0.75 mg intravenous bolus dose of palonosetron.

Pharmacokinetic Evaluation and Safety Profile of a 15‐Minute Versus 30‐Second Infusion of Palonosetron in Healthy Subjects

Palonosetron is a potent, selective 5‐HT3 receptor antagonist effective in the prevention of acute and delayed chemotherapy‐induced nausea and vomiting. In practice, 5‐HT3 receptor antagonists, including palonosetron, are often coadministered with dexamethasone over approximately 15 minutes, although the approval of palonosetron was based on administration as a 30‐second infusion. This open‐label, randomized, 2‐way crossover trial compared the pharmacokinetics and safety of palonosetron 0.25 mg administered as a 15‐minute 50‐mL intravenous infusion with a 30‐second 5‐mL infusion. Aside from an anticipated 40% decrease in maximum plasma concentration after a 15‐minute infusion, the pharmacokinetics of palonosetron (including area under the plasma concentration‐time curve [AUC], plasma elimination half‐life, total body clearance, and apparent volume of distribution at steady state) were similar for both treatments. Both treatments were well tolerated, with no significant changes in vital signs or electrocardiograms. Palonosetron infused over 15 minutes is well tolerated, with an AUC0‐∞ equivalent to a 30‐second infusion.

Single and multiple oral dose pharmacokinetics of clentiazem in normal volunteers

This study was designed to determine the pharmacokinetics and dose proportionality of clentiazem (CLZ) after single doses (SD) of 20, 40, and 80 mg and multiple dose administration (SS) of 40, 80, and 160 mg/day for 5 days. The study was an open‐label, randomized four‐period complete crossover design. Twenty‐four healthy male volunteers participated in the study, and blood samples were drawn over 48 hours after both SD and SS. Plasma samples were analyzed for CLZ and three metabolites by high‐pressure liquid chromatography. After SD, the area under the plasma concentration‐time curve (AUC0‐∞) and maximum concentration (Cmax) increased disproportionately with the increase in dose. At steady‐state, a twofold increase in dose (20 to 40 mg twice daily and 40 to 80 mg twice daily) resulted in an increase in AUCss of 2.14‐ and 2.51‐fold, respectively. Oral clearance of CLZ decreased (203.8 L/h at 40 mg/d to 140.2 L/h at 160 mg/d) and bioavailability increased (0.35 at 40 mg/d to 0.50 at 160 mg/d) with increasing doses. The terminal half‐life of CLZ remained unchanged with increasing doses (13.7–15.5 hours). The ratios of AUCss to AUC0‐∞ at SD ranged from 1.13 to 1.27, indicating no significant accumulation of CLZ (P > .05). The AUC ratio of N‐desmethyl CLZ to that of CLZ remained constant after SD. On SS, however, there was a small decrease in this ratio with increasing dose (0.77 at 40 mg/d to 0.61 at 160 mg/d). These results indicate that the degree of nonlinearity observed with CLZ pharmacokinetics may largely be due to saturable first‐pass metabolism.

Physical, Chemical, and Bioavailability Studies of Parenteral Diazepam Formulations Containing Propylene Glycol and Polyethylene Glycol 400

AbstractParenteral diazepam formulations (10 mg/ml), XXV and XXX were prepared using propylene glycol and/or polyethylene glycol 400. The viscosity of formulations XXV and XXX was found to be 9.72 and 11.13 Cps., respectively using Stormer viscosimeter at 22° C. The accelerated stability studies indicated shelf-life of formulations XXV and XXX to be 132

Evaluation of D‐ribose pharmacokinetics, dose proportionality, food effect, and pharmacodynamics after oral solution administration in healthy male and female subjects

This was a double blind, randomized, crossover study of three periods evaluating pharmacokinetics and pharmacodynamics in 12 healthy, adult subjects after administration of D‐ribose powder for oral solution, 2.5, 5.0, and 10.0 g, under fasting conditions followed by an open label, randomized, fourth period assessing the effect of food on the pharmacokinetics of D‐ ribose (10.0 g) under fed conditions with either a high fat (HF, N = 6) or high carbohydrate (HC, N = 6) meal. D‐ribose was absorbed rapidly with mean Tmax ranging between 18 and 30 minutes. Cmax and AUC increased more than proportionally with dose indicating increased absorption and saturation of metabolism. When D‐ribose was administered with meals, Tmax was unchanged; however, Cmax and AUC decreased by 42.6% and 40.8%, respectively with HF and 69.1% and 64.9%, respectively with HC. The amount of D‐ribose in urine ranged from 4.15% to 7.20% of the administered dose. Dose‐related decreases in serum glucose up to 26.3 mg/dL (30.3% of baseline) occurred in the first 60 minutes post dose and insulin response attained a dose‐related peak 15 minutes post dose. D‐ribose was generally safe and well tolerated in the dose range studied.

Pharmacokinetics of Clentiazem After Intravenous and Oral Administration in Healthy Subjects

This study characterized the pharmacokinetics of clentiazem (CLZ) after a single intravenous bolus (IV) and oral (PO) dose in humans. Twenty‐four healthy male subjects (28.5 ± 5.2 years; 77 ± 8.2 kg) received IV (20 mg) and PO (80 mg) doses of CLZ as part of a four‐way, randomized, complete crossover study. Serial blood samples were drawn up to 48 hours after administration of the drug. Plasma samples were analyzed for CLZ and three metabolites by a high‐pressure liquid chromatography method. The values (mean [CV,%])/or systemic clearance, volume of distribution at steady‐state, and half‐life of CLZ were 63.6 L/hour (23.5), 756.1 L (19.1), and 10.6 hours (33.1), respectively, after IV administration. The peak plasma CLZ concentration (Cmax) and time to Cmax were 37.0 ng/mL (38.7) and 3.7 hours (22.9), respectively, with a lag time after PO administration. The absolute bioavailability of PO CLZ was 45% (30.7). The ratio of area under the curve of N‐desmethyl CLZ to that of CLZ increased from 0.15 (57.0) after IV to 0.60 (21.4) after PO administration, suggesting a significant first‐pass effect. The mean residence time and mean absorption time of CLZ were 12.3 hours (24.3) and 3.1 hours (88.1), respectively. The plasma concentration‐time data of CLZ can be described by either a one‐ or two‐compartment pharmacokinetic model.

Abstract 3128: Efficacy of diethyldihydroxyhomospermine against human pancreatic adenocarcinoma using orthotopic implantation of human pancreatic L3.6pl cells into the pancreas of nude mice

Purpose: To determine the anti-neoplastic effects of (S,S)N1,N14-diethyl-3,12-dihydroxyhomospermine ([HO]2DEHSPM, SUN-101) after subcutaneous (s.c.) administration after orthotopic transplantation of human pancreatic cancer cells (L3.6pl) in the pancreas of nude mice. Methods: L3.6pl cells were injected into the pancreas of nude mice and seven to ten days later the treatment groups were: Study 1: mice (n=10/group) with saline (control), SUN-101 (25 mg/kg), SUN-101 (50 mg/kg), and SUN-101 (100 mg/kg) QD for 4 to 6 weeks. Study 2: mice (n=10/group) with saline (control), SUN-101 (25 mg/kg, QD), SUN-101 (25 mg/kg three times a week, QOD), SUN-101 (15 mg/kg, QOD), and SUN-101 (5 mg/kg, QOD) for 4 to 6 weeks Study 3: mice (n=10/group) with saline (control), Gemzar (100 mg/kg, intraperitoneal (i.p.), twice a week), SUN-101 (25 mg/kg, QOD), and Gemzar plus SUN-101 for 4 to 6 weeks. Results: In study 1, the optimal dose of SUN-101 was determined to be 25 mg/kg QD. This dose reduced up to 82.9% the weight of human pancreatic tumors in mice. Treatment with 50 and 100 mg/kg doses resulted in decreased body weight and proved to be toxic in mice. Histologic changes in the liver included hepatocyte reparative change and in the exocrine pancreas included a mild decrease of cytoplasmic granules in the epithelium of the pancreatic acini. In study 2, the optimal dose of 25 mg/kg administrated QOD was less toxic than daily 25 mg/kg administrations. The pancreatic weight and volume were decreased (47.8% and 66.6%, respectively) with 25 mg/kg administrated QOD and dose related decreases were observed at the 15 mg/kg QOD (20.1% and 52.6%, respectively). No decrease in tumor weight or volume was noted with 5 mg/kg administrated QOD. In study 3, the treatment of Gemzar, SUN-101, and Gemzar plus SUN-101 resulted in 18.7%, 35.6%, and 42.4% decreases in the body weight, respectively. Compared with tumor-bearing control, the treatment of Gemzar, SUN-101, and Gemzar plus SUN-101 resulted in 24.7%, 58.8%, and 67.2% decreases in the pancreas weight, respectively, and 37.8%, 58.4%, and 72.9% decreases in the tumor volumes, respectively. The incidence of liver metastasis was also decreased with SUN-101, Gemzar, and combination of Gemzar plus SUN-101. Conclusions: SUN-101 administered QD or QOD 25 mg/kg inhibited the growth of human pancreatic carcinoma in mice. SUN-101 demonstrated higher toxicity including disruption of the digestive process at daily 50 and 100 mg/kg doses. Co-administration of SUN-101 with gemcitabine appeared to have an additive or synergistic effect on reduction in the pancreatic tumor. Citation Format: Ajit K. Shah, Michael T. Cullen, Cheryl H. Baker. Efficacy of diethyldihydroxyhomospermine against human pancreatic adenocarcinoma using orthotopic implantation of human pancreatic L3.6pl cells into the pancreas of nude mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3128. doi:10.1158/1538-7445.AM2014-3128