Thomas L. Hunt

Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin®) administered by the intravenous and subcutaneous route to normal volunteers

Treprostinil sodium is a chemically stable analogue of prostacyclin administered as a chronic, continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension (PAH). There has been significant clinical interest in determining the feasibility of delivering treprostinil by intravenous infusion. Therefore, a bioequivalence and comparative pharmacokinetics study of the two routes of administration was conducted in normal volunteers. A randomized, two-period, crossover study design was employed. Each subject was dosed at 10 ng/kg/min for 72 hours by each route, with the infusions separated by a 4-day wash-out period. In the 51 subjects who received at least 24 hours of treprostinil administered subcutaneously and intravenously, the steady-state ratios of the geometric means (IV/SC) and 90% confidence intervals for AUCss and Cmaxss were 92.9% (89.8–96.1%) and 106% (99.4–113%), respectively. Secondary pharmacokinetic assessments confirmed the comparability of the two routes of administration at steady state, and also demonstrated that the elimination half-life of treprostinil was 4.4 and 4.6 hours following intravenous and subcutaneous administration, respectively. Based on these findings it was concluded that intravenously and subcutaneously administered treprostinil are bioequivalent at steady state.

FTY720: Placebo‐Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy Subjects

The purpose of this double‐blind, placebo‐controlled study was to measure the effects of FTY720, a novel immunomodulator, on heart rate and rhythm in healthy volunteers. Subjects (n = 66) were randomized to FTY720 1.25 mg or 5 mg or placebo administered once daily for 7 days. Continuous telemetry revealed an acute, dose‐dependent decrease in mean heart rate (10‐bpm decrease vs placebo) following the first dose of FTY720, with a nadir generally 4 hours postdose. Although a persistent FTY720‐related decrease in heart rate was measured from day 2 to day 7, additional doses of FTY720 after day 2 resulted in no further incremental decreases. Mean PR interval increased by approximately 8 to 10 msec in FTY720‐treated subjects on day 1. FTY720 did not increase the QRS or QT interval. These results confirm that the first dose of FTY720 has a mild to moderate negative chronotropic effect.

Multiple-Dose FTY720: Tolerability, Pharmacokinetics, and Lymphocyte Responses in Healthy Subjects

FTY720 is a sphingosine‐1‐phosphate receptor agonist being developed as an immunomodulator for acute rejection prophylaxis after organ transplantation. This study was performed to characterize the pharmacokinetics of and lymphocyte response to multiple‐dose FTY720. In this randomized, double‐blind study, three groups of 20 healthy subjects each received either placebo, 1.25 mg/day FTY720, or 5 mg/day FTY720 for 7 consecutive days. FTY720 blood concentrations and lymphocyte counts were assessed over the weeklong treatment phase and over a month‐long washout phase. The relationship between FTY720 blood concentrations and lymphocyte counts was explored by an inhibitory Emax model. First‐dose exposure was consistent with dose proportionality between the low‐ and high‐dose groups. Blood levels accumulated fivefold over the treatment period. Exposure on day 7 was dose proportional for Cmax (5.0 ± 1.0 vs. 18.2 ± 4.1 ng/mL) and for AUC (109 ± 24 vs. 399 ±85 ng•h/ mL). Washout pharmacokinetics after the last dose indicated an elimination half‐life averaging 8 days. Lymphocyte counts decreased by 80% in subjects receiving the lower dose to a nadir of 0.4 ± 0.1 × 109/L and by 88% in subjects receiving the upper dose to a nadir of 0.2 ±0.1 ×109/L. Descriptive exposure‐response modeling estimated that the lymphocyte response at 5 mg/day is near the maximal response achievable. By the end‐of‐study evaluation on day 35, lymphocyte counts had recovered to within 75% and 50% of baseline in the low‐ and high‐dose groups, respectively. In summary, systemic exposure to FTY720 was consistent with dose‐proportionality after both single‐ and multiple‐dose administration. Total lymphocyte counts decreased from baseline by 80% and 88% at regimens of 1.25 and 5 mg/day, respectively. Exposure‐response modeling provided evidence that 5 mg/day FTY720 resulted in a near‐maximal dynamic effect of this drug on lymphocytes.

Single- and Multiple-Dose Pharmacokinetics of Etoricoxib, a Selective Inhibitor of Cyclooxygenase-2, in Man

The single‐ and multiple‐dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase‐2, were examined in two clinical studies. Single‐dose pharmacokinetics—including dose proportionality, absolute bioavailability of the highest dose‐strength (120‐mg) tablet, and the effect of a high‐fat meal on the bioavailability of that tablet—were investigated in a two‐part, open, balanced crossover study in two panels of healthy subjects (12 per panel). Steady‐state pharmacokinetics were investigated in an open‐label study in which 24 healthy subjects were administered 120‐mg single and multiple (once daily for 10 days) oral doses of etoricoxib tablets. The pharmacokinetics of etoricoxib were found to be consistent with linearity through doses at least twofold greater than the highest anticipated clinical dose of 120 mg. Etoricoxib administered as a tablet was rapidly and completely absorbed and available; the absolute bioavailability was estimated to be 100%. A high‐fat meal decreased the rate of absorption without affecting the extent of absorption of etoricoxib; therefore, etoricoxib can be dosed irrespective of food. Steady‐state pharmacokinetics of etoricoxib, achieved following 7 days of once‐daily dosing, were found to be reasonably predicted from single doses. The accumulation ratio averaged 2.1, and the corresponding accumulation t1/2 averaged 22 hours, supporting once‐daily dosing. Etoricoxib was generally well tolerated.

Absolute Bioavailability and Pharmacokinetics of Treprostinil Sodium Administered by Acute Subcutaneous Infusion

The objective of this study was to evaluate the absolute bioavailability and acute pharmacokinetics of treprostinil sodium administered by continuous, short‐term subcutaneous infusion in normal subjects. Fifteen healthy volunteers received treprostinil via an intravenous infusion at 15 ng/kg/ min over 150 minutes, followed by a 5‐ to 7‐day washout and a subcutaneous infusion at the same rate administered over 150 minutes. Serial plasma samples were collected predosing, during dosing, and postdosing, and plasma treprostinil concentration levels were measured by a validated liquid chromatography atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 25 pg/mL. Acute administration of treprostinil administered by subcutaneous infusion at a rate of 15 ng/kg/min for 150 minutes achieved a mean Cmax of 1.47 ng/mL. Mean AUC∞ values for intravenous and subcutaneous dosing were 3.52 and 3.97 ng•h/mL, respectively, resulting in a mean apparent absolute bioavailability of 113% for subcutaneous administration. It was possible that the area under of the curve for the intravenous administration was underestimated because most of the terminal elimination phase could not be documented due to the LLOQ of the assay. The mean apparent elimination half‐life of treprostinil following subcutaneous administration was 1.38 hours, compared to 0.87 hours following intravenous administration. It was concluded that treprostinil administered by subcutaneous administration is completely absorbed, with a slightly longer half‐life compared to intravenously administered treprostinil.

Pharmacokinetics of treprostinil sodium administered by 28-day chronic continuous subcutaneous infusion.

The objective of this study was to assess the pharmacokinetics and safety of treprostinil sodium administered as a 28‐day continuous subcutaneous infusion at escalating infusion rates of 2.5 to 15 ng/kg/min in normal subjects. Fourteen healthy adult volunteers received a 28‐day continuous subcutaneous infusion of treprostinil at escalating infusion rates of 2.5, 5, 10, and 15 ng/kg/min. Doses were escalated every 7 days with no washouts between escalations. Serial plasma samples were collected predosing, during dosing, and postdosing. Samples were also collected every 3 hours on Day 7 of each dosing period to evaluate diurnal variation over a 24‐hour steady‐state interval. Plasma treprostinil concentration was measured by a validated liquid chromatography atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 25 pg/mL. Distinct steady states were achieved for each of the four treprostinil doses. Linear regression analysis of mean steady‐state treprostinil concentration versus targeted dose yielded a fitted line with an r2 of 0.92. Variation in apparent plasma clearance for the four doses was small (i.e., 9.77–10.4 mL/kg/min). Consistent diurnal cycles of two peak and two trough treprostinil concentrations were observed over a 24‐hour steady‐state interval for each dose with peak levels 20% to 30% higher than trough levels. The terminal half‐life of treprostinil was 2.93 hours. Intersubject variability for mean pharmacokinetic parameters was small (coefficients of variation ranging from 13.6%–25.5%). At clinically relevant doses, the pharmacokinetics of treprostinil were linear and dose independent with modest, consistent diurnal cycles consisting of two daily peaks and two daily troughs observed for all four doses. In addition, the elimination half‐life was about 3 hours.

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.

The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod in healthy subjects

AIMS The authors determined whether intravenous atropine can prevent or counteract the negative chronotropic effect of the immunomodulator fingolimod. METHODS In this randomized, placebo-controlled, two-period, crossover study, 12 healthy subjects received 5 mg fingolimod orally concurrently with intravenous atropine (titrated to a heart rate of 110-120 beats min(-1)) or intravenous placebo. A second group of 12 subjects received atropine/placebo 4 h after the fingolimod dose. Continuous telemetry measurements were made for 24 h after each fingolimod dose. RESULTS Fingolimod administration alone yielded a heart rate nadir of 51 +/- 5 beats min(-1) at a median 4 h postdose with heart rate remaining depressed at 51-64 beats min(-1) over the rest of the day. Concurrent administration of fingolimod and atropine yielded a nadir of 66 +/- 6 beats min(-1) resulting in an atropine: placebo ratio (90% confidence interval) of 1.30 (1.22, 1.36). When atropine was administered at the time of the nadir, it was able to reverse the negative chronotropic effect of fingolimod from a heart rate of 56 +/- 9 beats min(-1) (placebo) to 64 +/- 8 beats min(-1) (atropine) resulting in an atropine: placebo ratio of 1.15 (1.04, 1.26). Atropine had no influence on the pharmacokinetics of fingolimod. CONCLUSIONS Atropine administered concurrently with fingolimod prevented the heart rate nadir that typically occurs 4 h postdose. Atropine administered at the time of the heart rate nadir was able to reverse the negative chronotropic effect of fingolimod.