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Pharmacokinetics of Treprostinil Sodium Administered by 28-Day Chronic Continuous Subcutaneous Infusion

From United Therapeutics Corporation, Research Triangle Park, North Carolina (Dr. Wade, Ms. Baker, Dr. Roscigno, Mr. DellaMaestra, Mr. Arneson); CPKD Solutions, LLC, Research Triangle Park, North Carolina (Dr. Lai); and PPD Development, Austin, Texas (Dr. Hunt).

Address for reprints: Michael Wade, PhD, United Therapeutics Corporation, One Park Drive, P.O. Box 14186, Research Triangle Park, NC 27709.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
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 sub-cutaneous 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.

Key Words: Treprostinil sodium • Remodulin® • subcutaneous infusion • chronic pharmacokinetics • pulmonary arterial hypertension • prostacyclin

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Study Design
This was a single-center, open-label, nonrandomized, chronic, dose escalation study conducted at the PPD Development Clinical Research Unit (Austin, TX) between July 15 and August 26, 1999. Eligible volunteers received a 28-day, continuous, subcutaneous treprostinil infusion at escalating doses of 2.5, 5, 10, and 15 ng/kg/min. Dose increases were made at 7-day intervals with no washouts between escalations. Subjects were dosed in the clinic and remained confined in the clinic throughout the treatment phase of the study.

All subjects gave written informed consent prior to any study-related assessments. The study was approved by a local institutional review board (Research Consultants Review Committee) and conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and in conformance with the U.S. Code of Federal Regulations (Title 21 CFR, Parts 50 and 56).

Subject Population
Eligible subjects were healthy adult (ages 18-50 years) males and nonpregnant, nonlactating females who were in general good health, as confirmed by physical examination, medical history, and clinical laboratory evaluations, and without known symptomatic postural hypotension or a history of cardiovascular, pulmonary, or blood-clotting disorders. Prescription and over-the-counter medications were prohibited within 14 days and 72 hours of study entry, respectively.

Dosing
Treprostinil sodium was provided as a sterile, progeny-free isotonic solution in 20-mL multidose vials (Lot 800559). Each milliliter contained 1.0 mg treprostinil sodium, 6.3 mg sodium citrate, 3.0 mg metacresol (preservative), 0.24 mg sodium hydroxide, and 5.3 mg sodium chloride. The formulation was buffered with a citric acid/sodium citrate buffer. Hydrochloric acid or sodium hydroxide was used to adjust the pH to 6.5.

The initial dose rate was 2.5 ng/kg/min for 7 days (Period 1) followed by dose increases every 7 days, provided no clinically relevant abnormalities were observed at the previous dose. Escalations were made without washouts between doses as follows: 5 ng/kg/min during Week 2 (Period 2), 10 ng/kg/min during Week 3 (Period 3), and 15 ng/kg/min during Week 4 (Period 4).

Treprostinil was used as supplied without dilution and delivered via a subcutaneous catheter placed in the abdominal wall using a microinfusion, positive-pressure infusion pump designed for subcutaneous drug delivery (MiniMed, Sylmar, CA, Model 506). The infusion site was rotated every 24 hours. Dose escalations were made when the infusion site was moved with the pump and cannula primed and the MiniMed pump set to the appropriate new rate. Subjects received three planned meals a day on a fixed schedule throughout the study, and water was consumed as needed.

Pharmacokinetic Sampling
During each of the 7-day dosing periods, blood samples for pharmacokinetic analysis were collected predose and at the following time points relative to the start of the infusion: 0.25, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 48, 72, 96, 120, 144, 147, 150, 153, 156, 159, 162, and 168 hours. Multiple plasma samples were also collected on Day 7 of each dosing period (at 3-h intervals) to evaluate diurnal variations over a 24-hour steady-state interval. All blood samples were drawn from an arm vein. A saline lock was used to keep the catheter patent during frequent blood sampling on Days 1 and 7 of each dosing period.

At the end of Period 4, blood samples were collected following the termination of the infusion to monitor the decline of plasma treprostinil concentrations. These time points were as follows: 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, and 9 hours postinfusion. In the event of early study termination, every attempt was made to collect these postinfusion samples.

Assay Methodology
Plasma samples were analyzed for treprostinil sodium concentrations by Alta Analytical Laboratory (El Dorado Hills, CA). A validated liquid chromatography atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) assay with a lower limit of quantitation (LLOQ) of 25 pg/mL for a 1-mL aliquot of plasma was used to analyze plasma samples anticoagulated with K₃EDTA. The mean percent accuracy values of quality control samples for the method were 101.3%, 100.0%, and 99.4% of theoretical values, with precision (expressed as coefficient of variation [CV]) of 2.5%, 1.7%, and 1.3% at 0.075, 4.0, and 8.0 ng/mL of treprostinil, respectively. The CV was 8.9% at the LLOQ of 0.25 ng/mL. A dimethylene homologue of treprostinil (LRXA-97 J02, Cardinal Pharmaceutical Development, Morrisville, NC) was used as an internal standard. Pooled control human K₃EDTA plasma (Biochemed Pharmacologicals, Winchester, VA, and Bioreclamation, Inc., Hicksville, NY) was used to prepare calibration standards.

Plasma (1.0 mL) was extracted using a 30:70 (v:v) ethyl acetate/hexane mixture. Aqueous phase extracts were evaporated to dryness under nitrogen, reconstituted in 50:50 methanol/Mobile Phase A, and refrigerated until analyzed. Extracts were analyzed using a 100 x 2-mm reversed-phase C18 analytical column (Betasil C18, Keystone Scientific, State College, PA) at a flow rate of 0.3 mL/min. The mobile phase was isocratic (A/B = 35:65). Mobile Phase A was 95:5 water/100 mM NH₄COOH with 0.1% formic acid. Mobile Phase B was 95:5 ACN/NH₄COOH with 0.1% formic acid. Retention times for treprostinil and its internal standard were approximately 2.5 and 3.5 minutes.

Detection was by tandem mass spectrometry (PESCIEX API III or PE-SCIEX API 365). An ionspray atmospheric pressure ionization inlet connected the high-pressure liquid chromatography (HPLC) system to the mass spectrometer. Analysis was by negative ionization using the [M-H] molecular ions as precursors. Peak areas were integrated using PE-SCIEX MacQuan software. Calibration curves were derived from peak area ratios (analyte/internal standard) using a least squares regression of the ratio versus the nominal concentration of the standards. Reliability of the procedure was evaluated after analysis of duplicate standards at seven concentrations (0.025, 0.05, 0.100, 0.500, 1.000, 5.000, and 10.000 ng/mL). The LLOQ using a 25-mcL injection volume was 0.025 ng/mL.

Pharmacokinetic Parameters and Analyses
Each subject's plasma treprostinil concentration versus time profile over the 28 days (i.e., over four consecutive 7-day dosing periods) or until withdrawal from the study was plotted on Cartesian coordinates. The decline of plasma treprostinil concentrations postinfusion was plotted on semi-log coordinates. These plots were made to show the log-linear decline of the terminal elimination phase (data on file, United Therapeutics Corp.).

Pharmacokinetic evaluations focused on (a) the relationship of steady-state plasma concentration versus dose, (b) CL/F (clearance divided by absolute bioavailability) determined from the ratio of infusion rate and steady-state concentration for each treprostinil dose, (c) the presence of a diurnal cycle of plasma treprostinil concentrations over a 24-hour steady-state infusion interval (i.e., Day 7 of each dosing period), and (d) t_1/2 upon termination of chronic subcutaneous infusion.

Subjects considered evaluable for the determination of the relationship of steady-state plasma concentration versus targeted dose and CL had achieved steady-state plasma concentrations for at least 3 dosing days (72 h) in a dosing period. This included 14, 13, 13, and 12 subjects at 2.5, 5, 10, and 15 ng/kg/min, respectively. Subjects considered evaluable for analysis of diurnal cycles in steady-state plasma levels provided plasma samples on Day 7 for a particular dosing period. This included 14, 13, 13, and 6 subjects at 2.5, 5, 10, and 15 ng/kg/min, respectively. Finally, determination of t_1/2 values included 1 subject and 13 subjects who contributed plasma treprostinil concentrations for Periods 2 and 4, respectively.

The pharmacokinetic analyses were performed by CPKD Solutions, LLC (Research Triangle Park, NC) using the noncompartmental routine in WinNonlin Version 1.1. The results of pharmacokinetic analyses were summarized by topics (i.e., dose proportionality, diurnal cycles, and pharmacokinetic parameters of interest) in tabular form.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
A total of 14 healthy adult subjects were enrolled, including 8 females and 6 males (10 Caucasian, 2 Black, 1 Asian, and 1 Hispanic) who were 23 to 49 years of age (mean age = 36.2 ± 8.8 years) and 52.2 to 86.9 kg in weight (mean weight = 70.7 ± 10.3 kg). Six of the 14 subjects completed the study, and the other 8 subjects prematurely withdrew because of infusion site pain, a well-characterized side effect of treprostinil s odium.^11,12 One subject withdrew during the 5-ng/kg/min infusion, and the remaining 7 subjects withdrew during the 15-ng/kg/min infusion. Twelve subjects, including 6 who withdrew prematurely, provided steady-state treprostinil concentrations for all four dosing periods for analysis. A total of 141 adverse events were reported by 13 of the 14 subjects; none of these adverse events was serious, and all resolved without sequelae. The adverse events generally reflected well-characterized side effects of treprostinil and other prostanoids.^11,12 Other than infusion site pain, reaction, or hematoma, adverse events first reported by more than 1 subject during each dosing period included pain (general), asthenia, nausea, anorexia, diarrhea, myalgia, arthralgia, dizziness, and akathisia; these adverse events are summarized in Table I by the dosing period in which the events first occurred.

Figure 1 depicts the mean plasma treprostinil concentration profiles across the four dosing periods (i.e., across 28 days of dosing). This plot shows that four distinct steady states were achieved in this 28-day study, with each steady state corresponding to each of the four treprostinil infusion rates. Plasma treprostinil concentration achieved the first steady state within 24 hours at the initial dose of 2.5 ng/kg/min, and subsequent steady states were also achieved within a similar duration after treprostinil infusion rates were increased to 5, 10, and 15 ng/kg/min. The pattern for achieving steady state was similar across the four doses.

View larger version (11K): [in this window] [in a new window]   Figure 1. Mean plasma treprostinil plasma concentration across 28 days of dosing, with scheduled dose increases at 7-day intervals.

A descriptive summary of steady-state pharmacokinetic parameters is provided in Table II. Mean steady-state plasma concentrations for individual subjects (C_ss) increased in a dose-proportional fashion (ranging from 0.259-1.564 ng/mL), while mean CL values remained consistent across the four treprostinil doses (ranging from 9.77-10.446 mL/kg/min).

The linear regression analysis of steady-state treprostinil concentration versus targeted dose is depicted in Figure 2. The analysis yielded a fitted line, with a coefficient of determination (r²) of 0.92 demonstrating a linear relationship between steady-state concentration and dose. This finding, taken together with the consistency of the mean CL/F values across the four doses (ranging from 586.2-626.8 mL/h/kg), suggests that the pharmacokinetics of treprostinil are linear and dose independent.

View larger version (11K): [in this window] [in a new window]   Figure 2. Linear regression analysis of steady-state plasma treprostinil concentrations versus target dose.

Modest diurnal variations in plasma treprostinil concentration over a 24-hour steady-state interval for serial plasma samples collected on Day 7 of each dosing period are depicted by targeted dose in Figure 3. Over a 24-hour steady-state period, plasma treprostinil concentrations achieved peak levels twice (at 1 a.m. and 10 a.m.) and trough levels twice (at 4 p.m. and 7 a.m.) at all four treprostinil doses. The peak concentrations were about 20% to 30% higher than the trough concentrations. A comparison of apparent peak (infusion hour 147) and apparent trough (hour 153) concentrations using Wilcoxon's signed rank test showed that the concentrations appear different within each period (p = 0.0482, 0.048, < 0.001, and 0.031 in Periods 1, 2, 3, and 4, respectively).

View larger version (19K): [in this window] [in a new window]   Figure 3. Diurnal variation in plasma treprostinil concentration on Day 7 of each dosing period. Target doses in Periods 1, 2, 3, and 4 were, respectively, 2.5, 5, 10, and 15 ng/kg/min.

The mean t_1/2 value following the termination of chronic infusion in Period 4 was 2.93 hours, with a CV of 25.6% (Table I). However, plasma treprostinil concentration declined from 1.2 to 0.1 ng/mL (i.e., a 92% drop) within 9 hours from termination of the chronic infusion. The t_1/2 was 3.10 hours for 1 subject who withdrew from the study during Period 2. The decline in mean plasma treprostinil concentration following the end of the Period 4 infusion appeared to follow a straight line decay when plotted as a semi-log plot (data on file, United Therapeutics Corp.).

Intersubject variability around the various mean pharmacokinetic parameters was small, ranging from 13.6% to 25.6%.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The pharmacokinetics of treprostinil sodium administered as a long-term, continuous, subcutaneous infusion were determined in 14 normal subjects. A total of 141 adverse events were reported in 13 of the subjects; most of the events were well characterized in previous studies and considered related to treprostinil's pharmacologic effects. Eight subjects withdrew from the study because of the infusion site pain, although steady-state plasma level data were obtained from 12 subjects at all four dose levels. Plasma treprostinil concentration climbed from the origin and achieved the first steady state within 24 hours following the first treprostinil dose at 2.5 ng/kg/min. Subsequent steady states were also achieved in a similar pattern after treprostinil infusion rates were increased to 5, 10, and 15 ng/kg/min. Linear regression analysis of steady-state plasma treprostinil concentrations versus subcutaneous infusion rates yielded a coefficient of determination of 0.92. In addition, mean plasma CL values varied within a narrow range across the four treprostinil infusion rates (9.77-10.446 mL/kg/min), and mean CL/F values were also consistent across the four doses (586.2-626.8 mL/h/kg). Incidentally, the treprostinil plasma CL values determined in this study were similar to those observed in a previous acute-dose study in which treprostinil was administered in a single acute subcutaneous infusion at a fixed rate of 15 ng/kg/min given over 150 minutes in healthy volunteers (i.e., 589.4 mL/kg/h).¹³

These results suggest that the pharmacokinetics of treprostinil administered by long-term, continuous, subcutaneous infusion are linear and dose independent at clinically relevant doses. From a therapeutic perspective, the finding of dose-independent, linear pharmacokinetics for treprostinil during subcutaneous administration means that the systemic exposure to treprostinil increases proportionately with dose. In fact, the mean steady-state plasma concentrations increased with dose, ranging from 0.26 ng/mL at 2.5 ng/kg/min to 1.56 ng/mL at 15 ng/kg/min.

There were clear but modest diurnal cycles in steady-state treprostinil levels over a 24-hour period in each dosing period. The patterns of diurnal variations were similar for all four treprostinil doses, with peak levels observed at 10 a.m. and 1 a.m. and trough levels observed at 7 a.m. and 4 p.m. The peak levels were approximately 20% to 30% higher than the trough levels. Diurnal variations in plasma concentrations have been reported previously for native prostanoids.^14-17 This finding explained some of the "noise" observed during the climb of plasma treprostinil concentration from zero for a new infusion or from a previous steady-state concentration after the infusion rate had been increased.

The treprostinil elimination half-life following chronic infusion was approximately 3 hours, almost twice that observed following subcutaneous infusion in an acute-dose study.¹³ However, it should be noted that the plasma treprostinil concentration declined from 1.2 to 0.1 ng/mL (a 92% drop) within 9 hours from termination of the infusion (data on file, United Therapeutics Corp.). The elimination half-life of treprostinil could have been prolonged because of the slow return of the drug in deep tissues back into the systemic circulation. From a clinical point of view, the persistence of significant levels of treprostinil in the plasma for a few hours may provide a safety margin in patients with PAH relative to intravenous prostacyclin in the case of accidental interruption of delivery.

Upon initiation of a subcutaneous infusion or a change in subcutaneous dose, steady-state plasma treprostinil is expected to be achieved within 15 to 18 hours. Based on the same principle, treprostinil's presence in the systemic circulation is expected to disappear within 15 to 18 hours upon the termination of a subcutaneous infusion.

In conclusion, chronic continuous subcutaneous treprostinil was generally well tolerated in normal volunteers. Adverse events were common and consistent with the known pharmacologic effects of treprostinil. Subcutaneous infusion site pain was reported in most patients and led to the withdrawal of 8 of 14 subjects, although 12 subjects provided steady-state plasma-level data at all four doses. The chronic pharmacokinetics of treprostinil were linear and dose independent in normal volunteers across the range of doses (2.5-15 ng/kg/min). A modest diurnal pattern of two peaks and two troughs in plasma level was observed across all four doses. A new steady-state plasma treprostinil level is expected to be achieved within 15 to 18 hours of initiating the infusion or a dose change. The elimination half-life of subcutaneous treprostinil is approximately 3 hours.

	ACKNOWLEDGEMENTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
We thank Lauren Cierpial and Courtnay Peters for assistance with the manuscript. This study was funded by United Therapeutics Corporation.

	FOOTNOTES

 
DOI: 10.1177/0091270004264638

Submitted for publication July 18, 2003; Revised version accepted February 15, 2004.

	REFERENCES

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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