Continuous low volume delivery of intravenous treprostinil via a central venous catheter with a miniature pump in a conscious dog model
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《血管的通路杂志》
1.United Therapeutics Corporation, Research Triangle Park, NC - USA
2.ITR Laboratories Canada Inc, Quebec - Canada
3.CTBR Bio-Research Inc, Quebec - Canada
ABSTRACT
Purpose: Two animal studies were conducted to determine the feasibility of infusing treprostinil via a central venous catheter at an infusion rate of 0.1 mL/hour. Currently treprostinil is administered intravenously at infusion rates of approximately 1.0 to 2.0 mL/hour to patients with pulmonary arterial hypertension, which reflects standard clinical practice to ensure line patency with continuous intravenous administration via a central venous catheter.
Methods: In a pilot study three male beagle dogs were administered 50 ng/kg/min of treprostinil continuously at an infusion rate of 0.1 mL/hr via the MiniMed 407C infusion pump for 21 days. In a definitive study, six male beagle dogs were administered 50 ng/kg/min of treprostinil continuously at an infusion rate of 0.1 mL/hr via the MiniMed 407C infusion pump for 60 days. In both studies 搉o delivery?pump alarms were documented throughout the study in addition to pharmacokinetic data at specified time points.
Results: There were no documented occlusions in the 21-day pilot study. In the 60-day study one animal had a documented
catheter occlusion after 16 days of therapy. Following reimplantation with a new catheter this animal did not have any additional occlusions for 40 days. No other animals in this study had any significant problems. In both studies, pharmacokinetic data were similar to that observed in previous animal studies evaluating treprostinil administration at the same dose and at higher infusion rates.
Conclusion: These animal data support the evaluation of administering treprostinil at a low infusion rate via the
MiniMed 407C infusion pump in patients with pulmonary arterial hypertension.
Key Words: Treprostinil sodium, Remodulin? Hickman? Infusion, Catheter, Patency, 407C Pump
INTRODUCTION
Pulmonary arterial hypertension (PAH) is a lifethreatening disease characterized by dyspnea, chest pain, and syncope. PAH can occur without known cause (Idiopathic or Familial Pulmonary Arterial Hypertension) or in association with collagen vascular disease, congenital systemic-to-pulmonary
shunts, portal hypertension, HIV infection, or drugs (anorexigens) or toxins (1). The most significant clinical finding upon right heart catheterization
is an elevation in the mean pulmonary arterial pressure (PAP). The main objective of treatment for PAH is to reduce PAP and pulmonary vascular
resistance. Prostacyclin and its analogues, because of their favorable effects on pulmonary hemodynamics, are accepted therapies for patients with
PAH. Treprostinil sodium (Remodulin? United Therapeutics Corporation, Research Triangle Park, North Carolina) is a chemically stable, tricyclic benzindene analogue of prostacyclin that is approved in the United States and in other countries for continuous subcutaneous infusion in the treatment of PAH(2). In addition, treprostinil is approved in the US for intravenous administration for those patients with PAH not able to tolerate a subcutaneous
infusion. Currently, treprostinil is administered intravenously at infusion rates of approximately 1.0 to 2.0 mL/hour, which reflects standard clinical practice
to ensure line patency with continuous/chronic intravenous administration via a central venous catheter. These infusion rates require the use of large ambulatory pumps (Fig. 1) with up to 100 mL drug reservoirs (i.e. CADD Legacy Pump, Smiths Medical, St. Paul, Minnesota) which must be carried
by the patient continuously. Since treprostinil has potent anti-platelet aggregation characteristics and chemical stability over 48 hours, an obvious next step was to determine whether treprostinil could be infused at lower rates
using a smaller, less cumbersome intravenous infusion system than currently used to administer intravenous treprostinil. The MiniMed 407C pump (Medtronic MiniMed, Sylmar, California) has been frequently used to deliver treprostinil by continuous subcutaneous administration. This pump (Fig.
1) employs a custom 3-mL syringe and is accurate (?2%), easy to use, and has a no-delivery alarm. Therefore, it was considered that the 407C would
potentially be suitable for delivery of treprostinil intravenously.
Further, a delivery rate of approximately 0.1 mL/hour would allow a patient to
change the syringe once daily. Two animal studies (a 21-day pilot study and a 60- day definitive study) were conducted to determine the feasibility of infusing treprostinil via a central venous catheter at an infusion rate of 0.1 mL/hour. The main objective of these studies was to evaluate the potential for catheter occlusion when infusing treprostinil at this low infusion rate and to support the evaluation of this novel method of delivering treprostinil to patients with PAH in a clinical trial.
METHODS
Pilot study
Three male beagle dogs were administered treprostinil continuously at an infusion rate of 0.1 mL/hr via the MiniMed 407C infusion pump for 21 days.
Treprostinil was diluted with 0.9% sodium chloride in order to deliver approximately 50 ng/kg/min (based on an average body weight of the animals of 10 kg), a clinically relevant dose of treprostinil. The concentration of treprostinil was determined by HPLC from the dosing solutions on Days 1, 14, and 21. The intravenous catheter used to deliver treprostinil was a medical grade silastic catheter (approximately 122 cm in length with a 0.076 cm inner diameter) surgically implanted in the vena cava at the level of the kidneys via the femoral vein. During the course of the study all animals had the following examinations performed: verification of patency of the catheter system, mortality and signs of ill health or reaction to treatment twice daily,
and a detailed examination weekly. All pump alarms and suspected catheter occlusions were documented in the raw data. Individual body weights were measured weekly commencing prior to dosing and extending through the treatment period. Blood samples (approximately 1.0 mL each) for pharmacokinetic analysis were obtained on Days 3, 14, and 21 of the treatment period. Following the end of the infusion period, the catheters were tied off, cut and allowed to slip subcutaneously.
Definitive study
Six male beagle dogs were administered treprostinil at an infusion rate of 0.1 mL/hr via the MiniMed 407C infusion pump for 60 days. Treprostinil was diluted with 0.9% sodium chloride in order to deliver approximately 50 ng/kg/min of treprostinil (based on an average body weight of the animals). The intravenous catheter was a Hickman?(Bard Access Systems, Salt Lake City, Utah) 9.6 French single-lumen central venous catheter and was inserted into the femoral vein and advanced into the vena cava at the level of the kidneys. The appropriate connecting catheters (Baxa Administration Set, Minibore, Sterile, 76.2 cm x 0.076 cm inner diameter) were used to connect the Hickman catheter to the MiniMed 407C pump.
The syringes were changed approximately every 24 hours and the animal
weights recorded on a weekly basis. Dosing solution concentration djustments were made on a weekly basis based on a change in the average weight of the animals. The concentration of treprostinil was determined by HPLC from the dosing solutions on Days 1, 20, 40, and 60. The infusion system was checked daily for occlusions and any action to rectify the occlusion was documented. All pump alarms and a record of drug utilization was documented. Pump alarms were evaluated to determine if they were a result of a catheter occlusion or another pump malfunction (low battery, empty syringe, compromised extension set).
Cage-side clinical signs (ill health, behavioral changes, etc.) were recorded once daily during the treatment period. A detailed clinical examination
(including evaluation of all body surfaces, ill health and behavioral changes) of each dog was performed once pretreatment, weekly during the treatment
period and at the end of the study. Particular attention was paid to the surgical sites. Blood samples (approximately 1.0 mL each) for pharmacokinetic analysis were obtained on Days 3, 20, 40, and 60 of the treatment period. If the infusion terminated prior to Day 60 a blood sample for pharmacokinetic analysis was drawn on the last day of dosing, prior to infusion termination. At the end of the study the catheter tip was removed
from each animal, examined for presence of clotted material, and preserved in formalin.
Dosing solution and pharmacokinetic sample analysis methods
A validated high performance liquid chromatography (HPLC) assay was used to measure the concentration of treprostinil in the dosing solutions as previously described (3). A validated liquid chromatography tandem mass spectrometry (LC/MSMS) assay was used to measure the concentration of
treprostinil in the plasma samples of the dogs. Pharmacokinetic data gathered in the current studies were compared to toxicokinetic results evaluated in an earlier 13-week toxicology study that assessed the effect of continuous intravenous administration of Remodulin?via a central venous catheter to dogs at infusion rates of 0.75 mL/kg/hr. In this previous study 8 animals per group (7 to 10 kg each) received one of three Remodulin?doses (50, 100, or 200 ng/kg/min) or placebo for 13-weeks with full toxicological evaluation throughout the dosing and recovery period. Samples for toxicokinetic evaluation were collected on Day 1 (at 3 hours post start of infusion), and on Days 7, 21, 35, 49, 63, 77 and 91. The bioanalytical method used was similar to that previously described (4, 5) but with a lower limit of quantitation (LLOQ) of 0.250 ng/mL for dog plasma.
RESULTS
Pilot study
Three male beagle dogs were dosed with 50 ng/kg/min of treprostinil at an infusion rate of 0.1 mL/hr through a medical grade silastic central venous
catheter using the MiniMed 407C infusion pump. No pump alarms indicating occlusion of the infusion line were documented during the 21-day treatment period. On one occasion, a daily deviation of -61% was due to a pump programming error at the time of a dosing syringe change. This error was corrected after 12 hours of infusion at the erroneous rate. On all other days of dosing animals received within ?0% of their nominal dose. Analysis of dosing solutions confirmed that treprostinil concentrations were within 2% of the intended concentration. No adverse clinical signs that were considered related to treprostinil or problems with the catheter were noted in any animals. The results from the plasma analysis are presented in Table I. In general, plasma drug concentrations were comparable between animals
and days of dosing, with the exception of Animal 101 on Day 14. As no problems with the infusion set-up were documented, the reason for absence of drug on this occasion is unknown. Observed plasma concentrations were also comparable to pharmacokinetic data gathered in a 13-week toxicological evaluation of treprostinil in dogs when administered via a central venous catheter at a higher infusion rate (0.75 mL/kg/hr) and at the same dose (50 mg/kg/min). (Data on file, CTBR/United Therapeutics Corp).
Definitive study
Six male beagle dogs were dosed with 50 ng/kg/min of treprostinil at an infusion rate of 0.1 mL/hr through a Hickman?catheter using the MiniMed
407C infusion pump. Six pump alarms were documented throughout the 60 day treatment period. In most instances prior to a pump alarm, the catheter or extension set was compromised in some manner (e.g. severed catheter or kinked/twisted catheter or extension set). In these instances, a pump alarm was rectified with minimal intervention and restart of the infusion pump.
A 憂o delivery?pump alarm on Day 16 of treatment for animal 1006A required surgery to replace the catheter. Following three consecutive pump alarms
an attempt was made to withdraw the dosing solution from the catheter without success. Following a small bolus of saline and withdrawal from the catheter, small pieces of clotted material appeared from the catheter. Upon removal of this catheter from the animal, on Day 20, a dark, soft material 15 centimeters in length was found in the catheter lumen, near the catheter tip. There were no other abnormalities associated with the catheter. This same dog was implanted with a new Hickman catheter which remained patent for the remaining 40 days of the study. At the end of the 60-day dosing period catheters were removed from the animals and examined for damage or any clotted material adhered to the tip of the catheter. For all animals, including the animal that had previously experienced an occlusion, there was no clotted material or damage to any of the catheters or catheter tips. Over the course of the study all animals received the intended dose within ?5% with the exception of animal 1006A which received within ?10%. Analysis of dosing solutions confirmed that treprostinil concentrations were within 4% of the intended concentration. The pharmacokinetic data also supported that
treprostinil was delivered into the systemic circulation at the 0.1 mL/hr infusion rate. Table I displays the average plasma concentrations for animals undergoing dosing on the days when samples were collected. Overall the concentrations were consistent comparing the various days and animals, although Day 3 plasma concentrations appeared to be slightly greater and more variable than Days 20, 40, and 60 and compared to previous toxicology studies.
DISCUSSION
Currently available intravenous therapies for the treatment of PAH require the use of large ambulatory infusion pumps to administer drug continuously through a surgically placed central catheter. The ability to use a smaller infusion pump could represent a significant quality of life improvement
for PAH patients since prostacyclin therapy is a continuous, lifelong treatment for their disease. Infusion of intravenous treprostinil at a low infusion rate (0.1 mL/hour) leverages the pharmacology (potent inhibitor of platelet aggregation) (6) and chemical stability of treprostinil to allow patients to
receive an effective treatment for their disease using a much smaller pump (MiniMed 407C). In order to support the evaluation of this novel delivery
method in patients with PAH two pre-clinical studies were conducted to investigate the feasibility of using the MiniMed 407C to deliver treprostinil at
an infusion rate of 0.1 mL/hour. In general, the studies demonstrated that treprostinil can be infused at 0.1 mL/hour in dogs and maintain catheter patency. While one animal experienced an occlusion of its Hickman?catheter, this finding was potentially attributed to a catheter placement issue
subsequently pre-disposing the animal to an occlusion.
This was confirmed following replacement of the catheter and infusion at 0.1 mL/hour without an occlusion for an additional 40 days. For those animals dosed up to 60 days with this regimen, there was no evidence of clot formation or abnormalities upon removal of the catheter supporting
the feasibility of the infusion method. One variable that was taken into consideration in the design of these studies was the lack of anticoagulation
therapy in the animals. This circumstance provided a more rigorous test of this novel infusion method for two reasons. First, dogs have a more active
clotting system when compared to humans. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are estimated to be two and three times lower in dogs compared to humans, respectively. Additionally, dogs have been shown to have higher activity of factors involved in
the coagulation cascade, such as Factor XI, XII, and high molecular weight kininogen (7). Second, in clinical practice up to 85% of PAH patients receive
some form of anticoagulation (warfarin, heparin, low molecular weight heparin) as part of their disease management, as anticoagulation nearly doubles the three-year survival rate in this patient population (8, 9). Therefore, the relative risk of clot formation should be reduced in patients, since humans have a less active clotting system compared to dogs and most patients would be receiving anticoagulation therapy while administered treprostinil at low infusion rates. The scientific literature lacks information documenting the lowest infusion rate that can be used to administer a medication while maintaining catheter patency. Previously there has not been a need to reduce the volume of solution administered over time as patients receiving parenteral therapies are typically hospitalized or home bound for the duration of therapy. In the treatment of a chronic, life-threatening disease, such as PAH, it is not only important to treat patient symptoms but it is also necessary to maintain and/or improve quality of life. Reducing the size of the ambulatory infusion pump used to deliver therapy will enhance
patient satisfaction with intravenous prostacyclin administration.
These animal data support the clinical evaluation of administering treprostinil at a low infusion rate via the MiniMed 407C infusion pump in patients with pulmonary arterial hypertension.
REFERENCES
1. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43: 5S-12S.
2. Remodulin?(treprostinil sodium) Injection Package Insert. United Therapeutics Corporation, Research Triangle Park, North Carolina, USA. November 2004.
3. Phares K, Weires WE, Miller SP, et al. Stability and preservative effectiveness of treprostinil sodium after dilution in common intravenous diluents. Am J Health Syst Pharm 2003; 60: 916-922.
4. Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M. Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin? administered by the intravenous and subcutaneous route to normal volunteers. J Cardiovasc Pharmacol 2004; 44: 209-14.
5. Wade M, Baker FJ, Roscigno R, et al. Pharmacokinetics of treprostinil sodium administered by 28-day chronic continuous subcutaneous infusion. J Clin Pharmacol 2004; 44: 503-509.
6. Jorgensen KA, Dyerberg J, Stoffersen E. A biphasic effect of prostacyclin (PGI2) on platelet aggregation. Thromb Res 1980; 19: 877-81.
7. Noguchi M, Fujii T, Minamide S. Comparative studies of measuring condition of activated partial thromboplastin time and contact factors in experimental animals. Jikken Dobutsu 1989; 38: 221-9.
8. Fuster V, Steele PM, Edwards WD, Gersh BJ, Mc-Goon MD, Frye RL. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70: 580-7.
9. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327: 76-81.(K. Laliberte, S. Jerat, K)
2.ITR Laboratories Canada Inc, Quebec - Canada
3.CTBR Bio-Research Inc, Quebec - Canada
ABSTRACT
Purpose: Two animal studies were conducted to determine the feasibility of infusing treprostinil via a central venous catheter at an infusion rate of 0.1 mL/hour. Currently treprostinil is administered intravenously at infusion rates of approximately 1.0 to 2.0 mL/hour to patients with pulmonary arterial hypertension, which reflects standard clinical practice to ensure line patency with continuous intravenous administration via a central venous catheter.
Methods: In a pilot study three male beagle dogs were administered 50 ng/kg/min of treprostinil continuously at an infusion rate of 0.1 mL/hr via the MiniMed 407C infusion pump for 21 days. In a definitive study, six male beagle dogs were administered 50 ng/kg/min of treprostinil continuously at an infusion rate of 0.1 mL/hr via the MiniMed 407C infusion pump for 60 days. In both studies 搉o delivery?pump alarms were documented throughout the study in addition to pharmacokinetic data at specified time points.
Results: There were no documented occlusions in the 21-day pilot study. In the 60-day study one animal had a documented
catheter occlusion after 16 days of therapy. Following reimplantation with a new catheter this animal did not have any additional occlusions for 40 days. No other animals in this study had any significant problems. In both studies, pharmacokinetic data were similar to that observed in previous animal studies evaluating treprostinil administration at the same dose and at higher infusion rates.
Conclusion: These animal data support the evaluation of administering treprostinil at a low infusion rate via the
MiniMed 407C infusion pump in patients with pulmonary arterial hypertension.
Key Words: Treprostinil sodium, Remodulin? Hickman? Infusion, Catheter, Patency, 407C Pump
INTRODUCTION
Pulmonary arterial hypertension (PAH) is a lifethreatening disease characterized by dyspnea, chest pain, and syncope. PAH can occur without known cause (Idiopathic or Familial Pulmonary Arterial Hypertension) or in association with collagen vascular disease, congenital systemic-to-pulmonary
shunts, portal hypertension, HIV infection, or drugs (anorexigens) or toxins (1). The most significant clinical finding upon right heart catheterization
is an elevation in the mean pulmonary arterial pressure (PAP). The main objective of treatment for PAH is to reduce PAP and pulmonary vascular
resistance. Prostacyclin and its analogues, because of their favorable effects on pulmonary hemodynamics, are accepted therapies for patients with
PAH. Treprostinil sodium (Remodulin? United Therapeutics Corporation, Research Triangle Park, North Carolina) is a chemically stable, tricyclic benzindene analogue of prostacyclin that is approved in the United States and in other countries for continuous subcutaneous infusion in the treatment of PAH(2). In addition, treprostinil is approved in the US for intravenous administration for those patients with PAH not able to tolerate a subcutaneous
infusion. Currently, treprostinil is administered intravenously at infusion rates of approximately 1.0 to 2.0 mL/hour, which reflects standard clinical practice
to ensure line patency with continuous/chronic intravenous administration via a central venous catheter. These infusion rates require the use of large ambulatory pumps (Fig. 1) with up to 100 mL drug reservoirs (i.e. CADD Legacy Pump, Smiths Medical, St. Paul, Minnesota) which must be carried
by the patient continuously. Since treprostinil has potent anti-platelet aggregation characteristics and chemical stability over 48 hours, an obvious next step was to determine whether treprostinil could be infused at lower rates
using a smaller, less cumbersome intravenous infusion system than currently used to administer intravenous treprostinil. The MiniMed 407C pump (Medtronic MiniMed, Sylmar, California) has been frequently used to deliver treprostinil by continuous subcutaneous administration. This pump (Fig.
1) employs a custom 3-mL syringe and is accurate (?2%), easy to use, and has a no-delivery alarm. Therefore, it was considered that the 407C would
potentially be suitable for delivery of treprostinil intravenously.
Further, a delivery rate of approximately 0.1 mL/hour would allow a patient to
change the syringe once daily. Two animal studies (a 21-day pilot study and a 60- day definitive study) were conducted to determine the feasibility of infusing treprostinil via a central venous catheter at an infusion rate of 0.1 mL/hour. The main objective of these studies was to evaluate the potential for catheter occlusion when infusing treprostinil at this low infusion rate and to support the evaluation of this novel method of delivering treprostinil to patients with PAH in a clinical trial.
METHODS
Pilot study
Three male beagle dogs were administered treprostinil continuously at an infusion rate of 0.1 mL/hr via the MiniMed 407C infusion pump for 21 days.
Treprostinil was diluted with 0.9% sodium chloride in order to deliver approximately 50 ng/kg/min (based on an average body weight of the animals of 10 kg), a clinically relevant dose of treprostinil. The concentration of treprostinil was determined by HPLC from the dosing solutions on Days 1, 14, and 21. The intravenous catheter used to deliver treprostinil was a medical grade silastic catheter (approximately 122 cm in length with a 0.076 cm inner diameter) surgically implanted in the vena cava at the level of the kidneys via the femoral vein. During the course of the study all animals had the following examinations performed: verification of patency of the catheter system, mortality and signs of ill health or reaction to treatment twice daily,
and a detailed examination weekly. All pump alarms and suspected catheter occlusions were documented in the raw data. Individual body weights were measured weekly commencing prior to dosing and extending through the treatment period. Blood samples (approximately 1.0 mL each) for pharmacokinetic analysis were obtained on Days 3, 14, and 21 of the treatment period. Following the end of the infusion period, the catheters were tied off, cut and allowed to slip subcutaneously.
Definitive study
Six male beagle dogs were administered treprostinil at an infusion rate of 0.1 mL/hr via the MiniMed 407C infusion pump for 60 days. Treprostinil was diluted with 0.9% sodium chloride in order to deliver approximately 50 ng/kg/min of treprostinil (based on an average body weight of the animals). The intravenous catheter was a Hickman?(Bard Access Systems, Salt Lake City, Utah) 9.6 French single-lumen central venous catheter and was inserted into the femoral vein and advanced into the vena cava at the level of the kidneys. The appropriate connecting catheters (Baxa Administration Set, Minibore, Sterile, 76.2 cm x 0.076 cm inner diameter) were used to connect the Hickman catheter to the MiniMed 407C pump.
The syringes were changed approximately every 24 hours and the animal
weights recorded on a weekly basis. Dosing solution concentration djustments were made on a weekly basis based on a change in the average weight of the animals. The concentration of treprostinil was determined by HPLC from the dosing solutions on Days 1, 20, 40, and 60. The infusion system was checked daily for occlusions and any action to rectify the occlusion was documented. All pump alarms and a record of drug utilization was documented. Pump alarms were evaluated to determine if they were a result of a catheter occlusion or another pump malfunction (low battery, empty syringe, compromised extension set).
Cage-side clinical signs (ill health, behavioral changes, etc.) were recorded once daily during the treatment period. A detailed clinical examination
(including evaluation of all body surfaces, ill health and behavioral changes) of each dog was performed once pretreatment, weekly during the treatment
period and at the end of the study. Particular attention was paid to the surgical sites. Blood samples (approximately 1.0 mL each) for pharmacokinetic analysis were obtained on Days 3, 20, 40, and 60 of the treatment period. If the infusion terminated prior to Day 60 a blood sample for pharmacokinetic analysis was drawn on the last day of dosing, prior to infusion termination. At the end of the study the catheter tip was removed
from each animal, examined for presence of clotted material, and preserved in formalin.
Dosing solution and pharmacokinetic sample analysis methods
A validated high performance liquid chromatography (HPLC) assay was used to measure the concentration of treprostinil in the dosing solutions as previously described (3). A validated liquid chromatography tandem mass spectrometry (LC/MSMS) assay was used to measure the concentration of
treprostinil in the plasma samples of the dogs. Pharmacokinetic data gathered in the current studies were compared to toxicokinetic results evaluated in an earlier 13-week toxicology study that assessed the effect of continuous intravenous administration of Remodulin?via a central venous catheter to dogs at infusion rates of 0.75 mL/kg/hr. In this previous study 8 animals per group (7 to 10 kg each) received one of three Remodulin?doses (50, 100, or 200 ng/kg/min) or placebo for 13-weeks with full toxicological evaluation throughout the dosing and recovery period. Samples for toxicokinetic evaluation were collected on Day 1 (at 3 hours post start of infusion), and on Days 7, 21, 35, 49, 63, 77 and 91. The bioanalytical method used was similar to that previously described (4, 5) but with a lower limit of quantitation (LLOQ) of 0.250 ng/mL for dog plasma.
RESULTS
Pilot study
Three male beagle dogs were dosed with 50 ng/kg/min of treprostinil at an infusion rate of 0.1 mL/hr through a medical grade silastic central venous
catheter using the MiniMed 407C infusion pump. No pump alarms indicating occlusion of the infusion line were documented during the 21-day treatment period. On one occasion, a daily deviation of -61% was due to a pump programming error at the time of a dosing syringe change. This error was corrected after 12 hours of infusion at the erroneous rate. On all other days of dosing animals received within ?0% of their nominal dose. Analysis of dosing solutions confirmed that treprostinil concentrations were within 2% of the intended concentration. No adverse clinical signs that were considered related to treprostinil or problems with the catheter were noted in any animals. The results from the plasma analysis are presented in Table I. In general, plasma drug concentrations were comparable between animals
and days of dosing, with the exception of Animal 101 on Day 14. As no problems with the infusion set-up were documented, the reason for absence of drug on this occasion is unknown. Observed plasma concentrations were also comparable to pharmacokinetic data gathered in a 13-week toxicological evaluation of treprostinil in dogs when administered via a central venous catheter at a higher infusion rate (0.75 mL/kg/hr) and at the same dose (50 mg/kg/min). (Data on file, CTBR/United Therapeutics Corp).
Definitive study
Six male beagle dogs were dosed with 50 ng/kg/min of treprostinil at an infusion rate of 0.1 mL/hr through a Hickman?catheter using the MiniMed
407C infusion pump. Six pump alarms were documented throughout the 60 day treatment period. In most instances prior to a pump alarm, the catheter or extension set was compromised in some manner (e.g. severed catheter or kinked/twisted catheter or extension set). In these instances, a pump alarm was rectified with minimal intervention and restart of the infusion pump.
A 憂o delivery?pump alarm on Day 16 of treatment for animal 1006A required surgery to replace the catheter. Following three consecutive pump alarms
an attempt was made to withdraw the dosing solution from the catheter without success. Following a small bolus of saline and withdrawal from the catheter, small pieces of clotted material appeared from the catheter. Upon removal of this catheter from the animal, on Day 20, a dark, soft material 15 centimeters in length was found in the catheter lumen, near the catheter tip. There were no other abnormalities associated with the catheter. This same dog was implanted with a new Hickman catheter which remained patent for the remaining 40 days of the study. At the end of the 60-day dosing period catheters were removed from the animals and examined for damage or any clotted material adhered to the tip of the catheter. For all animals, including the animal that had previously experienced an occlusion, there was no clotted material or damage to any of the catheters or catheter tips. Over the course of the study all animals received the intended dose within ?5% with the exception of animal 1006A which received within ?10%. Analysis of dosing solutions confirmed that treprostinil concentrations were within 4% of the intended concentration. The pharmacokinetic data also supported that
treprostinil was delivered into the systemic circulation at the 0.1 mL/hr infusion rate. Table I displays the average plasma concentrations for animals undergoing dosing on the days when samples were collected. Overall the concentrations were consistent comparing the various days and animals, although Day 3 plasma concentrations appeared to be slightly greater and more variable than Days 20, 40, and 60 and compared to previous toxicology studies.
DISCUSSION
Currently available intravenous therapies for the treatment of PAH require the use of large ambulatory infusion pumps to administer drug continuously through a surgically placed central catheter. The ability to use a smaller infusion pump could represent a significant quality of life improvement
for PAH patients since prostacyclin therapy is a continuous, lifelong treatment for their disease. Infusion of intravenous treprostinil at a low infusion rate (0.1 mL/hour) leverages the pharmacology (potent inhibitor of platelet aggregation) (6) and chemical stability of treprostinil to allow patients to
receive an effective treatment for their disease using a much smaller pump (MiniMed 407C). In order to support the evaluation of this novel delivery
method in patients with PAH two pre-clinical studies were conducted to investigate the feasibility of using the MiniMed 407C to deliver treprostinil at
an infusion rate of 0.1 mL/hour. In general, the studies demonstrated that treprostinil can be infused at 0.1 mL/hour in dogs and maintain catheter patency. While one animal experienced an occlusion of its Hickman?catheter, this finding was potentially attributed to a catheter placement issue
subsequently pre-disposing the animal to an occlusion.
This was confirmed following replacement of the catheter and infusion at 0.1 mL/hour without an occlusion for an additional 40 days. For those animals dosed up to 60 days with this regimen, there was no evidence of clot formation or abnormalities upon removal of the catheter supporting
the feasibility of the infusion method. One variable that was taken into consideration in the design of these studies was the lack of anticoagulation
therapy in the animals. This circumstance provided a more rigorous test of this novel infusion method for two reasons. First, dogs have a more active
clotting system when compared to humans. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are estimated to be two and three times lower in dogs compared to humans, respectively. Additionally, dogs have been shown to have higher activity of factors involved in
the coagulation cascade, such as Factor XI, XII, and high molecular weight kininogen (7). Second, in clinical practice up to 85% of PAH patients receive
some form of anticoagulation (warfarin, heparin, low molecular weight heparin) as part of their disease management, as anticoagulation nearly doubles the three-year survival rate in this patient population (8, 9). Therefore, the relative risk of clot formation should be reduced in patients, since humans have a less active clotting system compared to dogs and most patients would be receiving anticoagulation therapy while administered treprostinil at low infusion rates. The scientific literature lacks information documenting the lowest infusion rate that can be used to administer a medication while maintaining catheter patency. Previously there has not been a need to reduce the volume of solution administered over time as patients receiving parenteral therapies are typically hospitalized or home bound for the duration of therapy. In the treatment of a chronic, life-threatening disease, such as PAH, it is not only important to treat patient symptoms but it is also necessary to maintain and/or improve quality of life. Reducing the size of the ambulatory infusion pump used to deliver therapy will enhance
patient satisfaction with intravenous prostacyclin administration.
These animal data support the clinical evaluation of administering treprostinil at a low infusion rate via the MiniMed 407C infusion pump in patients with pulmonary arterial hypertension.
REFERENCES
1. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004; 43: 5S-12S.
2. Remodulin?(treprostinil sodium) Injection Package Insert. United Therapeutics Corporation, Research Triangle Park, North Carolina, USA. November 2004.
3. Phares K, Weires WE, Miller SP, et al. Stability and preservative effectiveness of treprostinil sodium after dilution in common intravenous diluents. Am J Health Syst Pharm 2003; 60: 916-922.
4. Laliberte K, Arneson C, Jeffs R, Hunt T, Wade M. Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin? administered by the intravenous and subcutaneous route to normal volunteers. J Cardiovasc Pharmacol 2004; 44: 209-14.
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