Method and apparatus for controlled infusion via pulses having predetermined discrete bolus volumes to achieve controlled infusion responsive pharmacokinetics

Abstract

A fluid delivery device with low mechanical compliance delivers a controlled amount of fluid via discrete fluid pulses that achieve a target drug blood concentration profile or pharmacokinetics (PK) without requiring damped delivery, and thus compared to conventional fluid delivery devices with high mechanical compliance requirements for damped delivery to achieve continuous delivery. The fluid delivery device operates according to the pulsation profile, for example, using an algorithm that implements a pulsation delivery method. Also provided is a pulsation profile construction method that defines a fixed interval or a variable interval in a pulsation profile based on a PK of a drug measured by a single injection (e.g., based on an individual, a representative model, or extracted from a PK of a population), and whose PK is modeled using any of a plurality of example simulation methods.

Description

BACKGROUND

[0001] Generally, the combination of flow resistance within a fluid path and a characteristic known as "mechanical compliance" affects the instantaneous accuracy with which a medical fluid delivery device, such as an infusion pump, delivers an intended amount of fluid to a subject's body (e.g., a human patient). Flow resistance relates to the amount of pressure required for an intended amount of fluid to flow through a fluid path in a given duration of time. Mechanical compliance relates to how a fluid path (i.e., as defined by the structural body forming the path or a portion of the path) expands, contracts, or deflects under environmental inputs, such as pressure loads from pulse strokes of an infusion pump mechanism that is intended to deliver an amount of fluid to a catheter inserted into a patient's body. Additionally, mechanical compliance can also include how a drive system deforms under load.

[0002] Existing fluid delivery devices designed for smooth continuous delivery of medical fluids or medicaments use drive mechanisms in combination with fluid paths having high compliance. For example, infusion pumps that work in conjunction with infusion sets include high mechanical compliance, which often directly or indirectly serves to smooth the instantaneous flow at the outlet of the fluid system. However, if there is an inappropriate amount of compliance in a fluid delivery device that is supposed to deliver a desired volume of fluid over a (relatively) short period of time, the desired amount of fluid will not be dispensed by the device. While mechanical compliance can allow for smooth and controlled flow when the back pressure and fluid resistance seen by the pumping mechanism remains constant, the same compliance can prevent proper control of the drug delivery flow when the back pressure or fluid resistance varies over time. Many of these fluid delivery devices with high compliance requirements are disadvantageous because the compliance and resistance in the drive mechanism can vary over time, such that the delivery is not continuous and / or the intended amount of fluid is not accurately delivered to the patient. Transient accumulation of fluid in the deformed fluid path can result in a delivered volume that is lower than the target value (i.e., underdosing) during a first period of time and then higher than the target value (i.e., overdosing) after a second period of time, resulting in limited control of the instantaneous flow. In the simple case of constant flow infusion of a drug, changes in back pressure due to (partial) occlusion of the fluid path or changes in patient tissue properties can result in undesirable instantaneous flow variations of the drug leaving the drug delivery device and entering the target tissue. In certain cases, underdosing and overdosing events can significantly impact the efficacy of the treatment. SUMMARY

[0003] Advantageous illustrative embodiments of the present disclosure are provided in which a fluid delivery device having low mechanical compliance delivers a controlled amount of fluid via discrete fluid pulses that achieve a target drug blood concentration profile (i.e., pharmacokinetics (PK)) without the need for dampened delivery, thus contrasting with conventional fluid delivery devices having high mechanical compliance requirements for dampened delivery to achieve continuous delivery. The fluid delivery device operates, for example, using an algorithm implementing a pulsatile delivery method in accordance with example embodiments.

[0004] For example, one aspect of illustrative embodiments is to provide a method of operating an infusion pump to deliver a medication therapy fluid to a patient, the method comprising: generating a plurality of fluid pulses to output fluid to a patient receiving the medication therapy via the infusion pump. Each of the pulses comprises a fixed volume of fluid output from a fluid chamber of the pump over a time period corresponding to a pulse duration. The number of pulses and the duration of intervals between successive pulses in a selected medication therapy time period are configured in accordance with a pulsatile profile to achieve a target pharmacokinetics or target PK.

[0005] According to aspects of illustrative embodiments, the duration of the intervals is longer than the pulse duration. For example, the duration of the intervals is about 10 times the pulse duration.

[0006] According to aspects of illustrative embodiments, the infusion pump is a rotary metering pump comprising a sleeve having an inlet port and an outlet port, and a piston that translates in the sleeve to form the fluid chamber comprising the fixed volume of fluid after a suction stroke to draw fluid from a reservoir into the fluid chamber via the inlet port, and the fixed volume of fluid in the fluid chamber is dispensed to the patient via the outlet port through a fluid delivery channel in fluid communication with the outlet port.

[0007] According to aspects of illustrative embodiments, the medication concentration of the fluid and the fixed volume of the fluid per pulse are used to determine at least one of the number of pulses and the duration of intervals between successive pulses in the pulses.

[0008] According to aspects of illustrative embodiments, the pulsatile profile comprises a plurality of pulses with corresponding intervals between successive pulses in the plurality of pulses. For example, the duration of the intervals is varied to achieve a target pharmacokinetics or PK.

[0009] As a further example, according to aspects of illustrative embodiments, the corresponding intervals between successive pulses in the plurality of pulses have a maximum first interval duration, and the pulsatile profile comprises a pulse train comprising a plurality of pulses output with a minimum interval between the pulses. The pulse train is separated from a subsequent pulse of the successive pulses in the plurality of pulses by a second interval duration that is greater than the maximum first interval duration.

[0010] According to illustrative embodiments of the present disclosure, there is provided an advantageous bolus profile construction method that defines fixed or variable intervals in a bolus profile based on pharmacokinetics of a drug measured by a single injection of the drug (e.g., based on an individual, a representative model, or PK extraction from a population) and which PK is modeled using any of a plurality of example simulation methods.

[0011] According to aspects of illustrative embodiments, the intervals between pulses in a bolus profile that achieve a target PK are determined by a bolus profile construction operation that includes: using PK data measured for a single injection of a fluid; modeling the measured PK data to generate a predicted PK curve that is optimized to fit the target PK; generating respective PK traces of the predicted PK curve corresponding to different interval durations; and selecting an interval based on characteristics of the respective PK traces.

[0012] According to aspects of illustrative embodiments, the modeling includes using a simulation method selected from a convolution operation and a curve fitting operation.

[0013] According to aspects of illustrative embodiments, the simulation method using a convolution includes: obtaining a single dose PK curve corresponding to a single injection of the fluid from the measured PK data; scaling the single dose PK curve by a fixed volume of a pulse and a concentration of the fluid; superimposing the scaled single dose PK curve to the bolus profile using a convolution; and performing linear interpolation of the measured PK data for one of the plurality of superimposed pulse PK curves in the bolus profile as the predicted PK curve.

[0014] According to aspects of illustrative embodiments, the simulation method using a curve fitting operation includes: obtaining a single dose PK curve corresponding to a single injection of the fluid from the measured PK data; estimating a time constant from a reference PK curve; and generating the predicted PK curve using the time constant.

[0015] According to aspects of illustrative embodiments, the modeling includes: fitting the predicted PK curve to the measured PK data; varying the pulse interval duration to generate respective PK traces of the predicted PK curve; and selecting an interval based on respective characteristics of the respective PK traces.

[0016] According to aspects of illustrative embodiments, one or more of the bolus profile construction operations are performed iteratively.

[0017] According to aspects of illustrative embodiments, one or more of the bolus profile construction operations are performed iteratively to optimize the bolus profile.

[0018] According to aspects of illustrative embodiments, the bolus profile construction operation further includes minimizing a residual between the modeled predicted PK and the measured PK data during the curve fitting operation.

[0019] Additional and / or other aspects and advantages of the present disclosure will be set forth in the description that follows, or will be apparent from the description, or can be learned by practice of the illustrative embodiments. The illustrative embodiments can include devices and methods for operating the devices having one or more of the above aspects and / or features, and combinations thereof. The illustrative embodiments can include one or more of the above aspects and / or features, and combinations thereof, for example, as recited in the appended claims. BRIEF DESCRIPTION OF DRAWINGS

[0020] The above and / or other aspects and advantages of the illustrative embodiments will become more apparent by reference to the following description taken in conjunction with the accompanying drawings, in which:

[0021] Figure 1 is a perspective view of an example infusion pump;

[0022] Figure 2 is Figure 1 is a perspective view of an infusion pump in

[0023] Figure 3 and Figure 4 is a partial perspective view of example pump components in an example medicament fluid delivery device according to an illustrative embodiment of the present disclosure, the example medicament fluid delivery device operating according to a programmed pulsatile flow profile using an example pulsatile delivery method;

[0024] Figure 5A and Figure 5B is a perspective view of pump components in an example medicament fluid delivery device arranged according to a priming dispensing operational phase and a priming pumping operational phase, respectively; Figure 3 and Figure 4 are perspective views of pump components in

[0025] Figure 5C is a perspective view of components in an example medicament fluid delivery device including Figure 3 and Figure 4 example pump components of

[0026] Figure 6A is a block diagram of components in an example medicament fluid delivery device according to an illustrative embodiment of the present disclosure;

[0027] Figure 6B is a schematic diagram of a medicament fluid delivery device pump motor having a current sensor according to an illustrative embodiment of the present disclosure;

[0028] Figure 7 depicts example filtered pump measurement data (e.g., motor current) from an example medicament fluid delivery device during a pumping and dispensing stroke;

[0029] Figure 8 Pump measurement data from an example medicament fluid delivery device is depicted indicating respective pump strokes and corresponding pressure changes relative to respective pump strokes over time;

[0030] Figure 9 is a plot illustrating example pharmacokinetics based on and relative to a change in weight of a target patient;

[0031] Figure 10A is a plot illustrating example pharmacokinetics using different pulsatile profiles shown in Figure 10B and Figure 10C according to illustrative embodiments of the present disclosure;

[0032] Figure 11A is a plot illustrating example pharmacokinetics using different pulsatile profiles shown in Figure 11B and Figure 11C according to illustrative embodiments of the present disclosure;

[0033] Figure 12 is a plot illustrating example pharmacokinetics of a single dose injection as an example source data for a pulsatile profile construction method according to another embodiment of the present disclosure;

[0034] Figure 13A is an example pulsatile profile on which scaled PK curves are superimposed, Figure 13B shows blood concentrations predicted according to a first example embodiment employing a numerical simulation approach using a pulsatile profile construction method;

[0035] Figure 14A is a plot indicating predicted blood concentrations based on different pulse intervals using a pulsatile profile construction method according to the first example embodiment;

[0036] Figure 14B is a plot indicating predicted blood concentrations based on having a concentration adjustment for specifying a target PK constant plateau with a fixed concentration and pulse interval and according to the first example embodiment of the pulsatile profile construction method.

[0037] Figure 14C is a plot indicating predicted blood concentrations based on different animal model weights having a fixed concentration and pulse interval to assess PK sensitivity to animal weight according to the first example embodiment of the pulsatile profile construction method;

[0038] Figure 14D is a plot indicating a predicted peak blood concentration versus pulse interval relationship according to the first example embodiment of the pulsatile profile construction method;

[0039] Figure 14E FIG. illustrates predicted PK profiles using a pulsatile profile building method according to a first example embodiment;

[0040] Figure 15 FIG. illustrates predicted PK profiles using a pulsatile profile building method according to a second example embodiment employing a theoretical simulation approach.

[0041] Throughout the drawings, identical reference labels will be understood to refer to the same elements, features, and structures. DETAILED DESCRIPTION

[0042] Reference will now be made in detail to the illustrative embodiments depicted in the drawings. The embodiments described herein are exemplified by reference to the drawings but are not limited to the illustrative embodiments.

[0043] According to example embodiments of the present disclosure, an advantageous pulsatile delivery method is described herein that achieves a target drug blood concentration profile (i.e., pharmacokinetics (PK)) by controlling a fluid delivery device (e.g., a wearable infuser) configured to deliver a dose or bolus of a medication fluid using predetermined, discrete, fixed bolus volumes of pulses according to a specified pulsatile profile.

[0044] Pulsatile fluid flow according to the present disclosure is a pulsatile or intermittent dispensing of fluid using one or more pulses, where each pulse corresponds to a delivery of a predetermined, discrete, fixed volume of fluid. As described below, a pulsatile profile can include a selected number of pulses over a selected time period, where the pulses have a first interval between successive pulses, which can be fixed or varied over time. The first time interval duration between successive pulses is much longer than the pulse (e.g., the duration associated with delivery of the corresponding predetermined fixed bolus volume for a particular pulse). The example times associated with the pulses in the illustrative pulsatile profiles provided in the drawings represent the start of the pulse (e.g., the beginning of the delivery of the pulse), and not necessarily the duration or time period associated with delivery of the corresponding predetermined bolus. In some cases, a pulse can last for a few milliseconds (ms) or up to several seconds (s). For example, the expulsion of the piston / sleeve chamber 38 can be on the order of a few milliseconds. As another example, a pulse delivering 5 uL can last between 1-3 s, and a pulse delivering 50 uL can last on the order of 250 ms. Nonetheless, as described below, the time period for delivery of a predetermined bolus for a particular pulse is significantly less than the example first time interval between that pulse and an adjacent or successive pulse in the pulsatile profile. Moreover, as described below, a pulsatile profile can include one or more pulse strings, where a pulse string corresponds to a series of successive pulses, each separated by a first time interval, followed by a pulse pause for a second time interval that is greater than the first time interval.

[0045] According to further example embodiments of the present disclosure, an advantageous pulsatile profile construction method is described herein that defines fixed or variable intervals in a pulsatile profile based on pharmacokinetics (PK) of a drug measured with a single injection (e.g., based on an individual, a representative model, or PK extraction from a population), and whose PK is modeled using any of a variety of example simulation methods.

[0046] Example pulsatile delivery method

[0047] Reference will now be made to Figures 1 to 11C Example embodiments of a pulsatile delivery method that achieves a target PK by varying the pulse interval duration using a wearable drug delivery device having a predetermined discrete bolus volume are described. As described in the present disclosure, pharmacokinetics or PK is the activity of a drug in a subject (e.g., a human patient) over a period of time, including the processes by which the drug is absorbed, distributed in the body, localized in tissues, and excreted. PK can also be referred to as a target drug plasma concentration profile. Figures 1 to 8 An example fluid delivery device 10 configured to deliver pulses of a predetermined discrete bolus volume is depicted. Fluid delivery device 10 is a wearable drug delivery device (e.g., a patch pump) having low compliance that is advantageously configured to deliver a drug based on a specified pulsatile profile according to a pulsatile delivery method to achieve a target PK. It will be appreciated that other fluid delivery devices can be controlled according to the pulsatile delivery method.

[0048] Figure 1 A perspective view of an example fluid delivery device 10, such as an infusion pump. Patch pump or wearable infusion pump 10 is described in WO 2016 / 048878, which is incorporated herein by reference in its entirety. Pump 10 has a housing 11 including a main cover 12 that is fluidically sealed, or preferably hermetically sealed, to a base 19. Patch pump 10 can be provided with one or more user buttons (e.g., push button switches with associated button covers) indicated at 14a, 14b. An adhesive layer (not shown) can be provided on base 19 for application of infusion pump 10 to a patient’s skin. Base 19 carries various components.

[0049] Figure 2 Some of the main components of patch pump 10 are illustrated in perspective view, with main cover 12 and reservoir 70 Figure 6A) is removed. The patch pump 10 preferably includes a reservoir 70 for storing a fluid (e.g., a therapeutic fluid such as a medicament) and a pump 64 for pumping the medicament out of the reservoir 70. The patch pump 10 also preferably includes electronics 52 for programming and operating the patch pump 10, and an insertion mechanism 74 for inserting the cannula 72 into the patient's skin to deliver the medicament. According to one embodiment, the fill port 68 is a conduit for supplying the reservoir 70 with a medical fluid or medicament. In some embodiments, the fill port 68 can include a portion of a component that functions as a flow path for the medicament out of the reservoir 70, as described in WO 2017 / 053284, which is incorporated herein by reference in its entirety. The spigot 69 is connected to the insertion mechanism 74, for example, by a tube, to transfer the medicament to the insertion mechanism 74 prior to injection into the patient's skin.

[0050] An example infusion pump 64 will now be described with reference to Figure 3 、 Figure 4 、 Figure 5A 、 Figure 5B and Figure 5C The pump 64 is a rotary metering pump described in WO 2015 / 157174, which is incorporated herein by reference in its entirety. The pump 64 includes a pump assembly 20 that can be connected to a DC motor and gear box assembly (not shown) to rotate a sleeve 24 in a pump manifold 22. A helical groove 26 is provided on the sleeve. As the sleeve 24 is rotated in one direction and then in the opposite direction, a coupling pin 28 connected to a piston 30 translates along the helical groove to direct retraction and insertion of the piston 30 within the sleeve 24, respectively. The sleeve has an end plug 34. As depicted in Figure 5A , when the piston 30 is retracted after a suction stroke and thus ready for dispensing, two seals 32, 36 on the respective ends of the piston and end plug located inside the sleeve 24 define a cavity or chamber 38. Thus, the volume of the chamber 38 varies according to the degree of retraction of the piston 30. As depicted in Figure 5B , when the piston 30 is fully inserted and the seals 32, 36 are in substantial contact with each other after a dispensing stroke and thus ready for suction, the volume of the chamber 38 is negligible or substantially zero. According to an example embodiment, the chamber 38 of the pump 64 can be configured to correspond to the above-described predetermined, discrete, fixed bolus volume of a pulse. Two ports 44, 46 are provided relative to the pump manifold 22, including an inlet port 44 and an outlet port 46, through which the medicament can pass from the reservoir 70 Figure 4 A) for the pump 64 Figure 4A) Flow, having been drawn into the chamber 38 (e.g., by retraction of the piston 30 during a suction operation phase), can be dispensed from the chamber 38 through reinsertion of the piston 30 into the chamber 38 to, for example, a cannula 72 leading into a patient's body Figure 4 A) fluid path.

[0051] With continuing reference to Figure 3 , Figure 4 , Figure 5A , Figure 5B and Figure 5C , the sleeve 24 can be provided with an aperture (not shown) that aligns with the outlet port 46 or the inlet port 44 (i.e., depending on the degree of rotation of the sleeve 24 and thus the degree of translation of the piston 30) to allow the drug in the chamber 38 to flow through the corresponding one of the ports 44, 46. A pump measurement device 78 Figure 4 A), such as a sleeve rotation limit switch, can be provided having, for example, an interlock 42 and one or more stops 40 on the sleeve 24 or its end plug 34 that cooperate with the interlock 42. The interlock 42 can be mounted to the manifold 22 at each end of the manifold 22. When the pump 64 is in the first position, the stops 40 at the end face of the sleeve 24 are adjacent the tabs 48 of the interlock 42, whereby the side hole in the sleeve 24 is aligned with the inlet port 44 to receive fluid from the reservoir 70 into the chamber 38. Under certain conditions, such as back pressure, the friction between the piston 30 and the sleeve 24 can be sufficient to rotate the sleeve 24 before the piston 30 and the coupling pin 28 reach either end of the helical groove 26. This can result in an incomplete volume of liquid being pumped per dispense stroke corresponding to a pulse. To prevent this, the interlock 42 prevents rotation of the sleeve 24 until the torque exceeds a predetermined threshold, as shown in Figure 5A . This ensures that the piston 30 rotates fully within the sleeve until the coupling pin reaches the end of the helical groove 26. Once the coupling pin 28 hits the end of the helical groove 26, further movement of the DC motor and gearbox assembly or other type of pump and valve actuator 66 Figure 6A ) increases the torque on the sleeve 24 beyond the threshold, causing the interlock 42 to flex and allow the stops 40 to pass the tabs 48. As shown in Figure 5B , the stops 40 move past the tabs 48 in the interlock 42 when rotation of the sleeve 24 is complete such that its side hole is oriented with the cannula 72 or outlet port 46. Another sleeve feature 41 can be provided to engage an electrical switch (e.g., an end stop switch 90 provided on a printed circuit board 92 and disposed relative to the sleeve and / or end plug 34 to cooperate with the pump measurement device 78, as shown in Figure 5C ).

[0052] Figure 6Ais an illustrative system diagram illustrating example components in an example drug delivery device 10 having a pump such as Figure 3 , Figure 4 , Figure 5A , Figure 5B and 5C an infusion pump. The medicament delivery device 10 can include an electronics subsystem 52 for controlling operation of components in a fluid subsystem 54, such as a pump 64, and an insertion mechanism 74 for deploying a cannula 72 for insertion into an infusion site on a patient's skin. A power storage subsystem 50 can include a battery 56, for example, for providing power to the electronics and components in the fluid subsystems 52 and 54. The fluid subsystem 54 can include an optional fill port 68, for example, for filling a reservoir 70, e.g., with a drug, although the drug delivery device 10 can alternatively be shipped from the manufacturer with its reservoir already filled. The fluid subsystem 54 also has a metering subsystem 62 including the pump 64 and a pump actuator 66. As described above, the pump 64 can have two ports 44, 46 and associated valve subassemblies that control when fluid enters and exits the pump chamber 38 via the respective ports 44, 46. One of the ports is an inlet port 44 through which fluid, such as a liquid drug, flows from the reservoir 70 into the pump 64 due to, for example, a pump suction or pull stroke on the pump plunger or piston 30. The other port is an outlet port 46 through which fluid exits the pump chamber 38 and flows to the cannula 72 for administration to the patient due to a pump expulsion or push stroke on the pump plunger or piston 30. The pump actuator 66 can be a DC motor and gear box assembly or other pump drive mechanism for controlling the plunger or piston 30 and other related pump parts, such as a sleeve 24 that can rotate with respect to the translational motion of the pump piston 30. The microcontroller 58 can be provided with an integrated or discrete memory device having computer software instructions to actuate, for example, rotation of the sleeve 24 in a selected direction, translation or axial motion of the piston 30 in the sleeve 24 for a suction or dispensing stroke, and optionally rotation of the sleeve 24 and piston 30 together during a valve state change, as described in WO 2015 / 157174, referenced above. As described below, the microcontroller 58 can be provided with a programmed pulsatile flow profile according to the illustrative embodiments in accordance with the pulsatile delivery method described herein to achieve a target PK. In addition, the microcontroller 58 can be provided with an algorithm according to the second method for pulsatile profile construction, as described below.

[0053] Figure 6BAn example device for motor current sensing is shown. A sense resistor 142 is added to the PCB 92 to enable motor current measurement. The voltage drop across the sense resistor 142 is provided into an analog-to-digital converter (ADC) of the microcontroller 58. A blockage condition is then calculated by the microcontroller 58, and a blockage or empty reservoir event is reported by the microcontroller 58 when, for example, a specified blockage or empty reservoir motor current flag is detected. Other components can be used for current sensing to facilitate pump motor current measurement. For example, for a pulse width modulation (PWM) driven motor used as the pump actuator 66, motor current information can be extrapolated from the PWM data.

[0054] Reference will now be made to Figure 7 and Figure 8 . Figure 7 Example filtered pump measurement data (e.g., motor current) from the example delivery device 10 is depicted during a suction stroke 80 and a dispensing stroke 82. Figure 8 An example series of dispensing strokes 82 performed by the example delivery device 10 in an example continuous infusion operation is illustrated 1…n and a corresponding end stop time. As stated above, according to example embodiments of the present disclosure, one of these dispensing strokes can deliver a predetermined, discrete, fixed bolus volume corresponding to a pulse. According to the pulsatile delivery method described herein, an algorithm for the microcontroller 58 is configured to control the pump 64 (e.g., via a pump actuator 66 such as a motor) to deliver medicament from the reservoir 70 via the chamber 38 using pulses in a specified pulsatile profile to achieve a target PK of the medicament.

[0055] Control of a fluid delivery device according to an algorithm implementing a pulsatile delivery method to deliver pulses will now be described with reference to Figures 9 to 11C Figure 9 is a plot of example curves of PK 100 that vary based on and relative to a target patient’s weight. For example, an example PK curve 100a is shown for a certain target patient weight, and higher PK curve 100b and lower PK curve 100c are shown for patient weights of target patient weight - 10% and target patient weight + 10%, respectively.

[0056] Figure 10A is a plot of example curves of PK 100 achieved using different pulsatile profiles 102 shown in Figure 10B and Figure 10C illustrating the effect of selected groupings and timings of pulses 104 generated via an algorithm implementing the pulsatile delivery method described herein on a target PK. Figure 10A the higher PK curve 100c in Figure 10B ​The pulsatile profile 102 shown in FIG. 1 is generated with pulses 104 at intervals 106 between successive pulses. As described below, the intervals 106 need not be of fixed duration, but can vary over time and between pulse sequences. The intervals 106 are of longer duration than the duration of a dispensing stroke operation or delivery of a fixed volume of fluid associated with the pulses (e.g., the contents of the chamber 38 in the illustrated example fluid delivery device 10), such that the pulses 104 are discrete and intermittent with respect to one another. Example ranges for the duration of the intervals 106 can be from milliseconds (ms) or seconds (s) to tens of minutes and possibly even hours. During these intervals 106, 0 milliliters per minute (ml / min) or substantially no fluid is delivered for at least a few seconds (e.g., 10 seconds according to the examples below), such that the pulsatile profile 102 delivers well-controlled boluses using discrete pulses with intervals therebetween to achieve the target PK 100.

[0057] As stated above, pulsatile fluid flow according to the present disclosure is a pulsatile or intermittent dispensing of fluid using one or more discrete pulses 104, where each discrete pulse corresponds to delivery of a predetermined volume of fluid. The pulsatile profile 102 is a plurality of intermittent pulses 104, whereby each of the pulses 104 delivers a predetermined volume of fluid with a pause or duration 106 between successive pulses that is longer than the duration of the pulses 104 to deliver their predetermined fluid volume via the fluid delivery device 10 controlled to deliver fluid using the pulsatile profile 102.

[0058] Figure 10A The lower PK curve 100d in FIG. 1 corresponds to Figure 10C The pulsatile profile 102 shown in FIG. 1, and assumes a fixed injection volume and time similar to Figure 10B The pulsatile profile 102 shown in FIG. 1, and assumes a fixed injection volume and time similar to Figure 10C The pulsatile profile 102 shown in FIG. 1 includes several pulses 104 delivered in a pulse train 108 and separated by a first time interval 110, followed by a second time interval 112 that is longer than the first time interval 110 and separates the pulse train 108. Figures 10A to 10C FIG. 1 illustrates how different factors can influence the selected or specified pulsatile profile 102 chosen to achieve the target PK 100.

[0059] Figure 11A The pulsatile profile 102 shown in FIG. 1 includes several pulses 104 delivered in a pulse train 108 and separated by a first time interval 110, followed by a second time interval 112 that is longer than the first time interval 110 and separates the pulse train 108. Figure 11B The pulsatile profile 102 shown in FIG. 1 includes several pulses 104 delivered in a pulse train 108 and separated by a first time interval 110, followed by a second time interval 112 that is longer than the first time interval 110 and separates the pulse train 108. Figure 11C Graphs of example curves of PK 100 achieved using different pulsatile profiles 102 shown in FIG. 1, illustrating the effect of varying frequency of pulses 104 generated via an algorithm implementing the pulsatile delivery method described herein on the target PK. Figure 11A The PK curve 100c in FIG. 1 corresponds toFigure 11B pulsatile profile 102 shown in FIG. 1 16, where the pulses 104 are generated at a relatively intermediate frequency, as compared to the relatively low frequency generated pulses 104 indicated by 118 and the relatively high frequency generated pulses 104 indicated by 114. Figure 11A PK profile 100 in FIG. 1 16 corresponds to Figure 11C pulsatile profile 102 shown in FIG. 1 16, where the pulses 104 are generated at a relatively intermediate frequency, as compared to the relatively low frequency generated pulses 104 indicated by 118 and the relatively high frequency generated pulses 104 indicated by 114. Figure 11B pulsatile profile 102 shown in FIG. 1 16, where the pulses 104 are generated at a relatively intermediate frequency, as compared to the relatively low frequency generated pulses 104 indicated by 118 and the relatively high frequency generated pulses 104 indicated by 114.

[0060] As illustrated above, a number of different embodiments of algorithms for implementing the pulsatile delivery method can be implemented, but are not limited to the example embodiments listed below.

[0061] 1. According to an example embodiment, the intervals 106 between the pulses 104 are constant (e.g., as shown in the pulsatile profile 102 in FIG. 1 14) and are longer (e.g., > 10x) than the pulses (e.g., the duration of the delivery of the predetermined discrete bolus volume associated with that pulse). The pulses delivered by the fluid delivery device 10 under the control of the algorithm implementing embodiments of the pulsatile delivery method of the present disclosure are advantageous in that they provide a controlled infusion response pharmacokinetic. This controlled discrete delivery of pulses by the fluid delivery device 10 achieves an advantage over conventional devices (with high compliance for continuous delivery of medicament). If such a conventional device (e.g., a conventional syringe-type pump with a lead screw and a stepper motor and varying the time between steps) were to attempt to operate according to the pulsatile delivery method of the present disclosure, the intervals between steps could not be equivalent to the discrete pulses 104 according to embodiments of the present disclosure, as such steps and intervals between steps are damped by the compliance within the conventional fluid delivery system. Thus, the volume delivered by such a damped step / interval would take a relatively and undesirably longer time compared to the shorter time that the same volume could be delivered by the discrete bolus pulses 104 of the present disclosure. Figure 10B

[0062] 2. According to another example embodiment, the intervals 106 between the pulses 104 are variable (e.g., as shown in the pulsatile profile 102 in FIG. 1 16) and are longer (e.g., > 10x) than the pulses (e.g., the duration of the delivery of the predetermined discrete bolus volume associated with that pulse). The pulses delivered by the fluid delivery device 10 under the control of the algorithm implementing embodiments of the pulsatile delivery method of the present disclosure are advantageous in that they provide a controlled infusion response pharmacokinetic. This controlled discrete delivery of pulses by the fluid delivery device 10 achieves an advantage over conventional devices (with high compliance for continuous delivery of medicament). If such a conventional device (e.g., a conventional syringe-type pump with a lead screw and a stepper motor and varying the time between steps) were to attempt to operate according to the pulsatile delivery method of the present disclosure, the intervals between steps could not be equivalent to the discrete pulses 104 according to embodiments of the present disclosure, as such steps and intervals between steps are damped by the compliance within the conventional fluid delivery system. Thus, the volume delivered by such a damped step / interval would take a relatively and undesirably longer time compared to the shorter time that the same volume could be delivered by the discrete bolus pulses 104 of the present disclosure. Figure 11B and 11C ​but each interval 106 is much longer (>10x) than the pulse 104 (e.g., the duration of the delivery of the predetermined discrete bolus volume associated with the pulse). According to the pulsatile delivery method, the variation between pulses 104 is well controlled, digitized, and discrete. The algorithm implementing the pulsatile delivery method by generating the pulses 104 can vary the duration of the intervals 106 during the infusion to have an impact on the PK 100. For example, the infusion can provide more frequent pulses 104 with shorter intervals 106 during certain parts of the day or at the end of the treatment relative to the beginning of the treatment, etc.

[0063] 3. In further example embodiments, the combination of successive pulses 104 and intervals 106 between pulses 104 is used to achieve a desired PK. For example, a common dose can be 5 mL per pulse 104. For a 10 mL dose, the pulsatile delivery method provides for using two 5 mL successive pulses 104 with a long interval 106 between the two successive pulses 104.

[0064] 4. In other example embodiments, the algorithm implementing the pulsatile delivery method is configured to achieve a target PK selected from at least one of the following types of PK profiles: (1) zero order response; (2) steady rise; (3) steady plateau; (4) steady plateau of a desired duration; (5) steady decline; (6) cyclic pattern; (7) cyclic pattern synchronized with diurnal / nighttime / hormonal / biological patterns; and (8) non-cyclic variable pattern. An example of a target PK as (1) zero order response is 0 to plateau and back to 0; i.e., the concentration increases as steeply or quickly as possible to the plateau level. An example of a target PK as (2) steady rise corresponds to a blood concentration that steadily rises or slopes up over time, which can be used to reduce side effects of the delivered medicament, for example. Alternatively, an example of a target PK as (5) steady decline corresponds to a blood concentration that steadily declines or slopes down over time, which can be used to reduce withdrawal effects when a patient is discontinuing a certain medicament, for example. An example of a target PK as (3) steady plateau is a blood concentration that remains constant over time, which can be used to maintain a constant therapeutic effect, for example. An example of a target PK as (4) steady plateau of a desired duration is a blood concentration that remains constant for a desired duration, which can be used to maintain a constant therapeutic effect for a desired duration, for example. An example of a target PK as (6) cyclic pattern is a blood concentration that cycles over time, which can be used to mimic a natural biological cycle, for example. An example of a target PK as (7) cyclic pattern synchronized with diurnal / nighttime / hormonal / biological patterns is a blood concentration that cycles over time in synchronization with a diurnal / nighttime / hormonal / biological pattern, which can be used to mimic a natural biological cycle, for example. An example of a target PK as (8) non-cyclic variable pattern is a blood concentration that varies over time in a non-cyclic manner, which can be used to mimic a natural biological cycle, for example. Figure 14A and Figure 15The PK profile for a 120 minute pulse interval in B indicates that the PK profile oscillates to a steady and wavy to reach a dynamic equilibrium. The steady plateau can be a (4) desired duration of steady plateau, depending on the delivery instructions and efficacy of the medicament. An example of a (6) cyclic pattern of target PK can be a low concentration, then a high concentration, then a low concentration, where each change in concentration occurs over a long period of time relative to the duration of the treatment, such as on the order of hours, rather than minutes or seconds, in a 72 hour treatment. An example of a (7) cyclic pattern of target PK synchronized with a circadian / nighttime / hormonal / biological pattern can be a pulsatile profile with a delivery pulse pattern to achieve a target PK that varies over time that is synchronized with the patient’s circadian pattern (e.g., where the patient is more active during the day than at night), or other forms of chronotherapy where the medicament is administered for a specific period of time. As stated above, the target PK can also be a (8) non-cyclic variable pattern.

[0065] 5. According to another example embodiment, the mechanical compliance of the fluid delivery device 10 or other fluid delivery device in (e.g., Figures 1 to 5C is low enough to allow for delivery of discrete boluses without damping the delivery and still achieve continuous infusion. The fluid delivery devices of the present disclosure are controlled via algorithms, e.g., using the pulsatile delivery method of the present disclosure, to achieve discrete pulsed small injections for a target PK via the pulses 104 described herein that are explicitly defined in time. In contrast, conventional fluid delivery devices have high compliance requirements and can only achieve constant or variable continuous flow of fluid by damping and do not employ the pulses 104 described according to example embodiments. As stated above, if such a conventional high compliance delivery device (e.g., a conventional syringe-type pump with a lead screw and a stepper motor and varying the time between steps) attempts to operate according to the pulsatile delivery method of the present disclosure, the intervals between steps cannot be equivalent to the discrete pulses 104 according to embodiments of the present disclosure because such steps and intervals between steps are damped by the compliance within the conventional fluid delivery system. Thus, the volume delivered by such a damped step / interval will take a relatively and undesirably long time compared to the shorter time that the same volume can be delivered by the discrete bolus pulses 104 of the present disclosure. Thus, example embodiments of the present disclosure achieve the advantage of providing a control window in which a known volume is injected rather than continuous delivery.

[0066] 6. According to another example embodiment, the pulsatile profile of the medicament being delivered can drop to 0 ml / min between pulses 104 for at least 10s. This embodiment illustrates a distinction from continuous infusion devices that have high compliance and require a longer time to deliver the medicament than the pulsatile delivery method and related fluid delivery devices.

[0067] 7. In another embodiment, the pulsatile profile 102 is pre-programmed in a fluid delivery device operating according to a pulsatile delivery method.

[0068] 8. In yet another embodiment, one of a plurality of pre-programmed pulsatile profiles 1021...n can be selected. For example, when one or more pre-programmed pulsatile profiles 1021...n are provided to a fluid delivery device, a user can manipulate a button or other user input device provided on the fluid delivery device, or a remote control or auxiliary device connected to the fluid delivery device, to select a profile 102 from among a plurality of stored programmed pulsatile profiles 1021...n.

[0069] 9. According to example embodiments, the number of successive pulses 104 in a pulsatile profile 102 can be selected to define an equivalent single dose. For example, the number of pulses 104 and / or the duration of the interval(s) 106, 110, and / or 112 can be input by a user via a user interface provided on the delivery device or on a paired / connected remote control or auxiliary device. For example, input buttons 14a, 14b( Figure 1 ) on the fluid delivery device 10 or remote device can be pressed three times to deliver three doses, or can be manipulated to encode the number of pulses and intervals. The fluid delivery device or remote device can also have touch screen input or other input means.

[0070] 10. In another embodiment, the intervals between pulses can be selected from a pre-programmed selection in the manner described for embodiment 4 (8) to select from among a plurality of pre-programmed pulsatile profiles.

[0071] 11. In example embodiments, the number of successive pulses can be input numerically, for example by using successive presses of a button, or otherwise programmed using user input devices or interfaces (e.g., graphical user interfaces) on the fluid delivery device or paired / connected remote control device or auxiliary device.

[0072] 12. In one embodiment, the time interval(s) between pulses can be input numerically, for example by using successive presses of a button, or otherwise programmed using user input devices or interfaces (e.g., graphical user interfaces) on the fluid delivery device or paired / connected remote control device or auxiliary device.

[0073] Pulsatile profile construction method

[0074] According to further example embodiments of the present disclosure, described herein is an advantageous bolus profile construction method that defines fixed or variable intervals in a bolus profile based on pharmacokinetics (PK) of a drug measured with a single injection (e.g., based on an individual, a representative model, or PK extraction from a population), and whose PK is modeled using any of a number of example simulation methods.

[0075] The bolus profile construction method is configured to predict pharmacokinetics during a pulsatile infusion based on a single injection PK. The bolus profile construction method includes simulating the effect of injection parameters (e.g., one or more of pulse interval, subject weight, and drug concentration) on the PK of a target steady state blood concentration. Two simulation methods are described below; however, it should be understood that other simulation methods can be used. The present disclosure describes a bolus profile construction method that uses a numerical method for simulation, i.e., using a convolution of products. The present disclosure also describes a bolus profile construction method that uses a theoretical method for simulation, i.e., using a curve fitting.

[0076] Before describing the two simulation methods in more detail below, the bolus profile construction method will now be generally described. The bolus profile construction method will be described with reference to a fluid delivery device such as the patch pump or infusion pump 10 described above in connection with the pulsatile delivery method. The bolus profile construction method involves operating an infusion pump to deliver a medication fluid or medicament to a patient, determining intervals (e.g., 106, 110, and / or 112) between pulses 104 in a bolus profile 102 to achieve a target PK using measured PK data for a single injection of the fluid, modeling the measured PK data to generate a predicted PK curve that is optimized to fit the target PK, generating respective PK traces of the predicted PK curve corresponding to different interval durations, and selecting an interval based on characteristics of the respective PK traces. In example embodiments of the bolus profile construction method, the modeling includes using a simulation method selected from a convolution of products and a curve fitting operation.

[0077] For example, modeling by the simulation method using a convolution of products can include: i. obtaining a single dose PK curve corresponding to a single injection of the fluid from the measured PK data; ii. scaling the single dose PK curve by a fixed volume of a pulse and a concentration of the fluid; iii. superimposing the scaled single dose PK curve onto the bolus profile using a convolution; and iv. performing linear interpolation of the measured PK data for one of the plurality of superimposed pulse PK curves in the bolus profile as the predicted PK curve.

[0078] For example, modeling by the simulation method using a curve fitting operation includes: i. obtaining a single-dose PK profile corresponding to a single injection of fluid from the measured PK data; ii. estimating a time constant from the reference PK profile; iii. generating a predicted PK profile using the time constant.

[0079] Selecting intervals in the pulsatile profile 102 (e.g., intervals 106, 110, and / or 112 between pulses 104) based on characteristics of the corresponding PK traces includes, for example: i. determining the intervals by obtaining measured PK data for a single injection and fitting the predicted PK profile to the measured PK data; ii. varying the pulse interval duration to generate a corresponding PK trace of the predicted PK profile; and iii. selecting the intervals based on corresponding characteristics of the corresponding PK traces.

[0080] Numerical simulation method using convolution of products

[0081] Reference Figure 12 , source data (i.e., measured PK data) corresponding to a reference PK profile for a single-dose injection in subcutaneous (SC) tissue is obtained to obtain a simulated response as described below. In this example, the measured PK data used in the pulsatile profile construction method can be corrected for background noise (e.g., truncated and shifted to 0).

[0082] For example, Figure 13B The cumulative PK profile in Figure 12 is generated from the pulsatile profile construction method by scaling the single-dose PK profile in Figure 13B to obtain a selected pulse volume and concentration. The scaled single-dose PK profile is then superimposed via convolution on the pulsatile profile as shown in Figure 13A .

[0083] Figure 14A is a plot indicating predicted blood concentrations based on different pulse intervals (e.g., different values of interval 106) with a fixed concentration and subject weight. From Figure 14B , Figure 14C and Figure 14D observations support the use of a plot similar to Figure 14A for determining intervals via the pulsatile profile construction method. Figure 14B is a plot indicating predicted blood concentrations based on concentration adjustments with a fixed concentration and pulse interval for a specified target PK with, for example, a target of a constant plateau period. Figure 14Cis a plot indicating predicted blood concentrations based on different animal model weights with fixed concentration and pulse interval (for single bolus PK measurements) to assess the sensitivity of PK to animal model weight. It is observed that Figure 14C The amplitude of the blood concentration at plateau in the PK trace depicted in the middle is proportional to the change in subject weight (e.g., with different animal model weights as shown). Figure 14D is a plot indicating the relationship of predicted peak blood concentration to pulse interval, where it is observed that the relationship is non-linear.

[0084] Finally, Figure 14E Predicted PK curves are illustrated according to an embodiment of the pulsatile profile construction method using numerical simulation (e.g., convolution of products). Superimposed, scaled single dose PK curves are linearly interpolated against experimental data.

[0085] Theoretical simulation method using curve fitting

[0086] In the following example, the source data includes a two-species model with mass exchange, characterized as follows:

[0087] Where: S is the drug concentration in the subcutaneous space B is the drug concentration in the blood, a is the drug degradation rate in the subcutaneous b is the clearance rate in the blood g is the rate of subcutaneous / blood exchange

[0088] The blood volume per animal model weight is known (mL / kg). The concentration in the subcutaneous (SubQ) tissue is taken at the injection site, considered local and independent of animal model weight. Neglecting volume changes and local diffusion, the concentration S is equivalent to the mass of drug. V SubQ

[0089] From the single bolus PK curve, the following three constants are estimated according to an embodiment of the pulsatile profile construction method, where the animal model weight (kg) is known and the single bolus injection (mg) is known. For example: a is about 1 / (2 hours) b is about 1 / (0.5 hours) g is about 1 / (1000 hours)

[0090] The time constants above are used to generate a pulsatile profile as Figure 15the predicted PK curve shown in FIG. 6. The predicted blood concentrations can be analyzed with respect to different parameters, such as different pulse intervals with a fixed concentration and animal model weight (e.g., different values for interval 106). For example, a plot similar to Figure 14A FIG. 6 can be generated, but indicating predicted blood concentrations based on different pulse intervals using the pulsatile profile construction method according to the second example embodiment.

[0091] Reference is now made to Figure 14E and Figure 15 which depict respective predicted PK curves using convolution-like fitting and overshoot-like fitting according to the first and second example embodiments of the pulsatile profile construction method described above. In the example embodiments of the pulsatile profile construction method described above, either simulation method can produce a selected interval (e.g., x minute pulse interval 106) according to a target PK. For example, if a different target PK is desired, such as a PK with a stable plateau that is stable and oscillatory for a dynamic equilibrium oscillation (e.g., as indicated by the PK curves for 120 minute pulse intervals in Figure 14A and Figure 15 B), a 2* reference interval time 106 can be selected for the pulsatile profile. According to the first example embodiment of the pulsatile profile construction method, the numerical simulation method using convolution is generally considered to underestimate the plateau of the predicted PK curve (e.g., Figure 14E ), as the raw data is likely to not capture the peak of the blood concentration exactly. On the other hand, the theoretical simulation method using curve fitting according to the second example embodiment of the pulsatile profile construction method is generally considered to overestimate the plateau of the predicted PK curve (e.g., Figure 15 ), as the fitting to the raw data is generally qualitatively adjusted to obtain a meaningful good visual fit. Nonetheless, both simulation methods described above for the first and second example embodiments of the pulsatile profile construction method produce results that are of the same order of magnitude within approximately 30%.

[0092] The processing device can be provided with an algorithm implementing the pulsatile profile construction method. The simulation modeling can include source data for different medicaments in addition to insulin. The simulation results can be provided as an algorithm separate from and / or incorporated into the fluid delivery device for use with different medicaments and their manufacturers and / or distributors. For example, the algorithm implementing the pulsatile profile construction method can be for various medicaments (e.g., drugs) and target concentrations modeled and used for different pharmaceutical companies. The algorithm implementing the pulsatile profile construction method can be configured to be iterative and fine-tune or tune one or more parameters over time to reduce the number of iterations performed for a respective medicament (e.g., drug) and target concentration. As described herein, according to an embodiment, the algorithm implementing the pulsatile profile construction method can use the product of the convolution between the pulsed signal and the scaled-corrected PK response for a single bolus injection. According to another embodiment, the algorithm implementing the pulsatile profile construction method can use time constants extracted from a reference PK curve injection. According to another example embodiment, the scaled correction can be at least one of: a reference model patient or subject weight, a target patient weight, a drug concentration (e.g., used in a reference model single injection), a drug concentration (e.g., in a fluid delivery device such as wearable infusion pump 10), a drug volume (e.g., used in a reference model single injection), and a bolus volume (e.g., in a bolus volume of a fluid delivery device such as wearable infusion pump 10). Additionally, in example embodiments, the pulsatile profile 102 (e.g., the number of consecutive pulses 104 and / or the interval 112 between pulse trains 108) is optimized by minimizing the residual when fitting the simulated pattern on a target PK. In other words, the example embodiments described herein can design an optimal pattern or pulsatile profile for an injection by minimizing the residual between the simulated output and the target PK (e.g., the PK curve can be cyclic), and what is optimal is also defined by the closeness to the “fitted curve.” An iterative process can also be employed to achieve the optimal pattern or pulsatile profile 102.

[0093] The example embodiments described herein are advantageous and implement improvements over existing medicament delivery devices, as the example embodiments provide greater control over the precise dose delivered using a pulsatile profile or pattern when compared to existing devices designed for continuous infusion. Additionally, the example embodiments described herein allow for non-continuous infusion. The methods described herein (e.g., the pulsatile profile delivery method) allow for the use of a fluid delivery device to output discrete boluses for tunable infusion.

[0094] Existing delivery devices are disadvantageous in that they are designed for smooth continuous delivery of a drug using a driver with high compliance requirements; however, the compliance and resistance in their drive mechanisms vary over time such that their delivery is not continuous. Advantageous example embodiments of the present disclosure eliminate the need for continuous driving and its associated complexity and degradation of performance due to inevitable changes in the life of a continuous driving device. As demonstrated herein, there are demonstrable benefits to using PKs and pulses as compared to existing continuous drive mechanisms for fluid infusion. While existing fluid delivery devices modulate the speed of a constant infusion (e.g., syringe pumps, BD Evolve TM Ambulatory Infusion Systems, commercially available from Amgen Inc. Ambulatory Infusion Systems, commercially available from Amgen Inc. Ambulatory Infusion Systems, commercially available from Amgen Inc.

[0095] Those skilled in the art will understand that the disclosure is not limited in its application to the details of construction and the arrangement of components set forth in the above description or illustrated in the drawings. The embodiments herein are capable of other embodiments and of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising" or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. Unless otherwise restricted, the terms "connected," "coupled," and "mounted," and variations thereof herein are used broadly and encompass direct and indirect connections, couplings, and mountings. In addition, the terms "connected" and "coupled" and variations thereof are not restricted to physical or mechanical connections or couplings. Furthermore, terms such as up, down, bottom, and top are relative and are used for ease of description and are not limiting.

[0096] The components of the illustrative devices, systems and methods employed in accordance with the illustrated embodiments can be implemented, at least partially, in digital electronic circuitry, analog electronic circuitry, or computer hardware, firmware, software, or in combinations of them. These components can be implemented as a computer program product, such as a computer program, program code, or computer instructions tangibly embodied in an information carrier, or in a machine readable storage device, for execution by, or to control the operation of, data processing apparatus, such as a programmable processor, a computer, or multiple computers.

[0097] A computer program can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and are interconnected by a communication network. Also, the functional programs, codes, and code segments for implementing the illustrative embodiments can be easily identified by those skilled in the art as they are within the scope of the claims, given the benefit of this disclosure. Method steps associated with the illustrative embodiments can be performed by one or more programmable processors executing a computer program to perform functions by operating on input data and / or generating output. Method steps can also be implemented by, and / or used in, special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application-specific integrated circuit), or by a combination of such

[0098] The various illustrative logical blocks, modules, and circuits described in connection with the embodiments disclosed herein can be implemented or performed with a general purpose processor, a Digital Signal Processor (DSP), an ASIC, an FPGA or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general purpose processor can be a microprocessor, but in the alternative, the processor can be any conventional processor, controller, microcontroller, or state machine. A processor can also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration.

[0099] Processors suitable for the execution of a computer program include, by way of example, both general and special purpose microprocessors, and any one or more processors of any kind of digital computer. Generally, a processor will receive instructions and data from a read-only memory or a random access memory or both. The essential elements of a computer are a processor for performing instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto-optical disks, or optical disks. Information carriers suitable for embodying computer program instructions and data include all forms of non-volatile memory, including by way of example semiconductor memory devices, e.g., erasable programmable read-only memory, or ROM, electrically programmable read-only memory, or ROM, flash memory devices, and data storage disks such as magnetic disks, internal hard disks or removable disks, magneto-optical disks, and CD-ROM and DVD-ROM disks. The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry.

[0100] Those skilled in the art will appreciate that information and signals can be represented using any of a variety of different technologies and techniques. For example, data, instructions, commands, information, signals, bits, symbols, and chips that can be referenced throughout the above description can be represented by voltages, currents, electromagnetic waves, magnetic fields or particles, optical fields or particles, or any combination thereof.

[0101] Those skilled in the art will further appreciate that the various illustrative logical blocks, modules, circuits, and algorithm steps described in connection with the embodiments disclosed herein can be implemented as electronic hardware, computer software, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, circuits, and steps have been described above generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. Skilled artisans can implement the described functionality in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the claims of the application. A software module can reside in random access memory (RAM), flash memory, ROM, EPROM, EEPROM, registers, hard disk, a removable disk, a CD-ROM, or any other form of storage medium known in the art. An exemplary storage medium is coupled to the processor such that the processor can read information from, and write information to, the storage medium. In the alternative, the storage medium can be integral to the processor. In other words, the processor and the storage medium can reside in an integrated circuit, or the processor and the storage medium can be discrete components.

[0102] Computer-readable non-transitory media include all types of computer readable media, including magnetic storage media, optical storage media, flash memory devices, and solid state storage devices. It will be appreciated that software can be installed in and sold with a central processing unit (CPU) device. Alternatively, software can be obtained and loaded into a CPU device, including by obtaining the software through a physical medium or a distribution system, including, for example, from a server owned by the software creator or from a server used by the software creator, but not owned by the software creator. For example, the software can be stored on a server for distribution over the Internet.

[0103] The description presented above and the accompanying figures are intended merely to be illustrative and not restrictive of the illustrative embodiments, unless otherwise expressly stated in the following claims. In particular, it is noted that those skilled in the art can readily combine the various technical aspects of the various elements of the various illustrative embodiments that have been described above in many other ways, all of which are deemed to be within the scope of the claims.

Claims

1. A method of operating an infusion pump to deliver a fluid of a medication therapy to a patient, the method comprising: generating a plurality of fluid pulses to output the fluid to a patient receiving a medication therapy via an infusion pump; wherein each pulse of the plurality of fluid pulses comprises a fixed volume of fluid output from a fluid chamber of the pump for a time period corresponding to a pulse duration; wherein a number of pulses and a duration of intervals between successive ones of the pulses within a selected medication therapy time period are configured according to a pulsatile profile to achieve a target pharmacokinetic or target PK.

2. The method of claim 1, wherein, the duration of the intervals is longer than the pulse duration.

3. The method of claim 2, wherein, the duration of the intervals is about 10 times the pulse duration.

4. The method of claim 1, wherein, the infusion pump is a rotary metering pump comprising a sleeve having an inlet port and an outlet port, and a piston that translates in the sleeve to create a fluid chamber that comprises a fixed volume after a suction stroke that draws fluid from a reservoir into the fluid chamber via the inlet port, and the fixed volume in the fluid chamber is dispensed to a patient via the outlet port through a fluid delivery channel in fluid communication with the outlet port.

5. The method of claim 1, wherein, a medication concentration of the fluid and the fixed volume of fluid per fluid pulse are used to determine at least one of the number of pulses and the duration of intervals between successive ones of the pulses.

6. The method of claim 1, wherein, the pulsatile profile comprises a plurality of pulses with corresponding intervals between successive ones of the plurality of pulses.

7. The method of claim 6, wherein, the duration of the intervals is varied to achieve a target pharmacokinetic or target PK.

8. The method of claim 6, wherein, the corresponding intervals between successive ones of the plurality of pulses have a maximum first interval duration, and wherein the pulsatile profile comprises a pulse train comprising a plurality of pulses output with a minimum interval between the pulse train, the pulse train separated from a subsequent one of the successive ones of the plurality of pulses by a second interval duration that is greater than the maximum first interval duration.

9. The method of claim 1, wherein, the intervals between pulses in a pulsatile profile that achieves a target PK are determined by a pulsatile profile construction operation comprising: using measured PK data for a single injection of the fluid; modeling the measured PK data to generate a predicted PK curve that is optimized to fit the target PK; generating respective PK traces of the predicted PK curve corresponding to different interval durations; and selecting the interval based on a characteristic of the respective PK traces.

10. The method of claim 9, wherein, the modeling comprises using a simulation method selected from a convolution operation and a curve fitting operation.

11. The method of claim 10, wherein, the simulation method using a convolution operation comprises: obtaining a single dose PK curve corresponding to a single injection of the fluid from the measured PK data; scaling the single dose PK curve by the fixed volume of fluid pulses and the concentration of the fluid; superimposing the scaled single dose PK curve onto a pulsatile profile using a convolution; and performing a linear interpolation of the measured PK data for one of the plurality of superimposed pulse PK curves in the pulsatile profile as the predicted PK curve.

12. The method of claim 10, wherein, the simulation method using a curve fitting operation comprises: obtaining a single-dose PK profile corresponding to a fluid single injection from the measured PK data; estimating a time constant from the reference PK profile; and generating a predicted PK profile using the time constant.

13. The method of claim 9, wherein, the modeling includes: fitting the predicted PK profile to the measured PK data; varying a pulse interval duration to generate respective PK traces of the predicted PK profile; and selecting an interval based on respective characteristics of the respective PK traces.

14. The method of claim 9, wherein, one or more of the pulsatile profile construction operations are performed iteratively.

15. The method of claim 9, wherein, one or more of the pulsatile profile construction operations are performed iteratively to optimize the pulsatile profile.

16. The method of claim 12, wherein, the pulsatile profile construction operations further include minimizing a residual between the modeled predicted PK profile and the measured PK data during the curve fitting operation.

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