Method and apparatus for controlled infusion via pulses with predefined discrete bolus volumes to achieve controlled infusion response pharmacokinetics

Abstract

A fluid delivery device with low mechanical compliance delivers a controlled amount of fluid via discrete fluid pulses that achieves a target drug blood concentration profile or pharmacokinetics (PK) without the need for damping, as opposed to conventional fluid delivery devices with high mechanical compliance requirements that dampen delivery to achieve continuous delivery. The fluid delivery device operates according to a pulsatile profile, for example, using an algorithm that implements a pulsatile delivery method. Also provided are pulsatile profile construction methods that define fixed or variable intervals within the pulsatile profile based on the PK of a drug measured in a single injection (e.g., extracted from an individual model, a representative model, or a population PK), and the PK is modeled using one of several exemplary simulation methods.

Description

[Technical Field]

[0001] The present disclosure relates to methods and devices for controlled infusion via pulses with predefined discrete bolus volumes to achieve controlled infusion response pharmacokinetics. [Background technology]

[0002] In general, a combination of flow resistance and a property known as "mechanical compliance" within a fluid pathway 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 flow through a fluid pathway over a given time. Mechanical compliance relates to how a fluid pathway (i.e., defined by the pathway or structures forming part of the pathway) expands, contracts, or flexes under environmental input, such as a pressure load from a pulsatile stroke from an infusion pump mechanism intended to deliver a fixed amount of fluid to a catheter inserted into a patient. Additionally, mechanical compliance may also include how a drive system deforms under load.

[0003] Existing fluid delivery devices designed for smooth, continuous delivery of medical fluids or medications use drive mechanisms combined with fluid paths that have high compliance. For example, infusion pumps that interface with infusion sets have high mechanical compliance, which is often used directly or indirectly to smooth the instantaneous flow rate at the outlet of the fluid system. However, if an inadequate amount of compliance is present in a fluid delivery device designed to deliver a desired amount of fluid in a (relatively) short period of time, the device will be unable to deliver the desired amount of fluid. While mechanical compliance can achieve a smooth, controlled flow rate when the backpressure and fluid resistance seen by the pump mechanism are constant, the same compliance can prevent proper control of the drug delivery flow rate if the backpressure or fluid resistance changes over time. Many of these fluid delivery devices with high compliance requirements are disadvantageous because the compliance and resistance of the drive mechanism change over time, resulting in non-continuous delivery and / or the intended amount of fluid may not be accurately delivered to the patient. Temporary fluid accumulation in a distorted fluid path can result in the delivered amount being below the target value (i.e., underdosing) during a first time period and exceeding the target value (i.e., overdosing) after a second time period, thereby limiting control of the instantaneous flow rate. In the simple case of infusing a drug at a constant flow rate, changes in backpressure as a result of a (partially) occluded fluid path or changes in the patient's tissue properties can cause undesirable variations in the instantaneous flow rate of drug exiting the drug delivery device and entering the target tissue. In some cases, underdosing and overdosing can have a significant impact on the therapeutic outcome. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2016 / 048878 [Patent Document 2] International Publication No. 2017 / 053284 [Patent Document 3] International Publication No. 2015 / 157174 Summary of the Invention

[0005] Advantageous exemplary embodiments of the present disclosure are provided in which a fluid delivery device having low mechanical compliance delivers controlled amounts of fluid via discrete fluid pulses that achieve a target drug blood concentration profile (i.e., pharmacokinetics (PK)) without the need for damping delivery, as opposed to conventional fluid delivery devices that have high mechanical compliance requirements that dampen delivery to achieve continuous delivery.

[0006] For example, one aspect of an exemplary embodiment provides a method of operating an infusion pump to deliver a medication fluid to a patient receiving medication, the method comprising generating a plurality of fluid pulses via the infusion pump to pump fluid to the patient, each of the pulses comprising a fixed volume of fluid pumped from a fluid chamber of the pump within a time period corresponding to a pulse duration, the number of pulses over a selected medication time period and the duration of the interval between successive ones of the pulses being configured according to a pulsation profile to achieve target pharmacokinetics or PK.

[0007] According to aspects of the exemplary embodiment, the duration of the interval is longer than the pulse duration, for example, the duration of the interval is 10 times or more longer than the pulse duration.

[0008] According to an aspect of an exemplary embodiment, the infusion pump is a rotary metering pump including a sleeve having an inlet port and an outlet port, and a piston that translates into the sleeve to form a fluid chamber containing the fixed volume after drawing fluid into the fluid chamber through the inlet port from a reservoir by a suction stroke, the fixed volume in the fluid chamber being dispensed to a patient via the outlet port through a fluid delivery channel in fluid communication with the outlet port.

[0009] According to aspects of exemplary embodiments, the drug concentration of the fluid and the fixed amount of the fluid per pulse are used to determine at least one of the number of pulses and the duration of the interval between successive ones of the pulses.

[0010] According to aspects of the exemplary embodiment, the pulsatile profile includes a plurality of pulses and corresponding intervals between successive pulses of the plurality of pulses, e.g., the duration of the intervals is varied to achieve target pharmacokinetics or PK.

[0011] By way of further example, according to aspects of exemplary embodiments, the intervals corresponding to successive pulses of the plurality of pulses include a maximum first interval duration, and the pulsation profile includes a pulse train including a plurality of pulses output at minimum intervals, the pulse train separated from a subsequent pulse between successive pulses of the plurality of pulses by a second interval duration greater than the maximum first interval duration.

[0012] According to exemplary embodiments of the present disclosure, advantageous pulsatile profile construction methods are provided that define fixed or variable intervals within a pulsatile profile based on the pharmacokinetics of a drug measured in a single infusion (e.g., extracted from an individual model, a representative model, or population PK), and whose PK is modeled using any of several exemplary simulation methods.

[0013] According to aspects of an exemplary embodiment, the interval between the pulses of the pulsation profile to achieve a target PK is determined by a pulsation profile construction operation that includes: using measured PK data for a single injection of the fluid, modeling the measured PK data to generate a predicted PK curve optimized to meet the target PK, generating respective PK traces of the predicted PK curve corresponding to different interval durations, and selecting the interval based on characteristics of the respective PK traces.

[0014] According to an aspect of the exemplary embodiment, the modeling includes using a simulation method selected from a product of convolution operations and a curve fitting operation.

[0015] According to aspects of an exemplary embodiment, the simulation method using convolution products 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 to the fixed amount of the pulse and the concentration of the fluid, overlaying the scaled single-dose PK curve onto the pulsation profile using convolution, and performing linear interpolation on the measured PK data of one of multiple overlaid pulse PK curves in the pulsation profile to obtain the predicted PK curve.

[0016] According to aspects of an exemplary embodiment, 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.

[0017] According to aspects of an exemplary embodiment, the modeling includes fitting the predicted PK curve to the measured PK data, varying pulse interval durations to generate the respective PK traces of the predicted PK curve, and selecting intervals based on characteristics of the respective PK traces.

[0018] According to aspects of the exemplary embodiment, one or more of said pulsation profile building operations are performed iteratively.

[0019] According to aspects of the exemplary embodiment, one or more of the pulsation profile building operations are performed iteratively to optimize the pulsation profile.

[0020] According to an aspect of an exemplary embodiment, the pulsation profile construction operation further includes optimizing the residual between the modeled predicted PK and the measured PK data during the curve fitting operation.

[0021] Additional and / or other aspects and advantages of the exemplary embodiments will be set forth in, or will be apparent from, the following description, or may be learned by practice of the exemplary embodiments. Exemplary embodiments may include apparatus and methods of operation having one or more of the above-described aspects and / or one or more of the above-described features, and combinations of the above-described features. Exemplary embodiments may include one or more of the above-described aspects and / or combinations of the above-described features, for example, as set forth in the appended claims. [Brief explanation of the drawings]

[0022] The above and / or other aspects and advantages of the exemplary embodiments will be more readily understood from the following detailed description taken in conjunction with the accompanying drawings.

[0023] [Figure 1] FIG. 1 is a perspective view of an exemplary infusion pump. [Figure 2] FIG. 2 is a perspective view of the infusion pump of FIG. 1 with the housing cover removed to expose the components of an exemplary pump on a base plate. [Figure 3] FIG. 3 is a partial perspective view of exemplary pump components in an exemplary medication fluid delivery device operating according to a programmed pulsatile flow profile using an exemplary pulsatile delivery method, according to an exemplary embodiment of the present invention. [Figure 4] FIG. 4 is a partial perspective view of exemplary pump components in an exemplary medication fluid delivery device operating according to a programmed pulsatile flow profile using an exemplary pulsatile delivery method, according to an exemplary embodiment of the present invention. [Figure 5A]FIG. 5A is a perspective view of the pump components of FIGS. 3 and 4 in an exemplary medication fluid delivery device arranged according to a pre-dispense and pre-aspiration operational state, respectively. [Figure 5B] FIG. 5B is a perspective view of the pump components of FIGS. 3 and 4 in an exemplary medication fluid delivery device arranged according to a ready-to-dispense and ready-to-aspirate operating state, respectively. [Figure 5C] FIG. 5C is a perspective view of components of an exemplary medication fluid delivery device, including the exemplary pump components of FIGS. 3 and 4 and associated electronic circuitry on a printed circuit board. [Figure 6A] FIG. 6A is a block diagram of components of an exemplary medication fluid delivery device, in accordance with an exemplary embodiment of the present invention. [Figure 6B] FIG. 6B is a schematic diagram of a medication fluid delivery device pump motor having a current sensor according to an exemplary embodiment of the present disclosure. [Figure 7] FIG. 7 illustrates exemplary filtered pump measurement data (eg, motor current) from an exemplary medication fluid delivery device during an aspiration stroke and a dispense stroke. [Figure 8] FIG. 8 is a diagram illustrating pump measurement data from an exemplary medication fluid delivery device showing each pump stroke over time and the corresponding pressure change for each pump stroke. [Figure 9] FIG. 9 is a graph showing exemplary pharmacokinetics based on and varying as a function of a subject patient's weight. [Figure 10A] FIG. 10A is a graph showing an example of pharmacokinetics using different pulsatile profiles shown in FIGS. 10B and 10C, according to an exemplary embodiment of the present disclosure. [Figure 10B] FIG. 10B is a diagram showing a pulsation profile. [Figure 10C] FIG. 10C is a diagram showing a pulsation profile. [Figure 11A]FIG. 11A is a graph showing an example of pharmacokinetics using different pulsatile profiles shown in FIGS. 11B and 11C, according to an exemplary embodiment of the present disclosure. [Figure 11B] FIG. 11B is a diagram showing a pulsation profile. [Figure 11C] FIG. 11C is a diagram showing a pulsation profile. [Figure 12] FIG. 12 is a graph showing an example of the pharmacokinetics of a single dose injection as exemplary source data for a pulsatile profile construction method according to another embodiment of the present disclosure. [Figure 13A] FIG. 13A shows an exemplary pulsatile profile overlaid with a scaled PK curve as shown in FIG. 13B for predicted blood concentrations using a pulsatile profile construction method according to a first exemplary embodiment employing a numerical simulation approach. [Figure 13B] FIG. 13B shows the scaled PK curves. [Figure 14A] FIG. 14A is a graph showing predicted blood concentrations based on different pulse intervals using the pulsatile profile construction method according to the first exemplary embodiment. [Figure 14B] FIG. 14B is a graph showing predicted blood concentrations according to a first exemplary embodiment of a pulsatile profile construction method based on concentration adjustment, with the concentration and pulse interval fixed for a set target PK of a constant plateau. [Figure 14C] FIG. 14C is a graph showing predicted blood concentrations based on body weight of different animal models at fixed concentrations and pulse intervals to assess PK sensitivity to animal body weight according to a first exemplary embodiment of the pulsatile profile construction method. [Figure 14D] FIG. 14D is a graph showing predicted peak blood concentration versus pulse interval according to a first exemplary embodiment of the pulsatile profile construction method. [Figure 14E] FIG. 14E illustrates a predicted PK curve according to a first exemplary embodiment of the pulsation profile construction method. [Figure 15] FIG. 15 illustrates a PK curve predicted using a pulsation profile construction method according to a second exemplary embodiment employing a theoretical simulation approach.

[0024] Throughout the drawings, like reference numerals will be understood to refer to like elements, features and structures. DETAILED DESCRIPTION OF THE INVENTION

[0025] DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to exemplary embodiments, which are illustrated in the accompanying drawings. The embodiments described herein are presented by way of example only and are not intended to limit the invention.

[0026] In accordance with exemplary embodiments of the present disclosure, described herein is an advantageous pulsatile delivery method for achieving a target drug blood concentration profile (i.e., pharmacokinetics (PK)) by controlling a fluid delivery device (e.g., a wearable injector) configured to deliver a dose of a medicinal treatment fluid or agent using predefined, discrete, fixed-bolus amount pulses according to a specified pulsatile profile.

[0027] A pulsating fluid flow according to the present disclosure is a pulsating or intermittent infusion of fluid using one or more pulses, each pulse corresponding to the delivery of a predefined, discrete, fixed amount of fluid. As described below, a pulsation profile can include a selected number of pulses over a selected time period, with the pulses having a first interval between successive pulses that may be constant or may vary over time. The duration of the first time interval between successive pulses is much longer than the pulse itself (e.g., the duration associated with the delivery of a corresponding predefined, fixed bolus amount for a particular pulse). The exemplary times associated with pulses in the exemplary pulsation profiles shown in the accompanying drawings represent the start of the pulse (e.g., the start of pulse delivery) and do not necessarily represent the duration or time period associated with the delivery of the corresponding predefined bolus. In some cases, pulses can last from a few milliseconds (ms) to several seconds (s). For example, the ejection time of the piston / sleeve chamber 38 is on the order of a few ms. As a further example, a pulse delivering 5 μL can last 1-3 seconds, and a pulse delivering 50 μL can last approximately 250 ms. Nevertheless, as explained below, the predefined bolus time period of a particular pulse will be significantly shorter than an exemplary first time interval between that pulse and an adjacent or subsequent pulse in the pulsation profile. Also, as explained below, the pulsation profile can include one or more pulse trains, where a pulse train corresponds to a series of consecutive pulses, each separated by a first time interval, followed by a pause in pulses for a second time interval that is longer than the first time interval.

[0028] According to further exemplary embodiments of the present disclosure, advantageous pulsatile profile construction methods are described herein that define fixed or variable intervals in the pulsatile profile based on the pharmacokinetics (PK) of a drug measured in a single infusion (e.g., extracted from individual, representative model, or population PK), and the PK is modeled using any of several exemplary simulation methods.

[0029] Exemplary Pulsatile Delivery Methods

[0030] An exemplary embodiment of a pulsatile delivery method using a wearable drug delivery device with predefined, discrete bolus amounts to achieve target PK (pharmacokinetics) by varying the pulse intervals is described herein with reference to FIGS. 1 through 11C. As described in this disclosure, pharmacokinetics, or PK, refers to the way a drug acts in a subject's (e.g., a human patient's) body over a period of time, including the processes by which the drug is absorbed, distributed throughout the body, localized in tissues, and excreted. PK is also referred to as a target drug blood concentration profile. FIGS. 1 through 8 show an example of a fluid delivery device 10 configured to deliver pulses of predefined, discrete bolus amounts. The fluid delivery device 10 is a low-compliance, wearable drug delivery device (e.g., a patch pump) that is advantageously configured to deliver a drug based on a specified pulsatile profile to achieve target PK in accordance with the pulsatile delivery method. It will be understood that other fluid delivery devices can also be controlled in accordance with the pulsatile delivery method.

[0031] FIG. 1 is a perspective view of an exemplary fluid delivery device 10 (e.g., an infusion pump). Patch pumps or wearable infusion pumps 10 are described in U.S. Patent Application Publication No. 2007 / 0129994, the entire contents of which are incorporated herein by reference. Pump 10 has a housing 11, which includes a main cover 12 that is liquid-tight, or preferably airtight, sealed to a base 19. Patch pump 10 may be provided with one or more user buttons (e.g., push-button switches with associated button covers), designated 14a, 14b. An adhesive layer (not shown) may be provided on base 19 for adhering infusion pump 10 to a patient's skin. Base 19 carries various components.

[0032] FIG. 2 shows a perspective view of some of the major components of the patch pump 10, with the main cover 12 and reservoir 70 (FIG. 6A) removed for clarity. The patch pump 10 preferably includes a reservoir 70 for storing a fluid (e.g., a therapeutic fluid such as a drug) and a pump 64 for pumping the drug from 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 a cannula 72 into a patient's skin to deliver the drug. According to one embodiment, the fill port 68 is a conduit for supplying a medical fluid or drug to the reservoir 70. In some embodiments, the fill port 68 can include a portion that functions as part of a flow path for the drug to be discharged from the reservoir 70, as described in U.S. Patent Application Publication No. 2009 / 0129994, the entire contents of which are incorporated herein by reference. The receptacle 69 is connected to the insertion mechanism 74, for example, by tubing, and delivers the drug to the insertion mechanism 74 prior to injection into the patient's skin.

[0033] For illustrative purposes, an exemplary infusion pump 64 will now be described with reference to Figures 3, 4, 5A, 5B, and 5C. The pump 64 is a rotary metering pump as described in U.S. Patent Application Publication No. 2009 / 022999, the contents of which are incorporated herein by reference in their entirety. The pump 64 includes a pump assembly 20 that can connect to a DC motor and gearbox assembly (not shown) to rotate a sleeve 24 within a pump manifold 22. The sleeve is provided with a helical groove 26. A connecting pin 28 connected to a piston 30 translates along the helical groove to guide the retraction and insertion of the piston 30 within the sleeve 24 as the sleeve 24 rotates in one direction and then the opposite direction, respectively. The sleeve is provided with an end plug 34. Two seals 32, 36 at each end of the piston and end plug within the sleeve 24 define a cavity or chamber 38 when the piston 30 is retracted after the aspiration stroke and thus ready to dispense, as shown in Figure 5A. Thus, the volume of chamber 38 varies depending on the amount of retraction of piston 30. As shown in FIG. 5B, when piston 30 is fully inserted, seals 32, 36 substantially contact one another after the dispense stroke, and ready for aspiration, the volume of chamber 38 is negligibly small, essentially zero. According to an exemplary embodiment, chamber 38 of pump 64 can be configured to accommodate the pulsed, predefined, discrete, fixed bolus amounts described above. Two ports 44, 46 are provided to pump manifold 22: inlet port 44 allows medication to enter from reservoir 70 (FIG. 4A) of pump 64 (FIG. 4A), and outlet port 46 allows medication drawn into chamber 38 (e.g., by retraction of piston 30 during the aspiration phase of operation) to be dispensed from chamber 38 into a fluid path, for example, to cannula 72 (FIG. 4A) within the patient's body, by reinserting piston 30 into chamber 38.

[0034] 3, 4, 5A, 5B, and 5C, the sleeve 24 can be provided with openings (not shown) aligned with either the outlet port 46 or the inlet port 44 (i.e., depending on the angle of rotation of the sleeve 24 and, therefore, the angle of translation of the piston 30), thereby allowing drug in the chamber 38 to flow through either the corresponding port 44, 46. A pump metering device 78 (FIG. 4A), such as a sleeve rotation limit switch, can be provided, which includes, for example, an interlock 42 and one or more detents 40 on the sleeve 24 or its end plug 34 that interface with the interlock 42. The interlock 42 can be attached to both ends of the manifold 22. When the pump 64 is in a first position, the detents 40 on the end face of the sleeve 24 are adjacent to the protrusions 48 of the interlock 42, and in this first position, the side holes of the sleeve 24 are aligned with the inlet port 44, allowing fluid to flow from the reservoir 70 into the chamber 38. Under certain conditions, such as backpressure, friction between the piston 30 and sleeve 24 can become so great that the sleeve 24 rotates before the piston 30 and coupling pin 28 reach the ends of the spiral groove 26. This can result in an incomplete amount of liquid being dispensed per dispensing stroke. To prevent this situation, the interlock 42, shown in FIG. 5A, prevents rotation of the sleeve 24 until the torque exceeds a predetermined threshold. This ensures that the piston 30 rotates completely within the sleeve until the coupling pin reaches the end of the spiral groove 26. Once the coupling pin 28 reaches the end of the spiral groove 26, further movement of the DC motor and gearbox assembly, or other type of pump and valve actuator 66 (FIG. 6A), increases the torque on the sleeve 24 beyond the threshold, deflecting the interlock 42 and allowing the detent 40 to pass over the bump 48. Once the sleeve 24 has been rotated to its full extent and its side holes are facing the cannula 72 or exit port 46, the detents 40 pass over the projections 48 of the interlock 42, as shown in Figure 5B.Another sleeve mechanism 41 can be provided to engage an electrical switch (e.g., an end stop switch 90 provided on a printed circuit board 92 and positioned relative to the sleeve and / or end plug 34 and interfaced with a pump metering device 78, as shown in FIG. 5C).

[0035] FIG. 6A is a systems diagram illustrating exemplary components of an exemplary drug delivery device 10 having an infusion pump of FIGS. 3, 4, 5A, 5B, and 5C. The drug delivery device 10 can include an electronics subsystem 52 for controlling the operation of components within a fluidic 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. The power storage subsystem 50 can include, for example, a battery 56 for powering the components within the electronics subsystem 52 and the fluidic subsystem 54. The fluidic subsystem 54 can include, for example, an optional fill port 68 for filling (e.g., with a drug) a reservoir 70, although the drug delivery device 10 can optionally be shipped from the manufacturer with the reservoir already filled. The fluidic subsystem 54 also includes a measurement subsystem 62, including a pump 64 and a pump actuator 66. As described above, the pump 64 can have two ports 44, 46 and associated valve subassemblies for controlling the flow of fluid into and out of the pump chamber 38 via the respective ports 44, 46. One of the ports is the inlet port 44, through which fluid, such as a liquid medication, flows from the reservoir 70 into the pump 64 as a result of the suction or pull stroke of the pump plunger or piston 30. The other port is the outlet port 46, through which fluid flows from the pump chamber 38 towards the cannula 72 and into the patient pump as a result of the dispense or push stroke of the pump plunger or piston 30. The pump actuator 66 can be a DC motor and gearbox assembly or other pump drive mechanism for controlling the plunger or piston 30 and other associated pump components, such as the sleeve 24, which can rotate relative to the translational movement of the pump piston 30.The microcontroller 58 can be provided with an integrated or separate memory device containing computer software instructions, for example, to rotate the sleeve 24 in a selected direction, to translate or axially move the piston 30 within the sleeve 24 for an aspiration or dispense stroke, or to rotate the sleeve 24 and piston 30 together during a change of valve state, as described in U.S. Patent No. 6,277,999. As described below, a pulsatile flow profile programmed according to an exemplary embodiment can be provided to the microcontroller 58 according to the pulsatile delivery method described herein to achieve a target PK. Additionally, the microcontroller 58 can be provided with an algorithm according to a second method for constructing a pulsatile profile, described below.

[0036] FIG. 6B shows an exemplary apparatus for detecting motor current. A sense resistor 142 is added to PCB 92 to enable measurement of motor current. The voltage drop across sense resistor 142 is fed to an analog-to-digital converter (ADC) in microcontroller 58. The occlusion condition is then calculated by microcontroller 58, and an occlusion or empty reservoir event is reported by microcontroller 58 when, for example, a specified occlusion or empty reservoir motor current signature is detected. Other components can be used for current detection to facilitate pump motor current measurement. For example, in the case of a pulse-width modulated (PWM) driven motor used as pump actuator 66, motor current information can be extrapolated from the PWM data.

[0037] Reference is now made to Figures 7 and 8. Figure 7 shows exemplary filtered pump measurement data (e.g., motor current) from exemplary delivery device 10 during an aspiration stroke 80 and a dispense stroke 82. Figure 8 shows an exemplary series of dispense strokes 82 performed by exemplary delivery device 10 in an exemplary continuous injection operation. 1...nand a corresponding end stop time. As described above, according to exemplary embodiments of the present disclosure, one of these dispense strokes can deliver a predefined, discrete, fixed bolus amount corresponding to a pulse. According to the pulsatile delivery method described herein, an algorithm in microcontroller 58 is configured to control pump 64 (e.g., via pump actuator 66, such as a motor) to deliver medication from reservoir 70 through chamber 38 using pulses of a specified pulsatile profile to achieve a target PK of the medication.

[0038] 9 through 11C, the control of a fluid delivery device that delivers pulses according to an algorithm implementing a pulsatile delivery method will now be described. FIG. 9 is a graph illustrating an exemplary PK curve 100 based on and varying with a target patient's weight. For example, a PK curve 100a is shown for a target patient's weight, along with higher and lower PK curves 100b and 100c for target patient weights of -10% and +10%, respectively.

[0039] FIG. 10A is a graph of exemplary PK 100 curves achieved using different pulsation profiles 102 shown in FIGS. 10B and 10C, illustrating the effect on target PK of the selected grouping and timing of pulses 104 generated by an algorithm implementing the pulsatile delivery method described herein. The upper PK curve 100c in FIG. 10A corresponds to the pulsation profile 102 shown in FIG. 10B, in which pulses 104 are generated with intervals 106 between successive pulses. As described below, the intervals 106 need not be of fixed duration but rather can vary over time and with pulse order. The duration of the intervals 106 is longer than the duration of a dispense stroke or a fixed volume of fluid associated with a pulse (e.g., the contents of chamber 38 of the illustrated fluid delivery device 10), and the pulses 104 are discrete and intermittent from one another. Example durations of the intervals 106 include milliseconds (ms) or seconds (s) to tens of minutes, or even hours. During these intervals 106, 0 milliliters per minute (ml / min) or substantially no fluid is delivered for at least several seconds (e.g., 10 seconds in the example below), allowing the pulsation profile 102 to deliver a well-controlled bolus using spaced-apart, discrete pulses to achieve the target PK100.

[0040] As described above, pulsating fluid flow according to the present disclosure is a pulsating or intermittent fluid dispensing using one or more individual pulses 104, each individual pulse corresponding to the delivery of a predefined amount of fluid. The pulsating profile 102 is comprised of a plurality of intermittent pulses 104, each of which has a rest time or duration 106 between successive pulses that is longer than the duration the pulses 104 take to deliver the predefined amount of fluid through a fluid delivery device 10 controlled to deliver fluid using the pulsating profile 102.

[0041] The lower PK curve 100d of Figure 10A corresponds to the pulsation profile 102 shown in Figure 10C, which, like the pulsation profile 102 shown in Figure 10B, assumes a fixed injection volume and duration. However, the pulsation profile 102 shown in Figure 10C includes multiple pulses 104 delivered in a pulse train 108, 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-10C illustrate how various factors affect the pulsation profile 102 selected or specified to achieve the target PK 100.

[0042] FIG. 11A is a graph of exemplary curves of PK 100 achieved using different pulsation profiles 102 shown in FIGS. 11B and 11C, illustrating the effect on target PK of varying the frequency of pulses 104 generated by an algorithm implementing the pulsatile delivery method described herein. PK curve 100e in FIG. 11A corresponds to the pulsation profile 102 shown in FIG. 11B, where pulses 104 are generated at a relatively high frequency, indicated at 114, compared to pulses 104 generated at a relatively low frequency, indicated at 118. PK curve 100f in FIG. 11A corresponds to the pulsation profile 102 shown in FIG. 11C, where pulses 104 are generated at a relatively moderate frequency, indicated at 116, compared to pulses 104 generated at a relatively low frequency, indicated at 118, and pulses 104 generated at a relatively high frequency, indicated at 114, in FIG. 11B.

[0043] As mentioned above, the algorithm for implementing the pulsatile delivery method can be implemented in several different embodiments and is not limited to the example embodiments listed below.

[0044] 1. According to an exemplary embodiment, the intervals 106 between pulses 104 are constant (e.g., as shown in pulsation profile 102 in FIG. 10B ) and are long (e.g., 10 times longer) compared to the pulses (e.g., the time to deliver a predefined, discrete bolus amount associated with the pulse). Pulses delivered by fluid delivery device 10 under the control of an algorithm implementing an embodiment of the pulsatile delivery method of the present disclosure are advantageous in that they provide controlled infusion response pharmacokinetics. The controlled, discrete pulse delivery by such fluid delivery device 10 provides a significant advantage over conventional devices with high compliance in continuous delivery of medication. When such conventional devices (e.g., conventional syringe-type pumps with lead screws and stepper motors that vary the time between steps) are operated according to the pulsatile delivery method of the present disclosure, the intervals between steps are not equivalent to the discrete pulses 104 according to embodiments of the present disclosure because the compliance in the conventional fluid delivery system damps such steps and the intervals between steps. Thus, the amount delivered by such attenuated steps / intervals will take a relatively long, undesirable time compared to the shorter time that the same amount can be delivered by the individual bolus pulses 104 of the present disclosure.

[0045] 2. According to another exemplary embodiment, the intervals 106 between pulses 104 are variable (e.g., as shown in the pulsation profile 102 of FIGS. 11B and 11C), but each interval 106 is long (e.g., 10 times longer) compared to the pulses 104 (e.g., the time to deliver a predefined, discrete bolus amount associated with the pulse). The variation between pulses 104 is appropriately controlled, digitized, and discrete in accordance with the pulsation delivery method. The algorithm implementing the pulsation delivery method by generating the pulses 104 can vary the duration of the intervals 106 over the course of the infusion to affect the PK 100. For example, the infusion may provide more frequent pulses 104 with shorter intervals 106 at certain times of the day, or at the beginning and end of treatment, etc.

[0046] 3. In a further exemplary embodiment, a combination of consecutive pulses 104 and intervals 106 between pulses 104 are used to achieve the desired PK. For example, a typical dose may be 5 ml per pulse 104. For a 10 ml dose, a pulsatile delivery method uses two 5 ml consecutive pulses 104 with a long interval 106 between them.

[0047] 4. In other exemplary embodiments, an algorithm implementing a pulsatile delivery method is configured to achieve a target PK selected from at least one of the following types of PK curves: (1) Zero order response, (2) Steady increase, (3) Steady plateau, (4) Steady plateau of desired duration, (5) Steady decrease, (6) Cyclical pattern, (7) Cyclic pattern synchronized with diurnal / nocturnal / hormonal / biological pattern, and (8) Non-cyclical variable pattern. (1) An example of a target PK that is a zero order response would be a rise from zero to a plateau and then back to zero, i.e., increasing the concentration to the plateau level as sharply or rapidly as possible. An example of a (2) steady-state increasing target PK corresponds to a steady increase or gradual rise in blood concentration over time, which may be useful, for example, to reduce side effects of the delivered drug. Alternatively, an example of a (5) steady-state decreasing target PK corresponds to a steady decrease or gradual decline in blood concentration over time, which may be useful, for example, to reduce withdrawal symptoms when a patient is discontinuing a particular drug. An example of a (3) steady-state plateau target PK is shown by the PK curves for the 120-minute pulse interval in Figures 14A and 15B, which oscillate until they become stable and wavy due to dynamic equilibrium. Depending on the delivery instructions and drug efficacy, this steady-state plateau can be (4) a steady-state plateau of any desired duration. An example of a (6) cyclical pattern target PK is a low concentration, followed by a high concentration, followed by a low concentration, with each change in concentration occurring over an extended period of time relative to the treatment period, such as hours in a 72-hour treatment, rather than minutes or seconds.(7) Examples of target PK that are cyclical patterns synchronized with day / night / hormonal / biological patterns include pulsatile profiles with patterns of pulses delivered to achieve a variable target PK over time synchronized with the patient's diurnal patterns (e.g., patient activity is greater during the day than at night), or other forms of chronotherapy that administer a drug over a specific period of time. As previously mentioned, target PK can also be (8) a non-cyclical variable pattern.

[0048] 5. According to another embodiment, the mechanical compliance of a drug delivery device (e.g., the fluid delivery device 10 of FIGS. 1-5C or other fluid delivery devices) is sufficiently low to deliver discrete boluses without damping and achieve sustained infusion. The fluid delivery device of the present disclosure, for example, is controlled by an algorithm using the pulsatile delivery method of the present disclosure to achieve discrete, temporally well-defined pulsed small infusions to a target PK via pulses 104 as described herein. In contrast, conventional fluid delivery devices have high compliance requirements and can achieve a constant or variable continuous fluid flow rate only through damping, without pulses 104 as described in accordance with exemplary embodiments. As discussed above, when such conventional, high-compliance delivery devices (e.g., conventional syringe-type pumps with lead screws and stepper motors that vary the time between steps) are operated according to the pulsatile delivery method of the present disclosure, the compliance in the conventional fluid delivery system damps such steps and the intervals between steps, resulting in intervals between steps that are not equivalent to the discrete pulses 104 of the presently disclosed embodiments. Thus, the amount delivered by such attenuated steps / intervals will take a relatively long, undesirable time compared to the shorter time that the same amount can be delivered by the presently disclosed individual bolus pulses 104. Thus, exemplary embodiments of the present disclosure realize the advantage of providing a control window for injecting a known amount compared to continuous delivery.

[0049] 6. According to another exemplary embodiment, the pulsatile profile of the delivered medication can drop to 0 ml / min for at least 10 seconds between pulses 104. This embodiment represents a departure from continuous infusion devices, which have high compliance and require longer times to deliver medication than pulsatile delivery methods and associated fluid delivery devices.

[0050] 7. In another embodiment, the pulsatile profile 102 is pre-programmed into a fluid delivery device that operates according to a pulsatile delivery method.

[0051] 8. In yet another embodiment, multiple pre-programmed pulsation profiles 1021 ...n For example, one or more pre-programmed pulsation profiles 1021 may be selected. ...n When provided to the fluid delivery device, a user may operate buttons or other user input devices on the fluid delivery device, or a remote control or auxiliary device connected to the fluid delivery device, to select one of the plurality of stored programmed pulsation profiles 1021. ...n Profile 102 can be selected from the list.

[0052] 9. According to an exemplary embodiment, the number of consecutive pulses 104 in the pulsation profile 102 can be selected to define an equal single dose. For example, the number of pulses 104 and / or the duration of the intervals 106, 110, and / or 112 can be input by a user via a user interface on the delivery device or a paired / connected remote control or auxiliary device. For example, input buttons 14a, 14b (FIG. 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 may include a touchscreen input or other input means.

[0053] 10. In another embodiment, the interval between pulses can be selected from a plurality of pre-programmed pulsation profiles, selected from pre-programmed options as described in embodiment 4(8).

[0054] 11. In an exemplary embodiment, the number of successive pulses can be digitally entered, such as by successive button presses, or programmed using a user input device or interface (e.g., a graphical user interface) on the fluid delivery device or a paired / connected remote control device or auxiliary device.

[0055] 12. In one embodiment, the time interval between pulses can be digitally entered, such as by successive button presses, or programmed using a user input device or interface (e.g., a graphical user interface) on the fluid delivery device or a paired / connected remote control device or auxiliary device.

[0056] Pulsation profile construction method

[0057] According to further exemplary embodiments of the present disclosure, advantageous pulsatile profile construction methods are described herein that define fixed or variable intervals in a pulsatile profile based on the pharmacokinetics (PK) of a drug measured from a single infusion (e.g., extracted from an individual model, a representative model, or population PK), and the PK is modeled using any of several exemplary simulation methods.

[0058] The pulsatile profile construction method is configured to predict pharmacokinetics during a pulse infusion based on the PK of a single infusion. The pulsatile profile construction method includes simulating the effect of PK infusion parameters (e.g., one or more of pulse interval, subject weight, and drug concentration) on the target steady-state blood concentration. Two simulation approaches are described below, but it is understood that other simulation approaches can also be used. This disclosure describes a pulsatile profile construction method using a numerical approach, i.e., simulation using convolution products. This disclosure also describes a theoretical approach, i.e., simulation using curve fitting.

[0059] Before describing these two simulation approaches in more detail below, an overview of the pulsatile profile construction method will be provided. The pulsatile profile construction method will be described with reference to a fluid delivery device, such as a patch pump or infusion pump 10, described above in connection with the pulsatile delivery method. The pulsatile profile construction method includes operating an infusion pump to deliver a medicinal therapy fluid or agent to a patient, whereby intervals (e.g., 106, 110, and / or 112) between pulses 104 in a pulsatile profile 102 to achieve a target PK are determined using measured PK data for a single infusion of the fluid, modeling the measured PK data to generate a predicted PK curve optimized to meet the target PK, generating respective PK traces of the predicted PK curve corresponding to different interval durations, and selecting and setting intervals based on characteristics of the respective PK traces. In an exemplary embodiment of the pulsatile profile construction method, the modeling includes using a simulation approach selected from a product of convolution operations and curve-fitting operations.

[0060] For example, modeling by a simulation approach using convolution products can include: i. obtaining a single-dose PK curve corresponding to a single injection of fluid from the measured PK data; ii. Scaling the single dose PK curve to a fixed pulse volume and fluid concentration; iii. Using convolution to overlay the scaled single-dose PK curve onto the pulsatile profile; iV. Perform linear interpolation on the measured PK data of one of the multiple superimposed pulse PK curves in the pulsatile profile to obtain a predicted PK curve.

[0061] For example, modeling by a simulation approach using curve fitting operations can include: i. obtaining a single-dose PK curve corresponding to a single injection of fluid from the measured PK data; ii. Estimating the time constant from the reference PK curve; iii. Use the time constant to generate a predicted PK curve.

[0062] Selecting intervals within the pulsatile profile 102 (e.g., intervals 106, 110, and / or 112 between pulses 104) based on the characteristics of the respective PK traces can include, for example, i. obtaining measured PK data for a single infusion and determining the interval by fitting a predicted PK curve to the measured PK data; ii. Varying the pulse interval duration to generate respective PK traces of the predicted PK curve; iii. Selecting intervals based on corresponding characteristics of each PK trace; This includes:

[0063] A numerical simulation approach using convolution products.

[0064] 12, source data (i.e., measured PK data) corresponding to a reference PK curve for a single dose into subcutaneous (SC) tissue is obtained, and the simulated responses described below are obtained. In this embodiment, the measured PK data used in the pulsatile profile construction method can be corrected for background noise (e.g., truncated and offset to zero).

[0065] For example, the cumulative PK curve of Figure 13B is generated according to the pulsatile profile construction method by scaling the single-dose PK curve of Figure 12 with the selected pulse volume and concentration. The scaled single-dose PK curve is overlaid onto the pulsatile profile shown in Figure 13A via the convolution product shown in Figure 13B.

[0066] FIG. 14A is a graph showing predicted blood concentrations based on different pulse intervals (e.g., different values ​​of interval 106) with fixed concentration and subject weight. The use of graphs like FIG. 14A when determining intervals via the pulsatile profile construction method is supported by observations from FIGS. 14B, 14C, and 14D. FIG. 14B is a graph showing predicted blood concentrations based on concentration adjustments with fixed concentration and pulse interval for a specified target PK, e.g., a constant plateau. FIG. 14C is a graph showing predicted blood concentrations based on different animal model weights (used for single-bolus PK measurements) with fixed concentration and pulse interval to assess PK sensitivity to animal model weight. The amplitude of the blood concentration at the plateau of the PK trace shown in FIG. 14C is observed to be proportional to the change in subject weight (e.g., the change in weight for the different animal models shown in the figure). FIG. 14D is a graph showing the relationship between predicted peak blood concentrations and pulse interval, and it is observed that this relationship is nonlinear.

[0067] Finally, Figure 14E shows predicted PK curves according to one embodiment of a pulsatile profile construction method using a numerical simulation approach (e.g., convolution product). The overlaid scaled single-dose PK curves have been linearly interpolated to the experimental data.

[0068] Theoretical simulation approach using curve fitting

[0069] In the example below, the source data includes a two-species model in which mass exchange is characterized as follows:

[0070]

number

[0071]

number

[0072] where: S is the drug concentration in SubQ space, B is the blood drug concentration, α is the drug degradation rate in SubQ, β is the blood clearance rate, γ is the rate of SubQ / blood exchange.

[0073] The blood volume per body weight of the animal model is known (mL / kg). The concentration in the subcutaneous (SubQ) tissue is measured at the injection site and is considered to be a local concentration, independent of the body weight of the animal model. Neglecting volume changes and local diffusion, the concentration S is equal to the mass of the drug.

[0074]

number

[0075] is defined as the volume of subcutaneous tissue in which mass exchange occurs and is assumed to be constant, e.g., approximately 1 mL. Dilution of blood volume is assumed to occur rapidly due to forced convection.

[0076] According to an exemplary embodiment of the pulsatile profile construction method, when the body weight (kg) and single bolus dose (mg) of the animal model are known, the following three constants are estimated from the single bolus PK curve: α is approximately 1 / (2 hours), β is approximately 1 / (0.5 hours), γ is approximately 1 / (1000 hours).

[0077] Using the above time constants, predicted PK curves are generated, as shown in Figure 15. The predicted blood concentrations can be analyzed for different parameters, such as different pulse intervals (e.g., different values ​​of interval 106), with the concentration and animal model weight fixed. For example, a graph similar to Figure 14A can be generated, showing predicted blood concentrations based on different pulse intervals using the pulsatile profile construction method according to the second exemplary embodiment.

[0078] Reference is now made to FIGS. 14E and 15, which illustrate predicted PK curves using convolution-like fitting and overshoot-like fitting, respectively, according to the first and second exemplary embodiments of the pulsation profile construction method described above. In the exemplary embodiments of the pulsation profile construction method described above, either simulation approach can generate an interval (e.g., x-minute pulse interval 106) selected according to the target PK. If a different target PK is desired, such as PK with a stable plateau that stably undulates due to dynamic equilibrium (e.g., as shown in the PK curves with a 120-minute pulse interval in FIGS. 14A and 15B), 2*reference interval time 106 can be selected for the pulsation profile. It is generally believed that the numerical simulation approach using convolution according to the first exemplary embodiment of the pulsation profile construction method will generally underestimate the plateau of the predicted PK curve (e.g., FIG. 14E) because the raw data likely does not accurately capture the blood concentration peak. On the other hand, theoretical simulation approaches using curve fitting according to the second exemplary embodiment of the pulsation profile construction method are generally believed to overestimate the plateau of the predicted PK curve (e.g., FIG. 15) because the fit with the raw data is qualitatively adjusted to obtain a meaningful and good visual fit. Nevertheless, both simulation approaches described above for the first and second exemplary embodiments of the pulsation profile construction method produced results of the same order of magnitude, within about 30% error.

[0079] The processing device can include an algorithm implementing a pulsation profile construction method. The simulation model can be based on source data for various medications other than insulin. Simulation results can be provided as algorithms separate from and / or integrated into the fluid delivery device for various medications, their manufacturers, and / or distributors. For example, the pulsation profile construction method algorithm can target various medications (e.g., drugs) and target concentrations modeled and used for various pharmaceutical companies. The pulsation profile construction method algorithm can be configured iteratively and can be configured to reduce the number of iterations performed for each medication (e.g., drug) and target concentration by fine-tuning or tuning one or more parameters over time. As described herein, the algorithm implementing the pulsation profile construction method, according to an exemplary embodiment, can use the convolution product of the pulse signal and the scale-corrected PK response of a single single injection. According to another embodiment, the algorithm implementing the pulsation profile construction method can use a time constant extracted from a reference PK curve injection. According to another exemplary embodiment, the scale correction can be at least one of the weight of the patient or subject of the reference model, the weight of the subject patient, the drug concentration (e.g., used in the single injection of the reference model), the drug concentration (e.g., in the fluid delivery device such as the wearable infusion pump 10), the drug amount (e.g., used in the single injection of the reference model), and the bolus amount (e.g., of the fluid delivery device such as the wearable infusion pump 10). Further, in an exemplary embodiment, the pulsation 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 error when fitting the simulation pattern to the target PK.In other words, the exemplary embodiments described herein can design an optimal pattern or pulsatile profile for an infusion by minimizing the residual between the simulation output and the target PK (e.g., the PK profile can be periodic), with an approach to "curve fitting" defining what is optimal. An iterative process can also be employed to achieve the optimal pattern or pulsatile profile 102.

[0080] The exemplary embodiments described herein are advantageous and provide an improvement over existing drug delivery devices, since they allow for greater control over precise dosage using pulsatile profiles or patterns compared to existing drug delivery devices designed for continuous infusion. Furthermore, the exemplary embodiments described herein also allow for discontinuous infusion. The methods described herein (e.g., pulsatile profile delivery methods) allow for the use of fluid delivery devices to output discrete boluses for adjustable infusion.

[0081] Existing delivery devices are designed to smoothly deliver drugs continuously using drive mechanisms with high compliance requirements, but suffer from the drawback of non-continuous delivery due to changes in the drive mechanism's compliance and resistance over time. Advantageous exemplary embodiments of the present disclosure avoid the need for continuous drive and its associated complexity, as well as the performance degradation due to inevitable fluctuations over the life of a continuous drive device. As demonstrated herein, the use of PK and pulses offers advantages over existing continuous drive fluid infusions. While existing fluid delivery devices regulate the rate of a steady infusion (e.g., syringe pumps, BD Evolve™ on-body injectors, Neulasta® Onpro® on-body injectors commercially available from Amgen Inc., and Omnipod® injectors commercially available from Insulet Corporation), exemplary embodiments of the present disclosure provide a series of well-controlled, discrete infusions to achieve target PK.

[0082] Those skilled in the art will understand that the present disclosure is not limited 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. It will also be understood that the phraseology and terminology used herein are for descriptive purposes and should not be construed as limiting. As used herein, the words "including," "comprising," "having," and variations thereof are meant to encompass the items listed thereafter and equivalents thereof, as well as additional items. Unless otherwise limited, the terms "connected," "coupled," and "mounted," and variations thereof, as used herein, are used broadly to encompass both direct and indirect connections, couplings, and attachments. Furthermore, the terms "connected" and "coupled" and variations thereof are not limited to physical or mechanical connections or couplings. Furthermore, the terms "up," "down," "bottom," "top," and the like, are relative terms and are used to aid in description and not to be limiting.

[0083] Components of the example devices, systems, and methods used in accordance with the illustrated embodiments may be implemented at least in part in digital electronic circuitry, analog electronic circuitry, or computer hardware, firmware, software, or combinations thereof. These components may also be implemented as a computer program product, such as a computer program, program code, or computer instructions tangibly embodied in an information medium or machine-readable storage device, for execution by or used to control the operation of a data processing device, such as a programmable processor, a computer, or multiple computers.

[0084] Computer programs can be written in any type of programming language, including compiled and interpreted languages, and can be deployed in any form, such as a stand-alone program, a module, a component, a subroutine, or any other unit suitable for use in a computing environment. Computer programs can be deployed to run on a single computer, on multiple computers at a single site, or distributed across multiple sites interconnected by a communications network. Functional programs, codes, and code segments for implementing the exemplary embodiments can be readily interpreted by programmers skilled in the art to which the exemplary embodiments pertain as being within the scope of the claims illustrated by the exemplary embodiments. Method steps associated with the exemplary embodiments can be performed by one or more programmable processors executing computer programs, codes, or instructions to perform functions (e.g., operating on input data and / or generating output). Method steps can also be performed by, and apparatus of the exemplary embodiments can be implemented as, special purpose logic circuitry, such as, for example, a field programmable gate array (FPGA) or an application-specific integrated circuit (ASIC).

[0085] The various illustrative logic blocks, modules, and circuits described in connection with the embodiments disclosed herein may be implemented or performed by 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 may be a microprocessor, but alternatively, the processor may be any conventional processor, controller, microcontroller, or state machine. A processor may also be implemented as a combination of computing devices, such as a combination of a DSP and a microprocessor, multiple microprocessors, one or more microprocessors in combination with a DSP core, or other such configuration.

[0086] Processors suitable for executing computer programs include, by way of example, both general-purpose and special-purpose microprocessors, and one or more processors of any type of digital computer. Typically, a processor receives instructions and data from a read-only memory, a random-access memory, or both. The essential elements of a computer are a processor for executing instructions and one or more memory devices for storing instructions and data. Typically, a computer includes one or more mass storage devices, such as magnetic, magneto-optical, or optical disks, for storing data, or is operatively coupled to receive data from or transmit data to them, or both. Suitable information media for storing computer program instructions and data include all forms of non-volatile memory, including, by way of example, semiconductor memory devices, such as erasable programmable read-only memory (EPROM), electrically erasable programmable ROM (EEPROM), flash memory devices, and data storage disks (magnetic disks, internal hard disks, removable disks, magneto-optical disks, CD-ROMs, DVD-ROM disks, etc.). The processor and memory may be supplemented by, or incorporated within, dedicated logic circuitry.

[0087] Those skilled in the art will appreciate that information and signals may be represented using any of a variety of different technologies and techniques. For example, the data, instructions, commands, information, signals, bits, symbols, and chips that may be referenced throughout the above description may be represented by voltages, currents, electromagnetic waves, magnetic fields or particles, optical fields or particles, or any combination thereof.

[0088] Those skilled in the art will further appreciate that the various illustrative logic blocks, modules, circuits, and algorithm steps described in connection with the embodiments disclosed herein can be implemented as electronic hardware, computer software, or a combination of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, circuits, and steps have been described generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends on the particular application and design constraints imposed on the overall system. Skilled engineers may implement the described functionality in various ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the claims as exemplified by the illustrative embodiments. Software modules can be stored in random access memory (RAM), flash memory, ROM, EPROM, EEPROM, registers, hard disk, removable disk, CD-ROM, or any other form of storage medium known in the art. By way of example, the storage medium is connected to the processor such that the processor can read and write information from the storage medium. Alternatively, the storage medium may be integral to the processor. In other words, the processor and the storage medium may reside within an integrated circuit or may be implemented as discrete components.

[0089] Computer-readable non-transitory media include all types of computer-readable media, such as magnetic storage media, optical storage media, flash media, and solid-state storage media. It should be understood that the software can be sold installed on a central processing unit (CPU) device. Alternatively, the software can be loaded onto the CPU device, including obtained via physical media or a distribution system, for example, from a server owned by the software creator or from a server used but not owned by the software creator. The software can also be stored on a server for distribution, for example, via the Internet.

[0090] The above description and drawings are for illustrative purposes only and are not intended to limit the exemplary embodiments in any way, except as set forth in the claims. In particular, it should be noted that those skilled in the art may readily combine various technical aspects of the various elements of the various exemplary embodiments described above in a variety of other ways, all of which are considered to fall within the scope of the claims.

Claims

1. 1. A method of operating an infusion pump for delivering a medical therapy fluid to a patient, comprising: generating a plurality of fluid pulses to deliver fluid to a patient receiving drug therapy via the infusion pump; each of said pulses comprising a fixed amount of fluid pumped from a fluid chamber of the pump within a time period corresponding to a pulse duration; the number of pulses over a selected drug treatment time period and the duration of the interval between successive ones of said pulses are configured according to a pulsatile profile to achieve target pharmacokinetics or PK; The method includes:

2. the duration of the interval is longer than the pulse duration; The method of claim 1.

3. the duration of the interval is at least 10 times longer than the pulse duration; The method of claim 2.

4. the infusion pump is a rotary metering pump including a sleeve having an inlet port and an outlet port, and a piston translating into the sleeve to form a fluid chamber containing the fixed volume after drawing fluid into the fluid chamber through the inlet port from a reservoir by a suction stroke, the fixed volume in the fluid chamber being dispensed to a patient through the outlet port via a fluid delivery channel in fluid communication with the outlet port; The method of claim 1.

5. determining at least one of the number of pulses and the duration of intervals between successive ones of the pulses using the drug concentration of the fluid and the fixed amount of the fluid per pulse; The method of claim 1.

6. the pulsation profile includes a plurality of pulses and corresponding intervals between successive pulses of the plurality of pulses; The method of claim 1.

7. The duration of the interval is varied to achieve target pharmacokinetics or PK. The method of claim 6.

8. the corresponding interval between successive pulses of the plurality of pulses comprises a maximum first interval duration, and the pulsation profile comprises a pulse train comprising a plurality of pulses output at minimum intervals, the pulse train separated from a subsequent pulse between successive pulses of the plurality of pulses by a second interval duration greater than the maximum first interval duration. The method of claim 6.

9. The interval between the pulses of the pulsation profile to achieve a target PK is: A pulsation profile construction operation, using PK data measured for a single injection of said fluid; modeling the measured PK data to generate a predicted PK curve optimized to meet the target PK; generating PK traces for each of the predicted PK curves corresponding to different interval durations; selecting the intervals based on characteristics of the respective PK traces; a pulsation profile building operation, The method of claim 1 , wherein the value is determined by:

10. said modeling including using a simulation method selected from a product of convolution operations and a curve fitting operation; 10. The method of claim 9.

11. The simulation method using the convolution product 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 to the fixed amount of the pulse and the concentration of the fluid; superimposing the scaled single dose PK curve onto the pulsatile profile using convolution; performing linear interpolation on the measured PK data of one of a plurality of superimposed pulse PK curves within the pulsation profile to obtain the predicted PK curve; The method of claim 10, comprising:

12. 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 the time constant from the reference PK curve; generating the predicted PK curve using the time constants; The method of claim 10, comprising:

13. The modeling may comprise: fitting the predicted PK curve to the measured PK data; Varying pulse interval durations to generate the respective PK traces of the predicted PK curve; selecting an interval based on characteristics of each PK trace; 10. The method of claim 9, comprising:

14. one or more of the pulsation profile building operations are performed iteratively; 10. The method of claim 9.

15. one or more of the pulsation profile construction operations are performed iteratively to optimize the pulsation profile.

10. The method of claim 9.

16. The pulsatile profile construction operation further includes optimizing a residual between the modeled predicted PK and the measured PK data during the curve fitting operation. The method of claim 12.

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