A pharmacokinetic and tolerability evaluation of two continuous subcutaneous infusion systems compared to an oral controlled-release morphine

A pharmacokinetic and tolerability evaluation of two continuous subcutaneous infusion systems compared to an oral controlled-release morphine
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   © U.S. Cancer Pain Relief Committee, 20000885-3924/00/$–see front matterPublished by Elsevier, New York, New YorkPII S0885-3924(00)00130-5   Original Article   348Journal of Pain and Symptom ManagementVol. 19 No. 5 May 2000    A Pharmacokinetic and Tolerability Evaluation of Two Continuous Subcutaneous Infusion Systems Compared to an Oral Controlled-Release Morphine  Pia Mikkelsen Lynch, MD, Jackie Butler, PhD, Deanne Huerta, LVN,Izrail Tsals, PhD, Diana Davidson, BS, and Sharon Hamm, PharmD, RPh   Elan Pharmaceutical Research Corporation, Gainesville, Georgia, USA    Abstract   The pharmacokinetic profiles, safety, and tolerability of continuous subcutaneous infusion with a novel drug deliver system (the MEDIPAD system) was compared to a standard infusion pump (the CADD-Micro) and to controlled-release tablets (MS Contin) for the administration of morphine sulfate. This was a single-center, open-label, three-treatment study conducted in 24 male and female healthy volunteers. The mean age was 40.6 yr (SD      12.27). A three treatment design was chosen to compare differences between modes of administration within each subject to minimize the impact of intersubject variability: Treatment A was a continuous 48-hr subcutaneous infusion of morphine sulfate (165.6 mg at a rate of 3.45 mg/hr) with the MEDIPAD system attached to the chest, Treatment B was a series of four oral doses of morphine sulfate (120 mg each) at 12-hr intervals, and Treatment C was a continuous 48-hr subcutaneous infusion of morphine sulfate (163.2 mg at a rate of 3.40 mg/hr) with the CADD- Micro device attached to the chest. Subjects began treatment after eligibility was established and informed consent was obtained. The primary pharmacokinetic parameters (AUC, C    max   ) for the two devices were similar; 90% confidence intervals showed that the MEDIPAD system was bioequivalent to the CADD-Micro in terms of both rate and extent of morphine absorption. The mean morphine plasma concentration versus time plot suggested that plasma concentrations rise more rapidly with the MEDIPAD device than with the CADD-Micro or oral administrations. The MEDIPAD system showed mild application and injection site reactions; there were no site reactions for the CADD-Micro or oral doses. As expected nausea, somnolence, and abdominal  pain occurred more frequently in the oral treatment than the two infusion devices. These data suggest that the MEDIPAD system, which is currently undergoing clinical evaluation, is an acceptable alternative to the traditional oral treatment of morphine sulfate for delivery of analgesics as it allows rapid absorption of morphine; is small, easy to use, and disposable; and achieves plasma levels that are essentially equal to other standard infusion pumps.  J Pain Symptom Manage 2000:19:348–356.  © U.S. Cancer Pain Relief Committee, 2000.  Key Words   Morphine sulfate, continuous subcutaneous infusion, analgesia, pain   Address reprint requests to: Pia Mikkelsen Lynch, MD, Elan Pharmaceutical Research Corporation, 1300 Gould Drive,Gainesville, GA 30504, USA.  Accepted for publication: June 28, 1999.   Vol. 19 No. 5 May 2000Continuous Subcutaneous Infusion Systems349   Introduction   The use of opioid analgesics has been widely accepted in the treatment of pain associated with advanced cancer.   1   Although the oralroute of administration is preferred for thesemedications, it is ineffective or impractical forpatients who require very high doses or whohave difficulties with swallowing, nausea, vom-iting, or bowel obstruction.   1,2  For these pa-tients who are intolerant or unresponsive tooral administration, the use of controlled infu-sion pumps   3  and transdermal fentanyl patches   4  for delivery of analgesics has become an ac-cepted therapeutic intervention for cancerpain. Many studies have reported successfuluse of continuous subcutaneous opioids in pa-tients with cancer.   5–10  Continuous parenteralinfusion devices eliminate peak-level sedationand trough-level breakthrough pain associated with intermittent dosing regimens.   10  These de- vices can be administered in an outpatient set-ting, eliminating the need for inpatient visitsand intravenous access.   10,11  Conventional por-table infusion pumps, such as the CADD-Micropump, that deliver medication subcutaneously or intravenously are expensive and compli-cated. Although these pumps provide stableblood levels of the infused drug, the pumps areperceived to negatively affect the quality of lifebecause of their bulk and inconvenience dueto the separate intravenous or subcutaneousaccess device and tubing required.   1  Transder-mal fentanyl patches, though widely used,   4  have a delayed onset of delivery and a long de-pot effect.The present study focused on a novel drugdelivery system currently undergoing clinicalevaluation that avoids many of these problems.The MEDIPAD Drug Delivery System (MEDI-PAD) is a small-volume, adhesive-backed infu-sion device which can be inconspicuously wornon the body for up to 48 hours (Figure 1). Thesystem includes a short, fine-gauge needle andan integral pumping mechanism that continu-ously infuses drug subcutaneously. Approxi-mate MEDIPAD dimensions are 85 mm   62mm   20.5 mm. An empty system without thesyringe fill adapter weighs less than 50 grams.The MEDIPAD uses controlled gas generationas the delivery mechanism. Drug is placed intothe small reservoir in the MEDIPAD, which isbounded by an elastomeric membrane and ahard plastic housing. Gas generation is accom-plished via an electrochemical process. The gasgenerator includes an electrolytic cell and sim-ple circuitry. When the “Start” area is pressed(Figure 1), the top housing of the MEDIPADmoves downward, closing the circuit in the gasgenerator and starting current flow. Whenused as directed, the needle should not be visi-ble to the user throughout application and re-moval, thus minimizing needle phobia. Priorto application, the needle is retracted into thetop housing and is not visible to the user. At the end of the prescribed application time,MEDIPAD delivery is stopped by lifting the tophousing away from the skin. This motioncauses the needle to be retracted back into thetop housing of the system. The needle remainslocked within the MEDIPAD as the system is re-moved and discarded. A potential application for the MEDIPADsystem is for morphine sulfate administrationin the management of moderate to severe can-cer pain. In addition, the MEDIPAD systemmay have utility as an alternative to oral mor-phine sulfate, particularly in patients who donot tolerate oral administration well. The sub-cutaneous route using the MEDIPAD system al-lows for relatively rapid absorption of mor- Fig. 1.MEDIPAD drug delivery system.   350Lynch et al.Vol. 19 No. 5 May 2000   phine and achieves stable plasma levels that are essentially equal to other standard infusionpumps. This means of administering opioidsalso minimizes nausea, vomiting, and gas-trointestinal tract disorders often experiencedafter oral administration by allowing drug tobypass the stomach.   10  The purpose of the study was to establish thepharmacokinetic profile and tolerability of theMEDIPAD system. Safety was also evaluated.The system was applied to the chest and acti- vated to continuously deliver a fixed dose of morphine sulfate over a 48-hour period. TheMEDIPAD system was compared to the CADD-Micro pump (an established infusion pump)and to MS Contin Controlled-Release Tablets(oral morphine sulfate). The coadministra-tion of naltrexone hydrochloride, an opioidantagonist, was to minimize the potential ad- verse effects of high-dose morphine.  Methods   The study was approved by the InstitutionalReview Board. Eligible subjects were evaluatedfor study participation. Subjects were healthy male or female volunteers between the ages of 19 and 60 who were free from any clinically sig-nificant abnormality in medical history, physi-cal examination, and laboratory evaluations.Subjects were excluded if they had participatedin an opioid analgesic trial within the previous12 months; had received any prescription med-ication within 2 weeks prior to entry into study;had received known enzyme-altering drugs within 30 days; had consumed alcohol within48 hours; had given blood donations of 560mL or more within 30 days; had given plasmadonations within 7 days; had a history of drugor alcohol abuse; had a hypersensitivity to mor-phine; had skin allergies; had a history of glau-coma or other ophthalmological disease; orhad a history of excessive nausea, vomiting, orlight-headedness. Also excluded were subjects who deviated in excess of 10% below or 20%above ideal body weight; had clinical or bio-chemical evidence of impairment of liver func-tion; were lactating or pregnant females; had ahistory of clinically significant gastrointestinaltract, renal, hepatic, endocrine, oncology, pul-monary, or cardiovascular disease; had a his-tory of tuberculosis, epilepsy, diabetes, psycho-sis, glaucoma, or any other condition that  would jeopardize the safety of the subject; hadan abnormal diet within 30 days prior to study initiation; or had tattoos, surgical scars, or askin condition that interfered with the needleplacement or site assessments. Subjects wereasked to refrain from vigorous physical exer-cise from 7 days prior to the start of the study period until the end of the study. No smoking was permitted for the duration of residence inthe clinic.Subjects entered the study after eligibility  was established and informed consent was ob-tained. This was an open-label, three treat-ment, single-center study in which healthy sub- jects received morphine sulfate via a MEDIPADsystem infusion (Treatment A), a series of oraldoses (Treatment B), and a CADD-Micro infu-sion (Treatment C). Naltrexone hydrochlo-ride, an opioid antagonist, was coadministeredto minimize the potential adverse effects of high-dose morphine. All subjects received thesame study drugs and doses in the same order,using the same type of infusion devices andoral administration regimens. During the first period of confinement, each subject receivedTreatment A, a 48-hour continuous subcutane-ous infusion of 165.6 mg morphine sulfate at aconcentration of 50 mg/mL with the MEDI-PAD system. During the second period of con-finement, each subject received Treatment B, aseries of four oral doses of 120 mg MS ContinControlled-Release Tablets at 0 hours, 12hours, 24 hours, and 36 hours. During thethird period of confinement, each subject re-ceived Treatment C, a 48-hour continuous sub-cutaneous infusion of 163.2 mg morphine sul-fate at a concentration of 50 mg/mL with theCADD-Micro pump.The MEDIPAD systems were to be applied tothe anterior chest wall (pectoral area). On Day     1 of Period A, the chest was assessed for any preexisting irritation or problems. If necessary,excessive hair was clipped (not shaved) and washed with soap and water (no alcohol). OnDay 1 prior to application, the chest site wascleaned with warm water, dried with a nonfibercloth, and photographed. Subjects were supine while the MEDIPAD system was applied to thechest and remained semirecumbent for 1 hourafter application. No Opsite or other adhesivedressing was to be applied unless the device was not adhering properly. Dosing for each   Vol. 19 No. 5 May 2000Continuous Subcutaneous Infusion Systems351  study period was separated by at least a 7-day  washout period.Pharmacokinetic criteria included AUC   0-t   , AUC   0-inf   , elimination half-life, C   max  , T   max  , elimi-nation rate constant, and relative bioavailabil-ity of the test product compared to the refer-ence product. Venous blood samples (7 mL) were drawn by indwelling cannula or by direct  venipuncture of the antecubital veins. Thesamples were collected into lithium heparin va-cutainers and centrifuges at 3000 rpm for 15minutes at 2    C within 1 hour of sample collec-tion. The separated plasma was pipetted intopolypropylene tubes and stored at   20    C untilassayed. Pharmacokinetic samples were drawnon Days 1–3 during each treatment period; 18samples were collected during Treatments A and C, and 30 samples were collected duringTreatment B. For Treatments A and C samples were drawn on Day 1 at 0 hr (predose), 20 min,40 min, and 1, 2, 3, 6, 9, 12, and 18 hours; onDay 2 at 0, 6, 12, and 18 hours; and on Day 3 at 0, 3, 6, and 12 hours. For Treatment B, samples were drawn on Day 1 at 0 hr (predose), 30 min,and 1, 2, 3, 4, 6, 8, 12, 13, 14, 16, 18, and 20hours; on Day 2 at 0, 1, 2, 4, 6, 8, 12, 13, 14, 16,18, and 20 hours; and on Day 3 at 0, 3, 6, and12 hours.Tolerance for the MEDIPAD and CADD-Micro systems was assessed by means of appli-cation site assessments by the nurse and subject comfort evaluations during Treatment A andC. During Treatment A, the nurse assessed thesite for adhesion (rated as yes/no) and forerythema and edema reactions at the of timeapplication using a rating scale from 0 to 3 (Ta-ble 1) at 5 min, and 1, 12, 24, 36, and 48 hoursafter application; immediately upon removal;and at 5 min, and 1, 3, and 48 hours after re-moval. The nurse also assessed the site at theneedle site, within the MEDIPAD area, and be- yond the MEDIPAD area after removal for thepresence of erythema, edema, induration,pressure marks, puncture marks, and poolingfrom the injection site. These assessments wereconducted immediately upon removal of theMEDIPAD system and at 5 min, 1 hour, 3hours, and 48 hours after removal. DuringTreatment D, the CADD-Micro pump was as-sessed by the nurse 48 hours after removal of the device and at no other timepoint duringthe study for puncture marks, pressure marks,erythema, edema, induration, and poolingfrom the infusion site at the needle site, withinthe adhesion site, and beyond, the adhesionsite. The application site was also photo-graphed at these times. The subjects assessedthe comfort of the MEDIPAD system during in-fusion and after removal using a visual analogscale (VAS) with 0   extremely comfortableand 10   unbearable. Subjects assessed com-fort upon application, upon activation, and at 5 min and 1, 12, 24, 36, and 48 hours after theMEDIPAD system was applied. At the end of the infusion, subjects assessed comfort upondeactivation, upon removal, and at 5 min, 1hour, 3 hours, and post-study (48 hours afterdeactivation). Subjects wearing the CADD-Micro did not assess comfort.Safety was assessed by vital sign evaluations,12-lead ECGs, clinical laboratory tests, physicalexaminations (including site tolerance evalua-tions), and reports of adverse events. Bloodpressure was measured manually using a mer-cury sphygmomanometer with the subject sit-ting for at least 2 minutes prior to the reading.Pulse oximetry was measured using a Data-scope Passport machine (MediSource, Covina,CA) with the subject sitting for at least 2 min-utes prior to the reading. ECG recordings wereassessed for each treatment using a Hewlett Packard 4760A or equivalent. A crash cart andoxygen unit were immediately available at theclinic during the study. All data were analyzed using Statistical Analy-sis Systems (SAS Institute Inc., Cary, NC). Anal- ysis of variance (ANOVA) was performed onrelevant untransformed and log-transformed  Table 1  Nurse Assessment of MEDIPAD Application Site: Codes For Rating Erythema and Edema   SymptomCodeDescriptionErythema0No visible redness1Slight but well-defined redness2Moderate intense redness3Severe erythema (dark red discoloration of the skin)Edema0No visible reaction1Mild edema (corners of the area are  well-defined due to noticeable swelling)2Moderate edema (up to 1 mm swelling in diameter)3Severe edema (more than 1 mm swelling in diameter, protruding over the patch edges)   352Lynch et al.Vol. 19 No. 5 May 2000   pharmacokinetic data. The two one-sided hy-pothesis at the      0.05 significance level wastested for relevant untransformed and log-transformed pharmacokinetic parameters by constructing the 90% confidence interval forthe difference between the test and referenceaverages in untransformed parameters and theratio of the test and reference averages in log-transformed pharmacokinetic parameters. De-scriptive statistics (i.e., means, standard devia-tions) were calculated for pharmacokineticand demographic data.  Results   Twenty-five subjects were enrolled, and 24subjects (12 male and 12 female) completed thestudy. One female subject experienced nauseafollowing the first dose of naltrexone and dis-continued prior to receiving the first dose of morphine sulfate. The mean age was 40.6 years(SD      12.27). The weight of each subject was within 10% above or 20% below the ideal weight for the height and body frame size according tothe Metropolitan Life Height and Weight Tables.One subject was a current smoker (15 cigarettes/day). Previous medical history of the majority of subjects was unremarkable.The results of this study show that delivery of morphine via subcutaneous infusion reducesthe intersubject variability (%CV of pharmaco-kinetic parameters) compared to the MS Con-tin Controlled-Release oral administration,confirming the recommended dose-adjustedratio of 3:1 when converting oral administra-tion to subcutaneous administration. Not sur-prisingly, the only parameter that showedcomparable variability between the infusiontreatments and the oral administration was T   max  .The dose-adjusted F ratios for either infu-sion system versus oral administration confirmthe 1:3 dosing ratio reported in the literature when switching from subcutaneous infusion tooral delivery of morphine. The mean primary pharmacokinetic parameters (AUC, C   max  ) forthe two different infusion devices were very similar in this group of 24 volunteers. 90% con-fidence intervals showed that the MEDIPADsystem was bioequivalent to the CADD-Microin terms of both rate and extent of morphineabsorption. Peak plasma concentrations weresimilar (44.24   10.92   g/mL for MEDIPADand 44.50   11.74   g/mL for CADD-Micro).The dose-adjusted F ratio for the MEDIPADsystem compared to CADD-Micro was 1.08   0.21 for both AUC   (0-60)  and AUC   (0-inf)  .The mean morphine plasma concentration versus time plot (Figures 2 and 3) suggests that plasma concentrations rise more rapidly withthe MEDIPAD system than with the CADD-Micro or oral administrations. This was con-firmed by visual inspection of the individualplots. Twenty minutes following the applica-tion of the MEDIPAD system, only one sample was below the limit of quantitation comparedto 19 of 24 following application of the CADD-Micro pumps. These data support previous ob-servations that the time required to achieveplateau levels with the MEDIPAD may be lessthan expected. After removal of the devices at 48 hours, plasma morphine concentrations fellat a similar rate for both infusion treatments. Adverse events were recorded during the 48-hour treatment periods and during the 7-day  washout periods and were graded on a 3-point scale defined as mild (easily tolerated with nointerference in daily activity), moderate (causedsome interference with daily activity), or severe(all normal daily activities were completely halted). The most common adverse events were mild application site reaction (pressuremarks from the MEDIPAD) and mild injectionsite reactions from the MEDIPAD, which oc-curred in all 24 subjects during the MEDIPADperiod. During the MEDIPAD period, 8 sub- jects also experienced mild discomfort or sting-ing at the needle site, and 13 subjects ex-perienced mild pruritus. There were no sitereactions noted for the CADD-Micro pump;however, the protocol called for site reactionsassessments only at 48 hours after removal, at  which time most of the site reactions that could have been present for the CADD-Microearlier may have subsided, as was the case withthe MEDIPAD device.The most common adverse events for theoral treatment were mild or moderate nausea,mild somnolence, and mild abdominal pain.These adverse events occurred more fre-quently during the oral treatment than duringthe CADD-Micro and MEDIPAD infusion.Nurse and subject assessments during infu-sion and after the removal of the MEDIPADsystem and the CADD-Micro pump showedthat both devices were well tolerated. Only mi-
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