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Evaluation of Two Loading-Dose Regimens of MorphelanT in Healthy Volunteers*
Lise Eliot, PhDa
Allen Cato III, PhDb
Rita Geiser, RNa
Gordon Loewen, PhDa
aClinical Research, Ligand Pharmaceuticals Inc.
bCato Research Ltd.
*This study was supported financially by Ligand Pharmaceuticals Inc.
10275 Science Center Drive
San Diego, CA 92121
KEY WORDS: morphine, extended-release, pharmacokinetics, pain, loading dose, once-daily
Background: MorphelanT is a once-daily extended-release morphine formulation. A loading dose that quickly provides plasma morphine concentrations similar to those at steady state would optimize therapy during the initial days of treatment. The objective of this study was to assess two loading dose regimens of Morphelan.
Methods: In this open-label, multiple-dose study, 36 healthy men were assigned to one of three treatment groups. On Day 1, Group A received a single 60-mg Morphelan dose, Group B received two 60-mg Morphelan doses 12 hours apart, and Group C received a single 120-mg Morphelan dose. All groups received 60 mg of Morphelan once daily on Days 2 to 7. Pharmacokinetic and safety data were evaluated.
Results: Mean Cmax and area under the concentration-time curve (AUC) values on Day 2 were significantly less than values on Day 7 for subjects in Group A and statistically significantly higher for subjects in Group B. In contrast, mean Cmax and AUC values on Day 2 for subjects in Group C were comparable with values on Day 7, indicating that steady state was reached by Day 2. Peak-to-trough fluctuation on Day 2 was more similar to Day 7 for Group C than for Groups A or B. Adverse events were typical of opioid administration, but the incidence of nausea, primarily on Day 2 or later, was greater for Groups B and C than for Group A.
Conclusions: An initial loading dose of twice the intended subsequent daily Morphelan dose provides the optimal PK results, reaching steady-state concentrations within the first 2 days of therapy.
Morphine continues to be the drug of choice for the treatment of severe cancer pain, a degree of pain generally regarded as step three of the analgesic ladder developed by the World Health Organization.1 Conventional morphine formulations are safe and effective but usually must be administered every 3 to 4 hours. Several extended-release formulations of morphine have been developed, typically allowing dosage regimens of every 8 to 24 hours. Morphelan is an extended-release morphine formulation designed for once-daily dosing. This formulation contains both an immediate-release component and an extended-release component. Thus, Morphelan provides an initial rapid release of morphine followed by an extended release of the drug. Previous steady-state pharmacokinetic (PK) studies have demonstrated that once-daily administration of Morphelan rapidly provides target morphine concentrations and maintains these concentrations throughout a 24-hour period.2,3
Despite providing both an immediate and extended release of morphine to enable the advantage of once-daily dosing, Morphelan, like many long-acting formulations, requires multiple days of dosing to reach steady-state.3 Patient therapy would be optimized if a loading-dose regimen could be identified that provided plasma morphine concentrations similar to steady-state concentrations within the first 2 days of therapy. A loading-dose regimen could potentially reduce the number of rescue doses required during initiation of therapy and decrease the time needed to reach stable pain control. The purpose of this study was to assess the PK of morphine following administration of two loading-dose regimens of Morphelan in opioid-naive subjects. The goal was to attain steady-state morphine concentrations on the second day of dosing or sooner. In addition, safety data were collected and evaluated.
This was an open-label, single-center, multiple-dose, parallel-design study. The study was approved by a local IRB and conducted under the principles of the Helsinki declaration. All subjects signed an informed consent prior to dosing. Subjects were confined at the clinical site from Day -1 (10 hours before dosing on Day 1) to Day 8 (36 hours after the dose on Day 7). Subjects were assigned randomly to one of three dosing cohorts, each containing 12 subjects. Subjects assigned to Group A received a single Morphelan capsule (60 mg) once daily at 8 am for 7 consecutive days (no loading dose). Subjects assigned to Group B received a twice-daily loading dose regimen on Day 1 of one 60-mg Morphelan capsule administered at 8 am and 8 pm, followed by one 60-mg Morphelan capsule administered daily at 8 am for 6 consecutive days. Subjects assigned to Group C received a double-dose loading-dose regimen on Day 1 of two 60-mg Morphelan capsules (120 mg) administered at 8 am, followed by one 60-mg Morphelan capsule administered daily at 8 am for 6 consecutive days.
Subjects were not allowed to participate in any vigorous physical exercise for 7 days before the start of the study and until completion of the poststudy assessment. Subjects were also not allowed to consume alcohol for 48 hours before dosing and until 48 hours after discharge from the clinic. In addition, subjects fasted from 10 hours before the morning dose until 4 hours after the morning dose on Days 1, 2, and 7. Subjects were then served a standardized lunch after the 4-hour blood collection, an afternoon snack after the 6-hour blood collection, an evening meal after the 10-hour blood sample collection, and an evening snack after the 14-hour blood sample collection. On Day 1, subjects were to eat the evening meal within 30 minutes and then fast until completion of the 14-hour blood sample collection. All subjects received the same standardized daily diet on Days 3 to 6.
Subjects were instructed to swallow the study medication with 240 mL of water within 5 minutes while standing. A mouth check was performed to ensure ingestion of each dose. To minimize the effects of posture on absorption, subjects were instructed to avoid lying down for a minimum of 4 hours after each dose of study medication on Days 1, 2, and 7. Water was not allowed until 1 hour after dosing, at which time it may have been ingested ad libitum.
Throughout the study, safety data were collected and extensive blood sampling was conducted. Acetaminophen (maximum of 2 grams in 24 hours) was the only concomitant medication permitted for use by subjects in this study. Naloxone (Narcan®, Endo Laboratories Inc.) was available in case of an emergency. For each subject, 7-mL venous blood samples were collected into labeled lithium heparin blood collection tubes via an indwelling cannula or by venipuncture. The collection schedule was the same for each study treatment group. Sample collection times on Day 1 were pre-dose (5 to 15 minutes before the morning dose) and then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 12.5, 13, 14, 16, 18, and 20 hours after the morning dose. On Days 2 and 7, samples were collected pre-dose (5 to 15 minutes before the dose) and then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 and 20 hours post-dose. Samples were also collected 24 and 36 hours after the final dose on Day 7. Pre-dose (trough) samples were collected on Days 3 through 6. Blood samples were stored under refrigeration at 4°C and centrifuged at 4°C for 15 minutes within 1 hour after sample collection. Plasma was removed and placed in labeled polypropylene tubes and then stored at 220°C or lower until being assayed for morphine.
Morphine was isolated from human plasma by solid-phase extraction. The sample extracts were reconstituted in dilute acid and analyzed by a validated liquid chromatography-mass spectrometry (LC/MS/MS) assay. A calibration curve was constructed using peak area ratios of the calibration samples by applying a l/concentration2 weighted linear regression analysis. All concentrations were then calculated from their peak area ratios against the calibration line. This method was validated with a quantification range of 0.500 to 500 ng/mL for morphine. A prestudy validation was conducted to verify system performance, calibration standard, and quality control pool preparation before analysis of study samples. The average correlation coefficient for the analytical batches was 0.9973. The average back-calculated calibration standards had coefficients of variation for the 13 analytical batches that ranged from 3.33% to 8.17%, with percent differences from theoretical ranging from 27.00% to 4.78%. The inter-assay coefficients of variation of the quality controls for the analytical batches ranged from 4.12% to 5.85%, with percentage differences from theoretical ranging from 25.74% to 1.31%.
A noncompartmental analysis was performed to determine PK parameters for morphine after dosing with Morphelan on Days 1, 2, and 7 as appropriate. Maximum (Cmax) and minimum (Cmin) plasma concentration were recorded as the observed values during the 24-hour dosing interval. Area under the concentration-time curve (AUC) for each day (0 to 24 hours after the morning dose on each day) was calculated by the trapezoidal rule utilizing WinNonlin, Version 3.1 (Pharsight Corporation, Mountain View, CA, U.S.A.). Peak-to-trough fluctuation index (FI) was calculated as,FI 5 Cmax 2 Cmin. Both Cmin and FI were calculated only for Days 2 and 7.
To confirm that steady-state morphine concentrations had been reached by Day 7 of Morphelan dosing, a t-test was performed to compare the mean slopes of the regressions of the trough (Days 5, 6, and 7 pre-dose samples) plasma morphine concentrations with zero. Upon confirming that steady state was reached, an analysis of variance (ANOVA) was performed to determine any significant differences in the relevant PK parameters between Days 1 and 7 and Days 2 and 7. Within the ANOVA framework, point estimates for the ratio of parameter values on Days 1 or 2 to those on Day 7 were calculated, and 90% confidence intervals were constructed. Results of statistical comparisons of the parameter values are reported, and statistical significance was concluded at a probability (P) # .05.
Thirty-six healthy, nonsmoking, male volunteers were enrolled. The 36 subjects were 19 to 45 years (mean 30.8 years) of age and weighed 70.4 to 99.0 kg (mean 81.6 kg). Of these 36 subjects, 29 successfully completed the study with evaluable data. Twelve subjects were randomly enrolled into each of the three groups with evaluable data provided by subjects in Group A (n511), Group B (n511), and Group C (n57). The PK data from seven subjects were not evaluable due to vomiting within 4 hours following ingestion of study drug (n55), incomplete administration of study drug (n51), or lack of quantifiable morphine in plasma samples (n51).
Subjects had no history of drug or alcohol abuse and tested negative for human immunodeficiency virus infection, hepatitis B surface antigen, hepatitis C virus antibodies and urine screens for drugs of abuse (opioids, cannabinoids, cocaine, benzodiazepines, and alcohol). Subjects were judged to be in good health based upon the results of a medical history, physical examination, clinical laboratory evaluations, and an electrocardiogram. All subjects voluntarily agreed to participate by signing an informed consent form.
For all three groups, the slopes of the curves of morphine concentrations obtained from the trough blood samples (pre-dose samples collected on Days 5, 6, and 7), as a function of time, were not statistically significantly different from zero (P > .290). These results confirm that the final PK assessment days (Day 7) for the groups were representative of steady-state conditions.
Figure 1 illustrates the concentration-time profiles of morphine following administration of the three dosing regimens throughout the entire duration of the study. Comparisons of the mean concentration-time profiles for each group on Days 1 and 2 to Day 7 are displayed in Figures 2 through 4. Those subjects that did not receive a loading dose regimen on Day 1 (Group A), clearly had not reached exposures similar to steady-state concentrations within the first 2 days of dosing. In contrast, by the second day of dosing, both groups receiving a loading-dose regimen had achieved concentrations at least as high as the concentrations observed at steady state (Day 7). The mean Day 2 plasma morphine concentration-time profile was virtually superimposeable on the respective Day 7 profile for subjects receiving the double-dose loading-dose regimen on Day 1 (Group C). In addition, within 1 hour post-dose on Day 1, subjects in Group C reached mean concentrations similar to those at steady state (Day 7) at the same time post-dose (10.78 and 11.01 ng/mL, respectively). In contrast, the group that received the twice-daily loading-dose regimen administered 12 hours apart on Day 1 (Group B) generally had substantially lower mean concentrations on Day 1 but higher mean concentrations on Day 2 compared with those at steady state.
Mean PK parameters (Table 1) reflect the differences or similarities observed in the concentration-time profiles within groups for Days 1 and 2 compared with those on Day 7. Statistical comparisons of PK parameters across days are displayed in Tables 2 and 3. Mean Day 1 Cmax and AUC values were significantly lower than respective steady-state (Day 7) values for all groups (P < .008) with the exception of Cmax for Group C (P = .6362). The 90% confidence intervals of the ratio of Day 1 to Day 7 parameter values encompassed unity for Group C Cmax values (90% confidence intervals = 0.65 - 1.21) but were less than unity for the remaining parameters. These data indicate that Group C Cmax values were similar to steady-state values but that Group C AUC and Groups A and B Cmax and AUC values on Day 1 were less than respective Day 7 values (Table 2).
Group A demonstrated significantly lower Cmax and AUC mean values on Day 2 than respective Day 7 mean values (P < .0345, Table 3). In contrast, mean AUC and Cmax values on Day 2 were significantly higher than Day 7 values for those subjects receiving the twice-daily loading dose regimen (Group B, P < .0380). There were no significant differences in Cmax and AUC mean values on Day 2 compared with respective values on Day 7 for those subjects receiving the double-dose loading-dose regimen (Group C, P > .2822). The 90% confidence intervals of the ratio of Day 2 to Day 7 parameter values for Group C Cmax and AUC encompassed unity. In contrast, 90% confidence intervals for the ratio of Day 2 to Day 7 parameters for Groups A and B Cmax and AUC excluded unity.
Mean Cmin values on Day 2 were significantly lower than values on Day 7 for Group A (P 5 .0068) but not for Groups B or C (P > .3117). The 90% confidence intervals of the ratio of Day 2 to Day 7 Cmin values encompassed unity for both Group B and C. In addition, Day 2 mean peak-to-trough fluctuation, as measured by FI, was similar to the value on Day 7 for Group C (P 5 .3289) but was substantially higher than Day 7 values for Groups A and B (P 5 .0573 and .0758, respectively).
Adverse events (AEs) experienced by all three groups were mild to moderate in severity. AEs observed were those commonly experienced with opioid administration, the most common being nausea, constipation, dizziness, and headache. Table 4 details all observed AEs that occurred with a frequency of greater than 10%. Generally, the incidences of AEs were similar among the three dosing regimens. Nausea appeared to have had a greater incidence for subjects in Groups B (7/12) and C (8/12) compared with subjects in Group A (2/12). The most frequent time these subjects experienced nausea was around the time of the dose on Day 2. For Groups A, B, and C, 1/2, 6/7, and 7/8, respectively, experienced nausea on Day 2. No serious AEs or deaths occurred. Naloxone, an opioid antagonist, was not required during the study.
Immediate-release and sustained-release opioid formulations may be used to treat chronic, moderate-to-severe pain. Due to the relatively short half-life of morphine of approximately 2 hours,4 chronic dosing of immediate-release morphine formulations would be expected to achieve steady state by the end of the first day. In contrast, once-daily dosing of sustained-release formulations may require multiple days of chronic dosing to achieve steady state because of the prolonged effective half-life due to continued and prolonged release of morphine available for absorption. The sustained-release characteristics of these sustained-release formulations govern the length of time required to reach steady-state concentrations rather than the rate of elimination of the absorbed drug. Administration of a loading dose on the first day of therapy could reduce the time required to reach steady state.
Administered every 24 hours, Morphelan provides both an immediate release of morphine and a sustained release of morphine throughout the day with a low fluctuation in morphine plasma concentrations. However, once-daily dosing of Morphelan with no loading dose generally requires multiple days before reaching steady state.3 This PK study was conducted to determine the optimal loading-dose regimen of Morphelan in opioid-naive subjects that would rapidly and safely achieve concentrations of morphine similar to those observed at steady state.
As indicated by statistical analysis of the pre-dose trough concentrations on Days 5, 6, and 7, all three study groups reached steady state by Day 7. Therefore, comparisons of the PK parameters on Days 1 and 2 to those on Day 7 were appropriate to determine how rapidly the loading-dose regimens achieved morphine concentrations similar to those at steady state.
Subjects who did not receive a loading-dose regimen (Group A) had substantially lower concentrations of morphine on Days 1 and 2 compared with their concentrations at steady state. On average, subjects in Group A achieved only 45% and 78% of the Cmax and 36% and 69% of the AUC by Days 1 and 2, respectively, compared with steady-state values (Day 7). Thus, these subjects required more than 2 days of Morphelan administration before reaching steady-state concentrations of morphine. Although determination of the actual day that subjects in Group A reached steady state was not an objective of this study, having reached steady state by at least Day 5 is comparable to previous findings.3
In contrast, subjects receiving the twice-daily loading-dose regimen (Group B) had statistically significantly lower Cmax and AUC values on Day 1 and higher values on Day 2 compared with steady-state values on Day 7. In addition, a strong trend toward a significantly higher peak-to-trough fluctuation on Day 2 indicates that these subjects had not reached steady-state conditions by Day 2.
The subject group that received the double-dose loading-dose regimen of two 60-mg Morphelan capsules at once (Group C) was the only group receiving a loading-dose regimen that achieved steady-state concentrations within the first 2 days of dosing. Mean Cmax, AUC, and FI values for Day 2 were comparable to Day 7 values. In addition, mean morphine concentrations on Day 1 exceeded 10 ng/mL at 1 hour and 1.5 hours after administration. The rapid achievement of mean plasma morphine concentrations suggests that this dosage regimen provides the benefits of morphine therapy almost immediately after dosing on the first day of therapy, with steady state achieved on Day 2.
Subjects in both Groups B and C tended to have a greater incidence of nausea compared with subjects receiving no loading dose. However, nausea is a typical AE associated with the initiation of opioid therapy.5 Interestingly, the rapid increase of plasma morphine concentrations following administration of the double-dose loading-dose regimen was not associated with an increase in nausea on Day 1. Rather, nausea was most frequently observed on Day 2. Nausea was generally transient and resolved in most subjects before Day 7 of the study. No substantial differences in other reported AEs or safety data were observed between the three dose treatments. No serious AEs or deaths were reported, and naloxone was not needed. This study was conducted in healthy males with a relatively high average body weight of 81.6 kg. The safety profile observed in this study may not be consistent with that of patients with a lower body weight.
In comparison to the twice-daily loading-dose regimen (Group B), the double-dose loading-dose regimen (Group C) provided plasma morphine concentrations similar to steady-state levels more quickly and with less peak-to-trough fluctuation with a comparable AE profile. Plasma morphine concentrations for those subjects receiving the double-dose loading-dose of Morphelan reached concentrations comparable to concentrations observed at steady state (10 ng/mL) within the first few hours of administration on Day 1 and achieved Cmax values on Day 1 that were comparable to steady-state Cmax values. In contrast, those subjects receiving the twice-daily loading-dose regimen (Group B) did not reach plasma morphine concentrations of 10 ng/mL or Cmax values comparable to steady-state values on Day 1 and exceeded steady-state concentrations on Day 2. In addition, the mean AUC value on Day 2 was closer to steady-state values for Group C than for Group B and the fluctuation index on Day 2 for Group C was closer to the steady-state value than for Group B.
The results observed in this study are expected to be reproducible with initiation of Morphelan therapy at any intended daily dose. For example, if the intended daily therapeutic dose is 30 mg, a loading dose of two 30-mg capsules (60 mg total) on Day 1 is expected to provide steady-state concentrations by Day 2 of therapy. In addition, PK theory suggests that loading doses may be used to reduce the time required to achieve steady state when increasing daily Morphelan dosages during therapy. Although not evaluated during this study, a loading dose representing the original dose plus twice the intended increase in the daily dose on the first day of dose escalation followed by a once-daily dose at the new dose level would be expected to behave in a similar PK manner as the loading-dose paradigm evaluated in this study. Further clinical evaluation of loading doses for Morphelan dose escalations is warranted.
The results of this study demonstrate that a loading-dose regimen of Morphelan administered on the first day of therapy as an initial double dose quickly and safely achieved morphine concentrations similar to those at steady state by the second day of dosing. In contrast, a loading-dose regimen administered twice daily 12 hours apart on Day 1 exceeded steady-state concentrations on Day 2 and produced a larger extent of peak-to-trough fluctuation than the double-dose loading-dose regimen. A loading-dose regimen of Morphelan administered as an initial double dose provided the optimal PK results and could be of value in a clinical setting.
The authors thank Amanda Cross for assistance with the statistical analysis and Melissa Holmes for assistance with the illustrations and preliminary organization of the manuscript.
1. ‑Cherny N: New strategies in opioid therapy for cancer pain. J Oncol Manage January/February: 8-15, 2000.
2. ‑Eliot L, Loewen G, Butler J, et al: Steady-state pharmacokinetic comparison of MorphelanT ROERT (Morphine Sulfate Rapid Onset Extended Release) once-a-day and morphine oral solution administered q4h around-the-clock in healthy volunteers. American Academy of Pain Medicine (AAPM) 17th Annual Meeting, Miami, FL. February 15-18, 2001. Abstract No. 205.
3. ‑Portenoy RK, Eliot L, Loewen G, et al: Steady-state pharmacokinetic comparison of a new once-a-day dual-release oral morphine sulfate formulation and a twice-a-day controlled-release oral morphine formulation in patients with moderate-to-severe chronic pain. American Pain Society (APS) 20th Annual Meeting, Phoenix, AZ. April 19-22, 2001. Abstract No. 805.
4. ‑Reisine T, Pasternak G: Opioid analgesics and antagonists, in Hardman JG, Limbird LE (eds): Goodman & Gilman's The Pharmalogical Basis of Therapeutics, ed 9. New York, McGraw-Hill, 1996, pp 521-555.
5. ‑Cherny NI, Foley KM: Nonopioid and opioid analgesic pharmacotherapy of cancer pain. Hematol/Oncol Clin North Am 10:79-102, 1996.
Table 1. Mean ± SD Pharmacokinetic Parameters of Morphine After Once-Daily Administration of Morphelan for Groups A (no loading dose), B (twice-daily loading dose regimen), and C (double-dose loading dose regimen)
AUC = area under the concentration-time curve; Cmax = maximum observed plasma concentration; Cmin = minimum observed plasma concentration; FI = peak-to-trough fluctuation index calculated as (Cmax ‑ Cmin) / Cavg.
* Indicates statistical significant difference (P £ .05) in comparison to Day 7 values.
Table 2. Statistical Comparisons of the Pharmacokinetic Parameter Values of Morphine After Once-Daily Administration of Morphelan on Day 1 Versus Day 7 for Groups A (no loading dose), B (twice-daily loading dose regimen), and C (double-dose loading dose regimen)
* Antilogarithm of the difference of the least squares means for logarithms.
ANOVA = analysis of variance; AUC24 = area under the concentration-time curve; Cmax = maximum observed plasma concentration.
Table 3. Statistical Comparisons of the Pharmacokinetic Parameter Values of Morphine After Once-Daily Administration of Morphelan on Day 2 Versus Day 7 for Groups A (no loading dose), B (twice-daily loading dose regimen), and C (double-dose loading dose regimen)
* Antilogarithm of the difference of the least squares means for logarithms.
ANOVA = analysis of variance; AUC = area under the concentration-time curve; Cmax = maximum observed plasma concentration; Cmin = minimum observed plasma concentration; FI = fluctuation index.
Table 4. Number (%) of Adverse Events Reported by at Least 10% of Subjects After Once-Daily Administration of Morphelan in Groups A (no loading dose), B (twice-daily loading dose regimen), or C (double-dose loading dose regimen)
If a subject had more than one instance of the same
type of adverse event, that subject was counted once under that event.
Figure 1. Mean morphine plasma concentration-time profiles during 7 days of once-daily dosing of Morphelan with two groups receiving a loading dose on the first day. Group A (circles) received no loading dose on Day 1, Group B (open squares) received a second 60-mg capsule of Morphelan 12 hours after the first dose, and Group C (solid squares) received two 60-mg capsules of Morphelan together as an initial dose.
Figure 2. Mean morphine plasma concentration-time profiles for one dosing interval for Group A on Days 1 (triangles), 2 (solid circles), and 7 (open circles). Subjects received one 60-mg capsule of Morphelan on Days 1-7.
Figure 3. Mean morphine plasma concentration-time profiles for one dosing interval for Group B on Days 1 (triangles), 2 (solid squares), and 7 (open squares). Subjects received an additional capsule 12 hours after the first dose on Day 1, then one 60-mg capsule of Morphelan on Days 2-7.
Figure 4. Mean morphine plasma concentration-time profiles for one dosing interval for Group C on Days 1 (triangles), 2 (solid squares), and 7 (open squares). Subjects received two 60-mg capsules of Morphelan together as an initial dose on Day 1, then one 60-mg capsule of Morphelan on Days 2-7.
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