Académique Documents
Professionnel Documents
Culture Documents
Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
d
Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
e
Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark
b
c
a r t i c l e
i n f o
Article history:
Received 7 August 2014
Received in revised form 8 October 2014
Accepted 1 December 2014
Available online 5 December 2014
Keywords:
Morphine
Morphine-6-glucuronide
Dose escalation
Rectal administration
Population pharmacokinetics
a b s t r a c t
Introduction: To safely and effectively administer morphine as liquid formulation via the rectal route, a
thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a
population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2)
to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety.
Material and methods: This open label, dose escalation, four-sequence study was conducted in 10 healthy
males. Three escalating doses of morphine hydrochloride (10 mg, 15 mg and 20 mg) were administered
20 cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained
by centrifugation and assayed for contents of morphine and M6G with a validated high performance
liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the rst order
conditional estimation method with interaction.
Results: A two compartment distribution model with one absorption transit compartment for rectal
administration and systemic clearance from the central compartment best described data. Systemic PK
parameters were allometric scaled with body weight. The mean morphine absorption transit time was
0.6 h, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%).
To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufcient peak serum concentration levels and a 46 mg dose four
times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was
suggested to be an important covariate for morphine exposure. No severe side effects were observed.
Conclusion: A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The
model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses
were safe and well tolerated.
2014 Elsevier B.V. All rights reserved.
1. Introduction
Opioids are considered mainstay in management of moderate to
severe acute and chronic pain. They primarily produce analgesic
effect via activation of opioid receptors in the central nervous system. Additionally, peripheral opioid receptors may be responsible
for analgesia especially during inammation (Sehgal et al., 2011;
Stein and Lang, 2009). Among opioids, morphine is the golden
standard and oral administration is the cornerstone in pain management. When oral administration of morphine is not applicable,
the rectal route represents a non-invasive and cheap alternative.
Rectally administered non-standard liquid preparations, where
morphine is rapidly available for absorption, have to some extent
79
outlet 1 cm below the tip of the probe. The probe enabled medication to be sprayed evenly onto the rectosigmoid wall (see Fig. 1).
The dosages were administered with the participant in the leftlateral position with knees and hips exed. Subsequently, the
probe was perfused with 1 mL of isotonic saline to ensure a complete drug administration. The probe was then slowly removed
and subsequently, liquid leakage was checked by visual inspection.
Following this procedure, the participant was allowed to sit
upright. The participant fasted for at least 10 h before the initiation
of each experiment. Prior to the medication administration the
participant had his bowels cleansed with an enema (Toilax 2 mg/mL
(Bisacodyl) Orion Corporation, Espoo, Finland). A washout period
of minimum one week was left between the four different
treatment schedules.
2.3. Blood sampling
Blood samples for the determination of the serum concentrations of morphine and M6G were drawn at baseline and nine times
after morphine administration via a peripheral venous catheter.
The samples were allowed to clot for a minimum of 15 min and
then centrifuged for 15 min at 3500 RPM. Serum was then pipetted
into vials in 2 mL aliquots, and subsequently stored at 80 C. A
Rectum
Anus
Rectal probe
Fig. 1. The custom designed rectal probe inserted 20 cm into the rectum. The probe
had four channels for medicine administration with an outlet 1 cm below the tip of
the probe. The probe enabled medication to be sprayed evenly onto the rectosigmoid wall.
80
Pi P expgi
where Pi is the value of the parameter in the individual i, P is the
typical value of the parameter in the population, and gi is the normally distributed inter-individual variability (IIV) with mean 0 and
81
V3
Rectal dose
Peripheral mor
IV dose
Q3
V M6G
CL M6G
Central M6G
A1
Ktr, F
A4
Transit mor
ka
V2
Central mor
CL
Ktr, M6G
CL/(F*fadd)*fM6G
A6
Transit M6G
Fig. 2. Final PK model diagram for simultaneous description of serum concentrationtime proles of morphine (mor) and M6G following IV or rectal administration of
morphine. A is drug amount in the compartment and numbers denote the compartments (1: dosing; 2 and 3: the central and peripheral compartments of morphine; 4:
morphine transit compartment from compartment 1 to 2; 5: central compartment of M6G; 6: transit compartment for M6G between compartment 2 and 5). Q3 is intercompartmental clearance. V is volume of distribution. CLM6G is M6G clearance. ktr, ktr,M6G and ka are rst-order rate constants between compartments, F rectal bioavailability
and fadd is additional fraction of morphine converted to M6G after rectal administration. fM6G is fraction of total systemic morphine clearance converted to M6G (xed to 0.14).
3. Results
A total of 10 healthy male participants were included in this
study. Their mean age was 25.6 years (range 2329 years), mean
height 180.1 cm (range 170196 cm) and mean weight 77.1 kg
(range 63100 kg). No leakage was observed following morphine
administration, thus, the full dose was administered in all
participants.
3.1. Pharmacokinetic model
The observed serum concentrationtime proles of morphine
and M6G following intravenous or rectal administration of morphine are presented in Fig. 3. Based on the dened model development and evaluation criteria, the morphine serum concentration
time proles were best described by a two-compartment distribution model with one absorption transit compartment for rectal
administration and systemic clearance from the central compartment (Fig. 2).
Mean absorption transit time for rectally administered morphine was calculated to 0.6 h for a typical person (i.e. 70 kg) in
the population. Formation of the metabolite M6G was modelled
as a xed fraction of morphine clearance (0.14 as reported in a previous paper (Lotsch et al., 2002)) from the central morphine compartment via a transit compartment into the central M6G
compartment. For simultaneous modelling of M6G formation after
intravenous and rectal administration (where additional M6G is
assumed to be formed by rst-pass metabolism), the M6G formation rate was best described as CL/(F fadd). The morphine and
M6G parameters for the nal PK model are summarized in Table 1.
Parameter precision <42% was observed for the nal model with
acceptable shrinkage for all random effects (<17%, except IOV for
V2 which was 42%). The nal PK model included allometric scaling
of weight on morphine clearance and volume parameters. Signicant improvement of the model was found by inclusion of IOV
for morphine absorption rate constant (ka), V2 and F in addition
to ktr,M6G for M6G. The residual unexplained variability was
described by a proportional and additive term for morphine and
a proportional term for M6G. The predictive performance of the
nal model is presented in a pcVPC (Fig. 4). The pcVPC conrmed
that the model adequately described the morphine and M6G data.
82
(a)
10
(b)
100
Drug (ng/mL)
Drug (ng/mL)
100
10
0.1
0.1
0
(d)
(c)
100
Drug (ng/mL)
100
Drug (ng/mL)
Time (h)
Time (h)
10
0.1
10
0.1
Time (h)
Time (h)
Fig. 3. Serum concentrationtime proles of morphine (blue) and M6G (red) following administration of (a) 2 mg intravenous; (b) 10 mg rectal; (c) 15 mg rectal or (d) 20 mg
rectal morphine HCl (n = 10/dose).
Table 1
Population PK parameters of morphine and M6G from nal model, following intravenous (2 mg) or rectal (10, 15 and 20 mg) administration of morphine.
Parameter
Estimate (RSE%)
IIV (RSE%)
CL (WT/70)0.75 (L/h)
V2 (WT/70) (L)
V3 (WT/70) (L)
Q3 (WT/70)0.75 (L/h)
F (%)
ktr (h1)
ka (h1)
r1, prop error (%)
r2, add error (ng/mL)
r3, M6G prop error (%)
CLM6G (L/h)
VM6G (L)
ktr,M6G (h1)
fadd
fM6G
78 (12)
6.4 (31)
143 (14)
196 (18)
24 (11)
3.2 (30)
2.1 (9.5)
22 (12)
0.29 (41)
22 (9.7)
8.9 (7.3)
5.9 (22)
6.5 (27)
0.85 (9.2)
0.14 (FIX)
26 (23)
IOV (RSE%)
135 (16)
30 (27)
127 (34)
28 (22)
51 (20)
16 (29)
70 (26)
25 (29)
Description
Systemic clearance with allometric weight scaling
Central compartment with allometric weight scaling
Peripheral compartment with allometric weight scaling
Inter-compartmental clearance with allometric weight scaling
Rectal bioavailability
Transit compartment rate constant for rectal morphine absorption
Absorption rate constant
Proportional residual unexplained error
Additive residual unexplained error
Proportional residual unexplained error
Clearance of M6G from central M6G compartment
Volume of central M6G compartment
Transit compartment rate constant for M6G
Additional fraction converted to M6G from rectal administration
Fraction of total morphine clearance converted to M6G
IIV = inter-individual variability expressed as coefcient of variation, IOV = inter-occasion variability expressed as coefcient of variation, RSE = relative standard error
reported on the approximate standard deviation scale.
83
Fig. 4. Prediction-corrected visual predictive check (pcVPC) of nal morphine and M6G PK model following administration of morphine. (a) Intravenous morphine,
arithmetic; (b) Intravenous morphine, semi-logarithmic; (c) rectal morphine; (d) M6G after rectal morphine administration; (e) M6G after intravenous morphine
administration. Blue dotsobservations; red line median of the prediction-corrected observations; Red dotted lines 2.5th and 97.5th percentile of the observed data; blue
shaded areas- 95% condence intervals for the 2.5th percentile and 97.5th percentiles of simulated data; pink shaded area 95% condence interval for the median of the
simulated data.
84
80
(a)
Morphine (ng/mL)
Morphine (ng/mL)
60
40
20
(b)
60
40
20
0
0
10
20
30
Time (h)
Time (h)
Fig. 5. Simulation of morphine serum concentrationtime proles using the nal PK model (2000 simulations of 10 participants with demographics from the current study),
following rectal administration of (a) single dose 36 mg morphine HCl targeting a median maximum serum concentration of 21 ng/mL or (b) 46 mg morphine HCl 4 with
6 h intervals targeting a median steady-state serum concentration of 21 ng/mL. Solid lines are prediction median and dotted lines are 2.5 (lower) and 97.5 (upper) percentile
for the simulated data.
50
Morphine (ng/mL)
40
30
20
10
0
0
10
15
20
25
Time (h)
Fig. 6. Simulation of typical morphine serum concentrationtime proles following
rectal administration of 46 mg morphine HCl times four with 6 h intervals for a
100 kg person (red) or a 63 kg person (blue) using the nal PK model.
Table 2
Side effects observed during each of the three sequences (10, 15 and 20 mg morphine
hydrochloride, respectively).
Type of side effect
10 mg
morphine
15 mg
morphine
20 mg
morphine
Nausea
Dizziness
Itching
Sweating
Lower gastrointestinal complaints
Sedation
2
4
0
1
1
0
2
3
0
1
0
1
1
3
0
1
0
0
steady-state serum levels around 21 ng/mL for chronic pain treatment, simulations from the PK model suggest 46 mg morphine
hydrochloride four times daily may be sufcient for a typical person.
The PK model suggested body weight to be an important covariant
for morphine exposure. Simulating a multiple-dose PK prole for a
typical 63 kg person, suggested that steady-state serum levels will
be 41% higher than that of a typical 100 kg person. The model has
not been validated outside this body weight range. However, it
could be speculated that individuals weighing more than 100 kg
may have even lower morphine clearance, leading to sub-therapeutic serum concentrations, and vice versa for individuals weighing
less than 63 kg. This could warrant guidance for dose adjustments
for persons outside the normal body weight range according to
the allometric equation for total morphine clearance. To our knowledge, the current study is the rst to evaluate serum exposure of the
pharmacological active M6G metabolite after rectal administration
of liquid morphine. In vitro, M6G is reported to have 6-fold lower
binding afnity for the l-opioid receptors compared to morphine
(Kilpatrick and Smith, 2005). Using pupil diameter as a marker of
central opioid receptor activation, M6G is suggested to be almost
30-fold less potent than morphine relative to plasma exposure
(Skarke et al., 2003). Based on the current model, typical peak serum
values of M6G after rectal administration of morphine was estimated to be around 4-fold higher than morphine. Thus, it is unlikely
that M6G will contribute signicantly to morphine analgesia after a
single rectal dose.
4.2. Methodological considerations
To ensure a complete drug administration in the present study,
the rectal probe was perfused with 1 mL isotonic saline and subsequently, no leakage was observed. This implies that the full dose
was sufciently administered. Body position and movement as
well as individual rectal secretion are factors that may contribute
to variability in absorption, as seen in the present study. The participants were asked to calmly sit upright immediately after drug
administration. The movement and the inuence of gravity may
have contributed to spreading of morphine in the rectum, although
it seems unlikely with a volume of only 6 mL. Generally, spreading
of medication in the rectum is likely to be reduced by using a more
viscous solution and/or to minimize the volume. To further minimize the variability in future studies or in the clinic, it is essential
that the patient remain calm after administration. The population
of this study was healthy males, all with normal bowel movements
and before initiation of each study sequence the participant was
given a bowel cleansing enema. Thus, variation in absorption
caused by dysfunctional motility and faeces was considered
negligible. Given that the present study was performed in healthy
participants under standardized conditions and with limited
movement, it could be speculated that the observed variability in
absorption may be higher in the clinical setting. The probe used
for administration was custom-designed and thus, not commercially available. A similar device (e.g. a simple applicator) may in
theory enable patient self-administration. However, self-administration seems to be impractical due to the site of administration
in the upper rectum. In addition, as anatomical differences in hemorrhoidal venous drainage of the rectum may substantially inuence the systemic drug level achieved it is essential that the
administration device is placed correctly in the rectum. It is therefore recommended that medicine administration is performed by
professionals.
4.3. Safety assessment
This study found that liquid morphine administered rectally is
safe and well tolerable in healthy male participants in the dosage
85
5. Conclusions
A population PK model describing the PK prole of morphine
and M6G after rectal administration of liquid morphine was developed. Model simulations suggested a single rectal morphine dose
of 35 mg morphine hydrochloride to be sufcient to obtain clinically relevant peak serum levels in a typical person, while a dose
of 46 mg morphine hydrochloride rectally four times daily was
suggested to sustain clinically relevant steady-state serum levels
for chronic pain treatment. Body weight was shown to be signicantly related to population variability in morphine PK, and may
need to be accounted for by rectal administration to individuals
outside the normal weight range. The three studied doses of rectally administered morphine were all safe and well tolerated in
healthy male participants.
Acknowledgements
Support for this study was provided by The Danish Council for
Strategic Research and Det Obelske Familiefond. The authors
would like to thank Matias Nilsson, Mech-Sense, Department of
Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark for graphical illustration.
References
Bergstrand, M., Hooker, A.C., Wallin, J.E., Karlsson, M.O., 2011. Prediction-corrected
visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J.
13 (2), 143151.
Dahan, A., Romberg, R., Teppema, L., Sarton, E., Bijl, H., Olofsen, E., 2004.
Simultaneous measurement and integrated analysis of analgesia and
respiration after an intravenous morphine infusion. Anesthesiology 101 (5),
12011209.
Dahlstrom, B., Tamsen, A., Paalzow, L., Hartvig, P., 1982. Patient-controlled analgesic
therapy, Part IV: pharmacokinetics and analgesic plasma concentrations of
morphine. Clin. Pharmacokinet. 7 (3), 266279.
Davies, B., Morris, T., 1993. Physiological parameters in laboratory animals and
humans. Pharm. Res. 10 (7), 10931095.
de Boer, A.G., Breimer, D.D., 1997. Hepatic rst-pass effect and controlled drug
delivery following rectal administration. Adv. Drug Deliv. Rev. 28 (2), 229237.
De Conno, F., Ripamonti, C., Saita, L., MacEachern, T., Hanson, J., Bruera, E., 1995.
Role of rectal route in treating cancer pain: a randomized crossover clinical trial
of oral versus rectal morphine administration in opioid-naive cancer patients
with pain. J. Clin. Oncol.: Off. J. Am. Soc. Clin. Oncol. 13 (4), 10041008.
Holford, N.H., 1996. A size standard for pharmacokinetics. Clin. Pharmacokinet. 30
(5), 329332.
Jonsson, E.N., Karlsson, M.O., 1999. Xposean S-PLUS based population
pharmacokinetic/pharmacodynamic model building aid for NONMEM.
Comput. Methods Programs Biomed. 58 (1), 5164.
Karlsson, M.O., Sheiner, L.B., 1993. The importance of modeling interoccasion
variability in population pharmacokinetic analyses. J. Pharmacokinet.
Biopharm. 21 (6), 735750.
Keizer, R.J., Karlsson, M.O., Hooker, A., 2013. Modeling and simulation workbench
for NONMEM: tutorial on Pirana, PsN, and Xpose. CPT: Pharmacomet. Syst.
Pharmacol. 2, e50.
Kilpatrick, G.J., Smith, T.W., 2005. Morphine-6-glucuronide: actions and
mechanisms. Med. Res. Rev. 25 (5), 521544.
86
Lindbom, L., Ribbing, J., Jonsson, E.N., 2004. Perl-speaks-NONMEM (PsN)a Perl
module for NONMEM related programming. Comput. Methods Programs
Biomed. 75 (2), 8594.
Lotsch, J., Skarke, C., Schmidt, H., Liefhold, J., Geisslinger, G., 2002. Pharmacokinetic
modeling to predict morphine and morphine-6-glucuronide plasma
concentrations in healthy young volunteers. Clin. Pharmacol. Ther. 72 (2),
151162.
Lundeberg, S., Hatava, P., Lagerkranser, M., Olsson, G.L., 2006. Perception of pain
following rectal administration of morphine in children: a comparison of a gel
and a solution. Paediatr. Anaesth. 16 (2), 164169.
Mazoit, J.X., Butscher, K., Samii, K., 2007. Morphine in postoperative patients:
pharmacokinetics and pharmacodynamics of metabolites. Anesth. Analg. 105
(1), 7078.
Meineke, I., Freudenthaler, S., Hofmann, U., Schaeffeler, E., Mikus, G., Schwab, M.,
Prange, H.W., Gleiter, C.H., Brockmoller, J., 2002. Pharmacokinetic modelling of
morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma
and cerebrospinal uid of neurosurgical patients after short-term infusion of
morphine. Br. J. Clin. Pharmacol. 54 (6), 592603.
Osborne, R., Joel, S., Trew, D., Slevin, M., 1990. Morphine and metabolite behavior
after different routes of morphine administration: demonstration of the
importance of the active metabolite morphine-6-glucuronide. Clin.
Pharmacol. Ther. 47 (1), 1219.
Pannuti, F., Rossi, A.P., Iafelice, G., Marraro, D., Camera, P., Cricca, A., Strocchi, E.,
Burroni, P., Lapucci, L., Fruet, F., 1982. Control of chronic pain in very advanced
cancer patients with morphine hydrochloride administered by oral, rectal and
sublingual route. Clinical report and preliminary results on morphine
pharmacokinetics. Pharmacol. Res. Commun. 14 (4), 369380.
Ravn, P., Foster, D.J., Kreilgaard, M., Christrup, L., Werner, M.U., Secher, E.L., Skram,
U., Upton, R., 2014. Pharmacokineticpharmacodynamic modelling of the