Eur. J. Clin. Pharmacol. 18, 355—360 (1980)
`
`European Journal of
`Clinical Pharmacology
`© by Springer—Verlag 1980
`
`Pharmacokinetic Studies in Volunteers of Intravenous and Oral Cis (Z)-
`Flupentixol and Intramuscular Cis (Z) -Flupentixol Decanoate in Viscoleo®
`
`A. Jorgensen
`
`Biochemical Department, H. Lundbeck & Co, Copenhagen, Denmark
`
`Summary. Serum concentrations of cis (Z)-flupen-
`tixol have been estimated in three male human vol-
`
`unteers who received cis (Z)~flupentixol by intrave—
`nous infusion, flupentixol (cis (Z)/ trans (E) mixture,
`1 : 1) orally as single and repeated doses, and i. m. cis
`(Z)—f1upentixol
`decanoate
`in Viscoleo®. The
`intravenous data show that cis (Z)—flupentixol fol—
`lowed a multicompartment model, but
`it was not
`possible to fit the data to a two or three compartment
`model. The concentration curves after oral adminis-
`
`tration indicated relatively slow absorption with a
`peak concentration at 3—6 h, except for one case with
`peak at 1 h. The variation in the dosage interval after
`one daily oral administration was relatively limited
`(1.7—3.0 times), which indicates that 24 h is a reason—
`able dosage interval. Biological half—lives were esti—
`mated in different ways and showed some intra-indi—
`Vidual variation; the half—life was of medium length
`(19—39 h). The serum concentrations after intramus-
`cular
`injection of
`cis
`(Z)—flupentixol decanoate
`clearly demonstrated a depot effect, with a maximal
`concentration at
`3—5 days after
`injection. The
`descending part of the serum curves allowed an
`approximate estimation of half—life of 3—8 days. This
`was not the elimination half—life, but in all probability
`the half—life of release of drug from the oil depot
`which was the rate—limiting step. From the areas
`under the serum concentration curves the fraction of
`
`orally administered cis (Z)—flupentixol available to
`the organism was calculated to be 55% (range
`48—60%). The loss of drug might have been due to
`imcomplete absorption, but it is more likely that cis
`(Z)-f1upentixol underwent first-pass metabolism in
`the gut wall and the liver. As the tablets contained
`about 50% cis (Z)—flupentixol, while the depot pre—
`paration contained 74% cis
`(th—flupentixol,
`the
`pharmacokinetically equivalent doses are: 10 mg tab—
`let daily corresponds to 25 mg depot weekly. Calcu-
`
`of
`values
`gave
`systemic Clearance
`of
`lation
`0.44—0.49 1/min, and an apparent volume of distribu—
`tion was 12.5717.21/kg.
`
`Key words: cis (Z)—flupentixol; cis (Z)-flupentixol
`decanoate, serum concentration, biological half—life,
`pharmacokinetics, first—pass metabolism
`
`The thioxanthene drug, flupentixol, has been exten-
`sively used for the treatment of various mental disor—
`ders since its introduction in 1965. In the late sixties a
`
`decanoic ester dissolved in Viscoleo® was developed
`and introduced as a depot preparation to be adminis-
`tered by intramuscular injection every two to four
`weeks. The use of these drugs has been based only on
`clinical experience, as it was not possible to perform
`pharmacokinetic studies due to lack of a sensitive
`analytical method. Studies in animals (Jorgensen et
`al. 1969, 1971) and man (Jorgensen and Gottfries
`1972), mostly with radioactive compounds, gave
`some valuable information on the basic phar—
`macokinetics, and clearly demonstrated the depot
`properties of flupentixol decanoate in oil, but they
`did not supply the human data which would be useful
`in clinical practice. The development of a radioim-
`munoassay for cis (Z)-flupentixol, the neuroleptically
`active flupentixol isomer (Moller Nielsen et a1. 1973;
`Johnstone et a1. 1978), has now made it possible
`to initiate pharmacokinetic studies of
`this drug
`(Jorgensen 1978).
`The present report deals with investigation of its
`basic pharmacokinetics in volunteers after adminis—
`tration of cis (Z)—flupentixol by intravenous infusion
`and oral administration (single and repeated dosed)
`and intramuscular injection of cis (Z)-flupentixol
`decanoate in Viscoleo®.
`
`0031—6970/80/0018/0355/$01.20
`
`InnoPharma Exhibit 1077.0001
`
`

`

`356
`
`Materials and Methods
`
`Suhjects
`Three male volunteers participated in the study:
`
`Initials
`
`CC
`BIL
`AJ
`
`Age
`{years}
`24
`25
`38
`
`Height
`{an}
`186
`175
`170
`
`Body weight
`{kg}
`80
`70
`73
`
`Prior to the study they had appeared normal on clini—
`cal investigation, including a series of blood tests of
`bone marrow and hepatic and renal function. The
`subjects, who were all highly experienced in taking
`part in this kind of experiments, gave informed ver—
`bal consent.
`
`On the days of experiments the food intake of the
`volunteers was carefully controlled. They were
`allowed a light breakfast around ’7 a. m. Following
`drug administration no food was aIIOWed for 2h,
`after which time standardized meals were given for
`the rest of the day.
`
`Boring and Blood Sampling
`Intravenous Infusion. Each subject was given an
`intravenons infusion of cis (Z)-tlnpentixoi dihy—
`drochloride (corresponding to 1 mg cis (Z}—flupen~
`tixol dissolved in 100 ml sterile saline) througha But—
`tertly® infusion set inserted into a cubital vein. The
`infusion was given at a constant rate for 60 min, start—
`ing between 8 and 9 a. m. on the day of the experi—
`ment. The ECG was recorded continuously and the
`blood pressure was measured every 10 min during
`the infusion and just after it ceased. Blood samples
`were taken from the contralateral arm 0, 20, 40 and
`60 min after starting the infusion. At the end of the
`infusion, 11 blood samples were collected in the sub—
`sequent 48 11. Serum was separated by centrifugation
`and was kept frozen until analysed.
`
`Oral“ Administration. A single dose of Fluansol® tab~
`lets 8 mg (corresponding to cis (Z) —flupentixol 4 mg)
`was given to each subject together with 50486 mi
`tap water between 8 and 9 a. m. For repeated
`administration of Fluarnrol® tablets the subjects
`received 1 mg once daily {or three. days, followed by
`1.5 mg
`(corresponding
`to
`cis
`(Z)—flupentixol
`0.75 mg) for eleven days. Blood samples were col«
`lected 0, 1, 2, 3, 4, 6, 8, 10, 12, 15, 24 and 48 h after
`administration of the single dose or the last dose on
`repeated administration. Serum separated by cen—
`trifugation was stored frozen until analysis.
`
`A. Jorgensen: Pharmacokinetics of Cis (Z)—Flupentixol
`
`Intramuscular Administration. 2% Fluanxol® Depot
`0.5 ml, (cis (Z)—tlupentixol dccanoate 10 mg in Vis-
`coleo®, corresponding to cis (Z)~flupentixol 7.4 mg)
`was administered to each subject by deep intramus—
`cular injection in the gluteus muscle on the first
`experimental day between 8 and 9 a. m. Blood sam~
`ples were collected 0, l, 4 and 8h and l, 3, 5, 7, 9,
`11, iii-i: 17, and 21 days after the injection. Serum was
`separated by centrifugation and stored frozen until
`analysis.
`
`Drug Analysis
`
`The serum concentration of cis (Z)-ilupentixol was
`determined by a radioimmunoassay with a limit of
`sensitivity of O.2-O.3 ng/ml and good specificity with
`respect to cis (Z)—flupentixol (Jorgensen 1978). The
`major metabolites of
`flupentixol are N-dealkyl
`flupentixol and flupentixol sulphoxide (Jargensen et
`al. 1969), which are available as a cis (Z)/trans (B)
`mixture and as a pure cis (Z)~isomer, respectively.
`These metabolites interfere with the assay of cis (Z)—
`tlnpentixol to the extent of 2% and 1%, respectively.
`As the metabolites are found in human plasma in the
`same or lower amounts than of parent compound
`(Mnosze et al. 197?), the cross—reactivity can be con-
`sidered as of no practical
`importance. The two
`metabolites have no pharmacological effect (Chris-
`tensen. personal communication) and are in ail prob—
`ability of no therapeutic interest. In case of adminis—
`tration of Finanxol® tablets, the subjects received the
`same amount of the trans (Ehisomer as of the cis
`(Z)~isomer. The trans (E)~isomer is co—estimated to
`about 7 0/0, but as the. cis (Z)/trans (E) ratio remains
`constant at around 1 (Muusze et al. 1977) it is pos-
`sible to correct for this interference. The trans (E)—
`isomer has been shown to have very little
`pharmacological effect (Mallet Nielsen et al. 1973)
`and to be without clinical activity in schizophrenia
`(Johnstone et al. 1978). Cis (Z)~tlupentixol decano-
`ate is co-estirnated to about 6%, but the serum con—
`
`centration of this compound is considered to be too
`low to influence the determination of cis (Z)-flupen-
`tixol after administration of cis (Z)—flupentixol dec—
`anoate in Viscoleo (Jorgensen 1978). The within-
`assay standard deviation is 64%, and the between~
`assays standard deviation is about 20%. Due to this
`difference, all samples from the same subject were
`analysed in the same assay.
`
`Dara Treatment
`
`The intravenous data were treated according to a two
`compartment open model as described by Jorgensen
`and Hansen (1976), with weights of 1, 1/yi and My?
`
`InnoPharma Exhibit 1077.0002
`
`

`

`A. Jorgensen: Pharmacokinetics of Cis (Z)‘Flupentixol
`
`given to the squares of the deviations (yi—y)2. The
`data were also subjected to a kind of peeling techni—
`que, as the concentration figures originating from the
`fi-term in the equation describing the two compart—
`ment model were subtracted for from the original
`concentration data. The resulting concentration data
`were then treated according to a two compartment
`open model. The areas under the serum concentra-
`tion curves (AUC) after intravenous infusion were
`calculated by the trapezoidal rule from the start of
`infusion until 48 h, and by the formula C48//3 from
`48h to infinity. The flvalues were obtained from the
`data treatment according to the two compartment
`open model. The fi‘value also permitted calculation
`of the biological half—life (ti)2 = 0.693//3)
`The concentrations measured in the period 8—24/
`48 h after oral administration allowed graphical esti-
`mation of the biological half~life (Lg). The areas
`under the serum concentration curves after the single
`oral dose were estimated according to the trapezoidal
`rule in the time period 0—48 h, and by the formula
`C48 - lib/0.693 from 48 h to infinity. For subject CC,
`in whom no to, could be determined, the ,6 obtained
`from the infusion study was used for calculation of
`the AUC from 48 h to infinity. The area under the
`serum concentration curve in the dose interval after
`
`repeated administration (AUQH4 h) was determined
`by the trapezoidal rule.
`Provided that the kinetics do not differ between
`
`357
`
`(l
`
`4
`
`8
`
`12
`
`16
`
`I
`20
`Hours after starluf infusion
`
`24
`
`48
`
`Fig. 1. Serum concentrations of cis (Z)—flupentixol after intrave-
`nous infusion of cis (Z)-flupentixol
`‘1 mg in subject CC. Open
`circles indicate measured concentrations. The curve was estimated
`according to a two compartment open model (weight l/yiz)
`
`Table 1. Estimated halfdives of cis (Z)aflupentixol
`
`Subject Two com— Graphical estimation
`partment
`from the terminal
`curve
`parts of the oral
`fitting
`curves
`
`From AUC Mean
`values
`(SD)
`
`Single
`Repeated
`
`dose
`dosage
`
`19 ( 5)
`20
`14
`—
`24
`CC
`EIL
`22
`18
`17
`25
`21 ( 4)
`
`AJ
`33
`27
`36
`58
`39 (14)
`
`single and repeated doses, the areas under the serum
`concentration curves can also be used for calculation
`
`Results
`
`of [3 and then to, by using the formula: AUCO_24h
`(rep. dose) = AUCm24 h + C241“[9’
`(single
`dose)
`(AUG—values and C24 calculated for a 1 mg dose).
`From the terminal ends of the serum concentra—
`
`tion curves after intramuscular injection, a rough
`estimate of [3’ and hence the half-life was possible.
`The areas under the serum concentration curves were
`
`determined by the trapezoidal rule from time 0 to
`time (T) of the last measurable serum sample (1 1, 17,
`and 21. days, respectively, for the three subjects), and
`by CT/fi from this time to infinity.
`
`From the areas under the serum concentration
`
`curves after oral and parenteral administrations, the
`systemic availability of cis
`(Z)~~f1upentixol given
`orally as Fluanxol® tablets could be calculated.
`The systemic clearance, C15, which is an ex—
`pression
`of
`the
`overall
`elimination
`of
`drug
`from the organism, was calculated by the formula:
`
`v
`Dose
`ClS :
`
`. The apparent volume of distribution
`
`AUC
`
`in the B—phase ((Vd)5) was calculated from the data
`after intravenous infusion by the formula (Vd)/3 =
`Dose/[3" AUC.
`
`Although the doses were kept at a very low level in
`the present study, the three volunteers all experi—
`enced unpleasant side effects, such as sedation and
`restlessness. The side effects appeared 4—8 h after the
`intravenous infusion and the single oral dose, on
`Days 3 to 9 after depot injection and more or less
`continually in a very weak form during the last week
`of repeated oral doses.
`The
`serum concentrations measured
`
`after
`
`intravenous infusion of cis (Z)—flupentixol clearly
`demonstrate that the pharmacokinetics of cis (Z)—
`flupentixol must be described by a multicornpartment
`model. Treatment of the intravenous data according
`to a two compartment open model showed that use of
`weights 1 and 1/yi for the squares of the deviations
`gave a poor fit and high standard deviations of the
`model parameters. The use of weight 1/y§, which
`seems most reasonable as no indication of different
`relative standard deviations at different concentra—
`tion levels is indicated in the analytical assay, gave an
`estimation of the model parameters with reasonable
`standard deviations. However, a plot of the data and
`the computer estimated curves shows that the two
`
`InnoPharma Exhibit 1077.0003
`
`

`

`358
`
`A. Jergensen: Pharmacokinetics of Cis (Z)wFlupentixol
`
`ngfml
`
` c
`
`at
`
`l
`8
`
`i
`12
`
`a
`I
`20
`18
`Hum after administration
`
`24
`
`48
`
`a
`
`0
`
`t
`7
`
`i
`I
`21
`14
`Days after administratinn
`
`Fig.3. Serum concentrations of cis (Z)-flupentixol after oral
`administration of flupentixol tablets (Fluanxol®) and intramuscu-
`lar injection of cis (Z)-flupentixol decanoate in Viscoleo® (Fluan—
`x01® Depot) to Subject EIL. Closed circles: flupentixol 8mg
`orally. Open circles:
`cis
`(Z)—flupentixol decanoate
`10 mg
`intramuscularly
`
`Fig.2. Serum concentrations of cis (Z)—flupentixol after oral
`administration of flupcntixol tablets (Fluanx01®) to subject Al.
`Closed circles: single dose of flupentixol 8 mg. Open circles: Re-
`peated administration of flupentixol 1.5 mg once daily
`
`Table 2. Areas under the serum concentration curves (AUC) from time 0 to infinity (i. v. infus, oral single dose, i. m. depot) or time 0 to
`24 h (oral repeated dose) in ng - h/ml - mg and percentage bioavailability of oral cis (Z)-flupentixol.
`
`AUC values
`
`
`Per cent of oral
`
`cis (Z)-flupentixol
`Subject
`i. v. infus.
`oral single
`oral repeat.
`i. m. depot
`available for the organism
`dose
`dose
`
`
`57
`28
`14
`22
`34
`CC
`48
`40
`19
`18
`36
`EIL
`60
`60
`37
`24
`38
`AJ
`
`
`
`
`
`36 21 23 43Mean 55
`
`compartment open model is not valid (Fig. 1). It is
`striking that
`the curves did not fit the maximum
`points at 40 and 60 min (during and at the end of
`infusion, respectively). As the fit
`to the terminal
`phase,
`the fl-phase, was good, while the a~phase
`appeared to be composed of two functions, a type of
`peeling technique was attempted. We did not suc—
`ceed, however, with this procedure — the fit to the
`high serum concentrations was still poor, and in addi—
`tion the standard deviations of the parameters were
`rather high. The peeling technique reduced the
`number of data points and this may have contributed
`to a great extent to the poor result, but it may also be
`that more then three compartments are necessary to
`account for the kinetics of cis (Z)-flupentixol. How—
`ever, the small number of data points did not permit
`further computer treatment. Thus the only parameter
`of value supplied by the treatment of the data accord—
`ing to a two compartment open model was [3, from
`which the half—life was calculated (Table 1). From [5,
`dose and AUC the systemic clearance based on
`serum concentrations, C15, was calculated to be 0.44
`
`to 0.491/min (mean 0.461/min), and the apparent
`volume of distribution in the fi-phase (VJ/,2 was
`12.5—17.21/kg (mean 14.11/kg).
`'
`The serum concentration curves obtained after
`
`oral administration of a single dose of flupentixol
`8 mg and the last of a series of daily doses of flupen—
`tixol 1.5 mg in one of the subjects are shown in Fig. 2.
`The peak concentrations after oral administration
`were obtained at 3—6 h, except for one subject with a
`peak at one hour, indicating relatively slow absorp-
`tion. The biological half-lites estimated graphically
`from the terminal ends of the curves varied around
`
`one day (range 14—36 h, Table 1). No half—life could
`be estimated for the single oral dose given to subject
`CC. The maximum/minimum fluctuation in the 24—h
`
`dosage interval was 3.0, 1.8, and 1.7, respectively, for
`the three subjects.
`The areas under the serum concentration curves
`
`after single and repeated oral administration can be
`used to calculate [5 and hence tig, as already
`described. This calculation is based on the assump-
`tion that the kinetics of cis (Z)—flupentixol on single
`
`InnoPharma Exhibit 1077.0004
`
`

`

`A. Jorgensen: Pharmacokinetics of Cis (Z)-Flupentixol
`
`359
`
`and repeated administration do not differ. The fact
`that no trend was seen in the difference between the
`half-lives on i. V. infusion and the two oral treatments
`
`The mean biological half—life in the three subjects
`(19—39 h), and the rather limited fluctuation between
`maximum and minimum serum concentration in a
`
`supports this assumption. The half-lives calculated
`from the AUC values are given in Table 1, together
`with the half-lives obtained in other ways. Some
`intra—individual variability is seen in the half—lives,
`but this may be explained by the fact that we have
`operated close to the limit of sensitivity of the assay
`method, where the standard deviation is rather high
`(Jorgensen 1978). The mean half-life for the three
`subjects ranged from 19—39 h, which may be consid-
`ered a medium length half-life.
`The serum concentrations of cis (Z)-flupentixol
`after intramuscular injection of cis (Z)—f1upentixol
`decanoate 10 mg in one subject appear in Fig. 3. For
`comparison, the oral single dose curve has also been
`drawn on this figure. The serum concentration rose
`very slowly after the depot injections, reaching the
`maximum value 3—5 days after injection. Thus, com-
`pared to the oral single dose curve with its peak at
`3—6 h after administration, the depot effect was very
`evident. The three blood samples drawn on the day
`of injection (1, 4, and 8 h after injection) all showed a
`serum concentration of 0, as did the sample drawn
`before injection.
`The areas under the serum concentration curves
`
`(AUC) from time of administration to infinity after
`single dose administration and with a 24-h interval
`between repeated oral doses per mg of administered
`cis (Z)~flupentixol are given in Table 2. Based on
`these values the fraction of orally administered cis
`(Z)-flupentixol which reached the systemic circula—
`tion in unchanged form,
`i. e.
`is available for the
`organism after Fluanxol® administration, can be cal—
`culated. The available fraction was a mean 55%
`
`(range 48—60%).
`
`Discussion
`
`Administration of very potent psychotropic drugs
`like flupentixol to human volunteers in the course of
`pharmacokinetic studies is faced with certain prob—
`lems. Due to the high tissue binding of these drugs
`(mean (Vd)/3 for flupentixol is 14.l l/kg), the serum
`level is low relative to the tissue concentration. Thus,
`although a sensitive assay technique is available, as in
`this case, a dose of some magnitude has to be given in
`order to secure a valid drug estimation, and the vol—
`unteers, who seem to be very sensitive to this type of
`drug, will then suffer side-effects. This occurred in
`the present study, although we worked with doses
`giving serum levels close to the limit of determina—
`tion.
`
`24—h dosage interval on repeated administration,
`indicates that once a~day treatment is reasonable
`with cis (Z)—flupentixol given as ordinary tablets. The
`half—life of 3—8 days found after intramuscular injec—
`tion of cis (Z)—flupentixol decanoate indicates that
`the dosage interval for this preparation should be of
`the order of one week. Against this, however, is the
`limited fluctuation in serum concentration found by
`Stauning et al. (1979) with a dosage interval of two
`weeks. As cis (Z)—flupentixol decanoate is rapidly
`hydrolysed to liberate cis (Z)-flupentixol (Jorgensen
`et al. 1971), and the biological half—life of cis (Z)—
`flupentixol is of the order of l to 1.5 days, the half~
`lives found for cis (Z)—flupentixol decanoate (3—8
`days) are not elimination half—lives, but in all proba-
`bility refer
`to the release of cis
`(Z)~flupentixol
`decanoate from the oil depot as the rate—limiting
`step.
`The fraction of cis (Z)~flupentixol which is sytem—
`ically available after oral administration was a mean
`of 55%. The reduced systemic availability as com—
`pared to parenteral administration might be due to
`incomplete absorption.
`l-lOWever, since absorption
`has been shown to be complete in rats (Jorgensen et
`al. 1969), a more likely explanation is that cis (Z)—
`flupentixol is partly metabolized on passage through
`the gut wall or liver during absorption (first~pass
`metabolism). As the commercially available flupen-
`tixol tablets (Fluanxol® tablets) contain 50% cis (Z)—
`flupentixol, while the depot preparation (Fluanxol®
`Depot, Depixol® Inj.) contains 74% cis (Z)-flupen—
`tixol, the pharmacokinetic equivalence between the
`preparations is: a tablet dose of 10 mg daily should
`be equivalent to a weekly dose of 25 mg of the depot
`preparation. However, as the serum concentration
`produced by tablets fluctuates between maxima and
`minima in 24 h, while the same fluctuation is seen
`over 2—4 weeks with the depot preparation, the phar-
`macokinetic equivalence between the tablet and
`depot forms does not necessarily correspond to clini-
`cal equivalence of the two preparations, but it is a
`useful guideline.
`A peak in serum concentration on the day of
`injection, like that seen for fluphenazine decanoate
`in sesame oil (Curry et al. 1978, 1979; Wiles and
`Gelder 1979) is not seen with cis (Z)—flupentixol
`decanoate in Viscoleo, most probably because the cis
`(Z)~flupentixol decanoate preparation contains very
`little free cis (Z)*flupentixol base.
`The systemic clearance of 0.461/rnin, calculated
`on the basis of the serum levels measured after
`
`intravenous infusion, are in good agreement with the
`
`InnoPharma Exhibit 1077.0005
`
`

`

`360
`
`clearance of 0.5 l/min found after injection of cis (Z)-
`flupentixol palmitate in patients (Jorgensen and
`Fredricson Overo 1980), and is only slightly higher
`than the
`clearance of 0.31 l/min found after
`
`administration of cis (Z)-flupentixol decanoate to
`patients (Stauning et al. 1979). It should be noted
`that since the AUC values are higher after i. m. depot
`injection than after intravenous infusion, the clear-
`ance calculated on the basis of depot injection would
`be lower. Clearance values of the same order have
`
`been found after administration of the related drug,
`cis (Z)—clopenthixol decanoate, for which a mean sys—
`temic clearance of 0.7 l/min was found in one study
`(Jorgensen and Fredricson Overo 1980) and one of
`0.5 l/min in another study (Aaes-Jorgensen, personal
`communication).
`
`Acknowledgements. I wish to thank Dr. E. Lilje for
`performing the infusions and injections and for
`supervising the safety of the study. My thanks are
`also due to to the three volunteers, Mrs. J. Rasmus-
`sen for brilliant
`technical assistance, and to Mrs.
`R. S. Andersson for preparing the figures and the
`manuscript.
`
`References
`
`Curry SH, Whelpton R, De Schepper PJ, Vranckx S, Schiff AA
`(1978) Plasma fluphenazine concentrations after injection of
`long—acting esters. Lancet 2: 1217—1218
`Curry SH, Whelpton R, De Schepper PJ, Vranckx S, Schiff AA
`(1979) Kinetics of Fluphenazine after Fluphenazine Dihy-
`drochloride, Enanthate and Decanoate Administration to
`Man. Br J Clin Pharmacol 7: 325—331
`
`A. Jorgensen: Pharmacokinetics of Cis (Z)-Flupentixol
`
`Jorgensen A, Fredricson Overe K, Hansen V (1971) Metabolism,
`Distribution and Excretion of Flupentixol Decanoate in Dogs
`and Rats. Acta Pharmacol Toxicol 29: 339—358
`Jorgensen A, Gottfries CG (1972) Pharmacokinetic Studies on
`Flupentixol and Flupentixol Decanoate in Man using Tritium
`Labelled Compounds. Psychopharmacologia 27: 1—10
`Jorgensen A, Hansen V (1976) Pharmacokinetics of Amitriptyline
`Infused Intravenously in Man. Eur J Clin Pharmacol 10:
`337—341
`
`Jorgensen A (1978) A sensitive and specific radioimmunoassay for
`cis (Z)-flupentixol in human serum. Life Sci 23: 1533—1542
`Jorgensen A, Fredricson Overo K (1980) Clopenthixol and
`flupentixol depot preparations in outpatient schizophrenics. III
`Serum levels. Acta Psychiatr Scand 61: Suppl 279, 41—54
`Muusze RG, Visser-Van der Weel A], Van der, Verzijden R, Oei
`TT (1977) Fluorimetrische bepaling op de dunne laag van de
`blodkoncentratie van thioxanthenen (Sordinol® en Fluanxol®)
`na orale en intramusculaire (depot) toediening. Bulletin van de
`coordinatiecommissie biochemisch onderzoek van de psychia—
`trische instituten van de nationale ziekenhuisraad 10: 1—8
`Moller Nielsen I, Pedersen V, Nymark M, Franck KF, Boeck V,
`Fjalland B, Christensen AV (1973) The Comparative Phar—
`macology of Flupentixol and some Reference Neuroleptics.
`Acta Pharmacol Toxicol 33: 353—362
`Stauning JA, Kirk L, Jorgensen A (1979) Comparison of Serum
`Levels After Intramuscular Injections of 2% and 10% Cis (Z)—
`flupentixol Decanoate in Viscoleo® to Schizophrenic Patients.
`Psychopharmacology 65: 69—72
`Wiles DH, Gelder MG (1979) Plasma Fluphenazine Levels by
`Radioimmunoassay in Schizophrenic Patients Treated with
`Depot Injections of Fluphenazine Decanoate. Br J Clin Phar-
`macol 8: 565—570
`
`Received: October 26, 1979
`in revised form: March 14, 1980
`accepted: May 12, 1980
`
`Johnstone EC, Crow TJ, Frith CD, Carney MWP, Price JS (1978)
`Mechanism of the antipsychotic effect in the treatment of acute
`schizophrenia. Lancet 1: 848—851
`Jorgenscn A, Hansen V, Dahl Larsen U, Rauf Khan A (1969)
`Metabolism, Distribution and Excretion of Flupentixol. Acta
`Pharmacol Toxicol 27: 301—313
`
`Dr. Aksel Jorgensen
`Biochemical Department
`H. Lundbeck & Co. A/S
`Ottiliavej 7—9
`DK—2500 Valby, Kobenhavn
`Denmark
`
`InnoPharma Exhibit 1077.0006
`
`