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Current Medical Research and Opinion

Vol. 6, Suppl. 1, 1979

Fenfluramhe plasma concentrations after administration of a sustained-release capsule formulation and rapid-release tablets

D. B. Campbell, B.Sc., Ph.D., C.Chem.,M.R.I.C., Y. Hopkins, B.Sc., G.R.I.C., R. Richards, B.Sc., and D. Taylor, B.Sc. Servier Research Institute, Greenford, England

Curr. Med. Res. Opin., (1979), 6, Suppl. 1, 160.

Paper read: 20th October 1978

SUmmary A sustained-release capsule formulation of fenjluramine has been developed to provide a more convenient once daily dosage regimen. This new formulation, a capsule coniaining 60 mg fenjluramine, was compared with the existing 3 x 20 mg tablet formulation by an acute and a repeat-dose crossover bioavailability study. In these studies plasma fenjluramine concentrations were measured and the results obtained were analyzed statistically by both 2-way analysis of variance and strip plot analysis of variance. The results of the acute study showed similar plasma drug levelsfor both formulations, but with the capsule producing a smoother profile. The results of the repeat-dose study showed that steady state concentrations were achieved within 3 to 5 days and were statistically the samefor bothformulations, as was the elimination of the drug at the endof the study. The bioavailability of the capsule formulation with respect to the 20 mg tablets at the 95% confidence interval was 93% to 107%. An in vitro dissolution procedure has been developed which provides a good correlation with in vivo absorption, and this has been used for the examination of the stability of the product and in quality control. Key words: FenJluramine - delayed-action preparations - pharmacokinetics

Uneforme retard de fenJlurarnine a ktk mise au point ajin de disposer d’une posologie plus pratique avec une seule prise quotidienne. La nouvelle forme, une gelule contenant 60 mg de fenjluramine, a ktk comparke avec la forme existante, 3 comprimks d 20 mg, dans une ktude de biodisponibilitk en aigu et en chronique avec croisement. Dans ces dudes, les concentrations plasmatiques defenjluramine ont ktk mesurkes et les rksultats obtenus ont ktk analysks statistiquement par 2 mkthodes d la fois, analyse de variance et ‘split plot’ analyse de variance. Les rksultats de I’ktude en aigu ont montrk des taux plasmatiques du mkdicament similaires pour les deux formes mais avec pour la gelule un profilplus rkgulier. Les rksultats de 1’ktudeen chronique montrent que les concentrations d l’ttat constant etaient obtenues en 3 d 5 jours et ttaientstatistiquement lesm2mes pour les deux formes comme l’ktait l’klimination du mkdicament d la fin de I’ktude. La biodisponibilitt des gelules par rapport aux comprimts ttait de 93 d 107% (limite de confiance 95%). Une mtthode de dissolution in vitro a ttk mise aupoint, laquelle donne une bonne corrklation avec I’absorption in vivo. Cette mkthode a ktt utiliske pour kvaluer la stabilite‘ du produit et dans les contrdles de qualitk de routine. 160

D. B. Campbell, Y.Hopkins, R.Richards and D. Taylor

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Introduction For many patients the swallowing of large quantities of tablets daily is both a trial of the stomach and memory and the result is a lack of patient compliance and subsequent uncontrolled therapy. The extent to which this happens is alarming and it has been estimated that as many as a third of the patients taking hypotensive therapy or antidepressants do not adhere to their correct medication schedule.2.5 The problem is particularly exaggerated in the obese population since their gross corporeal volume necessitates the administration of large quantities of drug to ‘fill’ the high volume of distribution. Such is the case with fenfluramine therapy where doses as high as 240 to 320 mg per day have been administered*,’ to patients weighing 200 kg or more, which is equivalent to giving 16 tablets daily. The individuals’ reluctance to take such large quantities of tablets has necessitated the development of a sustained-release formulation of fenfluramine to provide prolonged action so that it need be administered only once a day. It was considered that such a development would lead to better patient compliance and to fewer side-effects which could o c c y when many fenfluramine tablets are taken together. Thirteen-years’ experience with fenfluramine in the treatment of obesity has shown that 3-times a day dosing of a 20 mg tablet at meal times is effective in producing weight loss.’ A sustained-release preparation of fenfluramine able to release 60 mg of the drug over one day, therefore, was developed. The formulation has a number of small coated pellets of the drug inside a hard gelatine capsule with the release characteristics of the pellets controlled in such a way as to mimic the effect of administering 20 mg fenfluramine tablets 3-times at 5-hour intervals. The work reported in this paper describes the bioavailability studies, which have been undertaken to compare the plasma concentrations of fenfluramine produced by the administration of fenfluramine in sustained-release capsule form and the rapidrelease 20 mg tablets to healthy human volunteers, after both acute and repeated dosage.

Methods and materials Subjects Healthy non-obese female volunteers, aged 21 to 28 years, weight 55 to 70 kg, were clinically assessed as to their suitability to take part in the studies. The subjects had no previous history of hepatic, renal, cardiac disease or hypersensitivity to drugs. The 5 subjects studied were not taking other medicaments except oral contraceptives and they were asked to abstain from alcohol at least 1 day before and during the studies, but tea, coffee and cigarettes were allowed in moderation. All subjects fasted 12 hours prior to the day of the acute study and for 4 hours post-administration. Acute study For this 2-day study, the volunteers received either a single capsule containing 60 mg fenfluramine hydrochloride in pellets or 3 x 20 mg fenfluramine hydrochloride sugarcoated tablets at 5-hour intervals. After a period of 1 week the volunteers were crossed 161

Fenfluramine plasma concentrations after administration of a sustained-release capsule formulation and rapid-release tablets

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over to the other formulation. The capsule was taken at 08.00 hours. The 20 mg tablets were taken at 08.00, 13.00, and 18.00 hours. Blood was collected into lithium heparinized tubes over a 50-hour period, centrifuged, and the plasma stored at -20°C prior to analysis. Repeat-dose study In this repeat-dose crossover study, the volunteers received on separate occasions either a 60 mg capsule at 08.00 hours each morning or 20 mg tablets 3-times daily at 08.00, 13.00 and 18.00 hours for a period of 13 days. Blood was collected at approximately 15.00 hours throughout the course of the study and also at various times after the final dose in order to observe the elimination kinetics of fenfluramine. Analytical techniques Plasma drug concentrations. All plasma samples were assayed for fenfluramine and in the repeat-dose study for norfenfluramine, by a modification of the procedure of Campbell.3 Statistical analysis o j bioavailability. All statistical analyses were carried out on a Wang 600-14 programmable calculator. Analysis of variance was carried out on two parameters obtained from the plasma concentration time data: (i) the areas under the plasma concentration time curves in the acute study, which are proportional to the extent of absorption of the drug, and (ii) the individual plasma concentrations. The areas under the curve from zero time to infinity were calculated using the trapezoidal rule. These were analyzed statistically by 2-way analysis of variance to yield formulation and subject effects using methods described by Wagner' and by Armitage.' A confidence interval about the formulation means was obtained using methods described by Spriet and Beiler.l3 The individual plasma concentrations were analyzed by a strip plot analysis of variance as described by Westlakc15 in both the acute and repeat dose studies for formulation and subject effects, and time/formulation and time/subject interaction effects. Absorption rate. The percentage of drug absorbed into plasma was calculated, assuming a one-compartment open model, by the method of Wagner and Nelson.' * Dissolution. The dissolution rate of fenfluramine from the capsule formulation was undertaken in a Buhler hot air bath (37f0.5"C) rotating bottle apparatus using 25 rnl bottles. Sampleswere taken at various times over 16 hours and the fenfluramine hydrochloride released into solution was measured using a specific chloride ion electrode (Selectrode Tm Type 1012C1 Radiometer A/S).

Results The comparison of plasma fenfluramine concentrations following acute administration of the two formulations is shown in Figure 1. 162

D. B. Campbell, Y. Hopkins, R. Richards and D. Taylor

Figure 1. Mean fenfluramine plasma concentrations after a single dose (C) of 60 mg fenflununine (1 capsule) and after 3 doses (T) of 20 mg fenfluramhe tablets: mean values for 5 subjects

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n----n 60mg capsule 20mg tablet t.i.d.

C/T T

T Time (hrs)

It can be seen that fenfluramine is slowly released from a single capsule with a mean peak concentration of 42&6 nglml occurring at 1 I hours. For 3 x 20 mg tablets, the typical peaks and troughs of plasma concentrations associated with multiple dosing were observed and the maximum concentration of 40*4 ng/ml was found between 12 to 15 hours. Following this absorption phase, fenfluramine was eliminated at the same rate from the plasma of the volunteers, with biological halflives of 24 hours for both formulations. The availability of the capsule with respect to the tablets was found to be 98 % (range 89 % to 1 10%)as measured by a comparison of infinite areas under the plasma time curve (Table I). Table I. Comparative bioavailability of a single sustained-release capsule (60 mg fenfluramhe) in respect to 3 x 20 mg tablets, as measured by the areas under the fenfluramineplasma time wrve from zero time to infinity (ng/ml.hr)

Subject

Sustained-release capsule

Tablets

DJ MG JD

PF

794 1025 956 I596 1187

871 1156 979 1349 1295

91 89 98 110 92

Mean

1112

I130

98

AS

available

No significant difference was found between mean area values for the two formulations although there was a significant inter-subject variation (Table 11). The 95 % confidence interval for differences between the areas was calculated to be 7 %. The strip plot comparison of the individual blood levels of fenfluramine in the acute study showed no significant effect due to formulation and no significant inter163

Fenfluramine plasma concentrations after administration of a sustained-release capsule formulation and rapid-release tablets

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Table II. Comparison of the 2-way analysis of variance of areas under the fenffuramine plasma time curve for a single sustained-release capsule (60 mg) and 3 x 20 mg tablets Source of variation

Df

F-ratio

F 0.05

Significance

Subject Treatment Residual

4

10.39 0.07

6.39 7.71

p < 0.05 N.S.

1 4

N.S. =not significant

action between time and formulation or time and subject (Table 111). However, there was a significant inter-subject difference (p < 0.05) and, as would be expected for non-steady state conditions, a time difference (p < 0.01) was also found. Table 111. Strip plot analysis of variance of the feduramine plasma concentrations after a single sustained-release capsule (60 mg) and 3 x 20 mg tablets Df

F-ratio

F 0.05

Significance

Mean blood level Formulation Subject

I 4

0.005 27.201

7.71 6.39

N.S.

Profile Time Time/formulation Tirne/subject

9 9 36

14.665 1.471 0.895

2.27 2.27 1.62

p

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