Medifoxamine: Oral Tolerance and Pharmacokinetic Study in Healthy Human Volunteers

Eur J Clin Pharmacol (1990) 39:16%171 E.ropoanJooma,o,

@ Springer-Verlag 1990

Medifoxamine: Oral tolerance and pharmacokinetic study in healthy human volunteers

S. Saleh, A. Johnston, and R Turner Clinical Pharmacology, St. Bartholomew's Hospital, London EC1A 7BE, UK

Received: November 22, 1988/Accepted in revised form: February 27,1990

Summary, Medifoxamine is a monoamine reuptake in- healthy volunteers and to develop a pharmacokinetic hibiting antidepressant drug. We have investigated its profile of the drug that might allow a more rational ap- pharmacokinetics in normal healthy volunteers. After an proach to its clinical evaluation. overnight fast, ascending doses of 200, 500, 750 and 1000 mg of medifoxamine were taken orally. Plasma samples were analysed using a specific HPLC method. Method Medifoxamine was well tolerated and exhibited a first order linear pharmacokinetic profile. It underwent rapid Fourteen healthy volunteers (5 male, aged 20-34 y, weighing 57- absorption and peak plasma concentrations were 78 kg and within 10% of their ideal body weight) consented to par- achieved about 1.0 h after administration. Thereafter the ticipate in the study, which was approved by the Ethics Committee of St. Bartholomew's Hospital. Each subject was screened prior to the elimination profile was biphasic with a mean terminal half start of the study to exclude subjects with history of cardiac, renal, life less than 3 hours. hepatic or other medical dysfunction which could represent a hazard We found a linear relationship (r = 0.80) between ad- to the subject or interfere with the study. ministered dose and AUC values for the four doses. High Volunteers rested supine and a teflon cannula was inserted into values were obtained for the apparent volumes of dis- the antecubital vein of one forearm and maintained patent with tribution and the plasma clearance. saline. After an overnight fast, ascending doses of 200,500, 750 and 1000 mg of medifoxamine were taken in the form of 2 capsules with 200 ml of water. Doses were administered to subjects in groups of Key words: antidepressant, medifoxamine; tolerance, three, no subject receiving more than 2 doses and each dose at least pharmacokinetics healthy volunteers one week apart. The fast was continued for 3 h after dosing. Each higher dose was given only after we had determined that the previous dose was well tolerated both clinically and by laboratory Medifoxamine is a monoamine reuptake inhibiting anti- tests. Blood pressure, heart rate and ECG were recorded immedi- ately before and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 and 6 h depressant drug which is marketed in France for treat- after administration. Subjects were asked to complete a visual anal- ment of depression in a tablet dosage form (150-300 mg ogue scale (VAS) for drowsiness, nausea and dryness of mouth. daily) after undergoing clinical investigation [1, 2 and They were also asked to answer a side-effects questionnaire to re- Bonnet J. et al.; 1984, unpublished data]. Single oral doses port any unusual effects after the administration. Routine labora- of 50 and 100 mg have been compared with amitriptyline tory blood tests were repeated two days after each administration. and atropine and have been found to be free of sedation Blood samples (10 ml each) were drawn at 0 (predrug), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 and 6 h after dosing. The samples and anticholinergic effects and to be well tolerated [3]. Al- were analysed for the drug using a specific high performance liquid though medifoxamine has been in clinical use, its disposi- chromatography (HPLC) method. Standard pharmacokinetic par- tion has not been previously studied in man. We have de- ameters were calculated by standard techniques using the STRIPE veloped a high pressure liquid chromatography method to computer program [5]. measure medifoxamine in plasma [4] and have investi- gated its pharmacokinetics in normal healthy volunteers given single oral doses. Doses of 50 and 100 mg orally do Results not produce plasma levels which can be measured accur- ately. It was therefore necessary to carry out a tolerance Medifoxamine was generally well tolerated in all subjects study with larger doses of the drug before attempting to at the 200 and 500 mg doses. Two subjects who com- investigate its pharmacokinetics after oral administration. plained of nausea following 500 and 1000 mg doses, and The present investigation was undertaken to evaluate the vomited 3 h after administration were excluded from fur- safety of single ascending oral doses of medifoxamine in ther study. One subject also had a mild dry mouth after 170 S. Saleh et al.: Medifoxamine kinetics 10000 Medifoxamine was rapidly absorbed with a maximum X 200mg [] 500mg peak plasma concentration achieved at 0.93 h (Range [] 750 mg "A" 1000mg 0.59-1.29h), individual peak plasma concentrations f (Cmax) being directly proportional to the dose given. There was marked variation in two subjects, one giving high plas-

o= ma levels, high AUC and a low clearance value following re 1000 the 750 mg dose. The other subject had non detectable

g plasma levels following 750 mg and low plasma levels fol- ~J lowing 1000 mg with a high clearance value and low AUC. o g Individual values for the AUC were directly proportional E n~ to the dose given. This results suggest that medifoxamine does not demonstrate dose dependent kinetics over the g

E dose range studied. re lOO o~

Discussion

This study was established that medifoxamine is well tol- erated by normal healthy volunteers when given as single 10 doses up to and including 1000 mg orally. Reported side 0 1 2 3 4 5 6 7 effects were mild with drowsiness the most common side Time (h) tag/[ effect. Its clinically useful dose for the treatment of de- Fig.1. Examples of plasma concentration-time curves obtained pression is 150-300 mg daily orally, in which it appears to from four subjects who received oral medifoxamine have similar efficacy to clomipramine and maprotiline in controlled double blind trials [2, 6]. A high margin of safety exists, therefore, in the light of this present toler- treatment with the 750 mg dose. There were no changes in ance study. Our results suggested that the kinetics of medi- mean supine and erect heart rate, systolic and diastolic foxamine given orally are adequately described by a two- blood pressure following 200, 500, 750 or 1000 mg single compartment model. The drug underwent rapid oral dose of medifoxamine. The visual analogue scales absorption and peak plasma concentrations were (VAS) for drowsiness, nausea and dryness of mouth were achieved about 1.0 h after administration. Thereafter the not changed when compared with base line. In the ques- elimination profile was biphasic with a mean terminal half tionnaire, drowsiness was reported as the most prominent life (tlJ2) of 1.7 h (Range 0.9-4.1 h). We found a linear rela- side effect. When drowsiness occured, it began i h after tionship (r = 0.80) between administered dose and AUC drug administration and persisted for up to 2 h. In all cases values for the four doses even though different subjects it was mild, and could be easily overcome by activity. All were used at each dose level. Almost identical half lives biochemical and haematological data for the subjects were observed following these oral doses, indicating simi- after each treatment were within the normal ranges of the lar rates of elimination. High values were obtained for the laboratory. apparent volumes of distribution. Plasma clearance Plasma concentrations of medifoxamine after the four values were apparently greater than liver plasma flow doses were detected in all subjects. The disposition of which suggests a low bioavilability due to high first pass medifoxamine exhibited a biphasic decline in plasma con- metabolism. This is consistent with pharmacokinetic data centration (Fig. 1). Mean pharmacokinetic parameters in animals showing that the absolute bioavilability of C-14 are listed in Table 1. After the lowest dose (200 mg), the labelled medifoxamine after oral doses was only 0.25, 0.16 complete plasma concentration-time curve could not be and 0.35 in the rat, dog and pig respectively [Labaune J. P. well defined because the plasma concentrations of the ter- et al., 1984, unpublished data]. The clearance of medifox- minal phase were below the limit of assay sensitivity. amine, was highly variable for two subjects within this

Table 1. The means of pharmacokinetic parameters following200, 500,750 and 1000 mg orally. Mean and (SEM) Kinetic parameters Doses 200 mg 500 mg 750 mg 1000 mg Lag time(h) 0.36 (0.05) 0.43 (0.04) 0.50 (0.04) 0.34 (0.08) Abs. tlz2(h) 0.15 (0.07) 0.17 (0.02) 0.17 (0.03) 0.25 (0.02) El. tla(1)(h) 0.64 (0.19) 0.33 (0.12) 0.48 (0.10) El. tla(z) (h) 0.90 (0.27) 1.80 (0.17) 1.33 (0.20) 2.15 (0.64) AUC(gg.I-I.h) 264 (88) 1679 (108) 2690 (752) 3789 (742) CL (ml.min -I) 5137 (3800) 5065 (320) 5706 (1313) 5103 (1257) V(1) 995 (33) 773 (58) 649 (190) 1129 (634) Cm~x(btg'l 1) 226 (100) 793 (81) 1540 (485) 1412 (299) tm~(h) 0.47 (0.48) 0.49 (0.06) 1.06 (0.14) 1.01 (0.08) s. Saleh et al.: Medifoxamine kinetics 171 group, indicating the need for a study in a larger group of Paupry M, Saustre M (1986) Etude clinique en double avengle subjects. comparant l'activite de Cledial et de la maprotiline dans les etats depressifs. Psychol Med 18:2295-2302 In conclusion, medifoxamine is well tolerated orally 3. Randhawa A, Hedges A, Johnston A, Turner P (1988) A Psycho- and exhibits a linear pharmacokinetic profile with pharmacological Study to Assess Anti-Muscarinic and Central biphasic decline. There were no significant dose related Nervous Effects of Medifoxamine in Normal Volunteers. Hum effects in either absorption half lives, elimination half Psychopharmacol 3:195-200 lives, clearances, lag time or volumes of distribution. Area 4. Saleh S, Johnston A, Chanon M, Turner P (1989) The analysis of under the plasma concentration-time curve and maximum medifoxamine in plasma and urine by high performance liquid chromatography. J Chromatogr 496:223-227 plasma concentrations were linearly correlated with the 5. Johnston A, Woollard RC (1983) STRIPE: An interactive com- dose. These results suggestet that medifoxamine does not puter program for the analysis of drug pharmacokinetics. J Phar- have dose-dependent kinetics over the dose range stu- macol Methods 9:193-199 died. 6. Scharbach H, Blanchard CH, Grivel A, Houri Z, Lachaud JD (1986) Double blind trial comparing medifoxamine versus clomi- Acknowledgement. S.S. is sponsered by A1-Fatah University, Tripo- pramine in neurotic reactive depression. Psychol Med 18: 1485- li, Libya. We thank Laboratoires Anphar-Rolland for supplying 1493 medifoxamine.

Dr. R Turner References Department of Clinical Pharmacology St. Bartholomew's Hospital 1. Poirier JL, Viellefond H (1986) Effects of Cledial on psychomotor Medical College performance. Psychol Med 18:1925-1930 University of London, West Smithfield 2. Leger JM, Malauzat D, Karczewski R Pareaud M, Parmentier G, London ECIA 7BE, UK