Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects

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1 Br. J. lin. Pharma. (1991), 31, AD NS Lak of enzyme indution with oxarbazepine (6 mg daily) in healthy subjets J. G. LARKN, P. J. W. MKEE, G. FORREST, G. H. BEASTALL1, B. K. PARK2, J.. LOWRE3, P. LLOYD3 & M. J. BRODE Epilepsy Researh Unit, University Department of Mediine and Therapeutis, Western nfirmary, and 'Department of Biohemistry, Royal nfirmary, Glasgow, 2Department of Pharmaology and Therapeutis, University of Liverpool, Liverpool, and 3Ciba-Geigy Pharmaeutials, Horsham, West Sussex 1 Oxarbazepine (OXC), the 1-keto analogue of arbamazepine (CBZ), has similar antionvulsant effiay and possibly improved patient tolerability. Unlike CBZ, it is metabolised by redution and may not indue hepati monooxygenase enzymes. 2 Serum onentrations of OXC and its ative metabolite 1-OH-arbazepine (1-OH- CZ) were followed after a single 3 mg dose and during and after 3 mg OXC twie daily for 29 doses in eight healthy male volunteers. 3 Antipyrine metabolism, urinary 6-,-hydroxyortisol exretion, sex hormone binding globulin (SHBG) levels and irulating androgens were measured as indies of hepati enzyme indution before, during and after treatment with OXC. 4 Elimination half-lives (mean ± s.e. mean) of 1-OH-CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 ± 1.1 h; after 13.9 ± 3 h). Trough plasma onentrations of 1-OH-CZ at steady-state (31 ± 2.2,umol 1-1) were higher than predited ( ,umol 1-1). 5 Antipyrine metabolism, urinary 6-13-hydroxyortisol exretion, SHBG levels and irulating androgens were unaltered by treatment with OXC. 6 OXC (6 mg daily) does not indue hepati monooxygenase enzymes and so is likely and to produe fewer to have more preditable dose-onentration relationships physiologial and pharmaologial interations than CBZ. Keywords oxarbazepine antionvulsant metabolism enzyme indution ntrodution Carbamazepine (CBZ) is an established first-line treatment for generalised toni-loni and partial seizures (Editorial, 1989). Attempts to modify its struture and redue side-effets have produed oxarbazepine (OXC), the 1 keto-analogue of CBZ whih has similar antionvulsant effiay both in animal models of epilepsy (Baltzer & Shmutz, 1978) and in linial pratie (Bulau et al., 1987; Dam et al., 1989; Houtkooper et al., 1987; Reinikainen et al., 1987). Patient studies have suggested improved tolerability with the newer drug inluding a lower inidene of allergi reations (Dam et al., 1989) and less psyhomotor impairment (Bulau et al., 1987; Dam et al., 1989; Houtkooper et al., 1987; Reinikainen et al., 1987). Hyponatraemia, on the other hand, may be as ommon with OXC as with CBZ (Nielson et al., 1988). An important drawbak to the linial use of CBZ is its ability to indue hepati monooxygenase enzymes (Wagner & Shmid, 1987). Chroni dosing shortens its elimination half-life (Eihelbaum et al., 1975; Rapeport et al., 1983) thus reduing steady-state onentrations whih oasionally results in breakthrough seizures (Maphee & Brodie, 1985). The extent of this proess ontributes to the three-fold variation in trough and peak plasma CBZ onentrations in patients reeiving the same daily dose (Maphee et al., 1987). The metabolism of other lipid-soluble drugs inluding antionvulsants an be similarly indued (Baiewiez, 1986) and irulating onentrations of endogenous hormones are also affeted (Connell et al., 1984; Larkin et al., 1989b; Maphee et al., 1988). OXC is immune to oxidative attak (Figure 1) and is Correspondene: Dr Martin J. Brodie, Epilepsy Researh Unit, nfirmary, Glasgow Gll 6NT 65 University Department of Mediine and Therapeutis, Western

2 66 J. G. Larkin et al. N Carbamazepine CarbarT HO OH trans-diol-arbazepine Oxarbazepine 1- OH-Carbazepine Figure 1 Comparison of the metaboli pathways of arbamazepine and oxarbazepine in man rapidly redued to 1-hydroxy-arbazepine (1-OH-CZ). ndeed, it is the antionvulsant properties of this metabolite (Shutz et al., 1986) whih aount for the drug's pharmaologial ations, as OXC itself is only transiently present in the irulation (Kramer et al., 1985; Theisohn & Heimann, 1982). As a onsequene of this variation in metaboli profile, OXC may lak the enzyme-induing properties of CBZ in man (Kramer et al., 1985). This may be the ase despite demonstration of indution with OXC in the rat (Wagner & Shmidt, 1987) as the redution of OXC to 1-OH-CZ does not take plae in this speies (Feldmann et al., 1978). The parent ompound OXC is, therefore, present in higher onentrations for longer, leading to the indution of oxidative pathways. The major metabolite, 1-OH-CZ auses minimal indution in the rat (Wagner & Shmidt, 1987). The present study was designed to investigate enzyme indution with OXC, in partiular its effet on serum onentrations of the ative metabolite, 1-OH-CZ, and its influene on other endogenous and exogenous substanes metabolised by induible pathways and previously shown to be affeted by treatment with equivalent doses of CBZ (Connell et al., 1984; Rapeport et al., 1983). Methods Eight healthy male volunteers (ages years, weight 7-89 kg) took part. None had linial or biohemial evidene of haematologial, hepati or renal disease. Other mediation and alohol were avoided for the duration of the study. Approval was obtained from the Western nfirmary Ethis Committee and all subjets gave written, informed onsent. The study was performed in two stages. Single dose After an overnight fast 3 mg OXC was ingested at 9. h and blood was drawn from an ante-ubital vein, 1, 2, 3, 4, 6, 8, 1, 12, 24, 32,48, 56, 72 and 96 h later for measurement of serum OXC, its major metabolite 1-OH-CZ and a further metaboli produt 1, 11- dihydrotrans-1, 11-dihydroxy-arbamazepine (transdiol). Chroni dosing After a washout period of 7 days, subjets ommened OXC 3 mg at 9. h and 21. h daily for 2 weeks finishing with the 29th dose at 9. h on the 15th day. Blood was drawn for measurement of trough (predosing) serum onentrations of the three hemial moieties before doses 1, 2, 3, 4, 5, 7, 15, 21, 23 and 29. After dose 29, serial blood samples were taken as in the single dose stage. ndution markers Antipyrine kinetis were assessed at least 48 h before the single dose state ('baseline'), on days 8 and 15 of hroni dosing, and 2 weeks after OXC was disontinued ('post-study'). Subjets took 6 mg antipyrine by mouth and supplied 5 ml saliva samples 3, 5, 8, 12, 24 and 32 h later. Urinary exretion of 6-3-hydroxyortisol in a 24 h sample pwas measured at baseline, on days 8 and 15 and post-study as were serum onentrations of testosterone (T), sex hormone binding globulin (SHBG), androstenedione (A) and dehydroepiandrosterone sulphate (DHAS). Free androgen index (FA) was alulated from the expressiont x 1%, Luteinis- SHBG ing hormone (LH) follile stimulating hormone (FSH) and prolatin onentrations were also measured. Assays Blood samples were entrifuged immediately after withdrawal and serum was stored at -2 C for bath analysis. The onentrations of OXC and its metabolites were measured using the h.p.l.. method of Kumps (1984) as we found that antipyrine did not interfere with this assay. The limit of assay was.2,umol 1-1 for OXC, 1-OH-CZ and trans-diol and oeffiients of intraassay variation were 5.4%, 4% and 4.1% at.5, 1 and 1,umol 1-1, respetively.

3 Lak of indution with oxarbazepine 67 Antipyrine onentrations in saliva were measured using h.p.l.. as desribed by Maphee et al. (1984). Serum T, A, DHAS, FSH, LH and prolatin were measured by standard radioimmunoassay (Connell et al., 1984) and SHBG was analysed using a ommerial immunofluorometri assay (DELFA, Pharmaia Ltd). Urinary 6-,-hydroxyortisol was measured by a speifi radioimmunoassay method (Park, 1978). Kinetis and statistis Kineti parameters were obtained by linear regression using the method of least squares. Areas under the onentration-time urve (AUC) were alulated by the linear trapezoidal rule. Trough onentrations during hroni dosing were predited from the single-dose data using superposition (Gibaldi & Perrier, 1982) and ompared with atual values. Non-parametri statistial tests were used beause of small numbers, but means (and s.e. mean) are shown for illustrative purposes. Wiloxon mathed-pair, signed-ranks tests were performed for diret omparisons and Friedman two-way analysis of variane was employed for more than two groups. differ signifiantly on day 15 from baseline values (Figure 4; 95% C hange -2.9 to +5 h). Mean predited trough onentrations from data obtained in the single dose stage and means of atual results are shown in Figure 5. Eah individual subjet had higher measured than predited values at all steadystate time points. Markers of indution Antipyrine half-life (95% C hange, -2.7 to 3.1 h) and learane (95% C hange, -.1 to +.29 ml kg-1 min-') and 6-,3-hydroxyortisol exretion (95% C hange, -151 to + 197,ug 24 h-') were not altered by hroni dosing with OXC (Table 1). The hormone and binding protein levels showed no signifiant hanges during OXC treatment (Table 2) although DHAS and FA both showed a possible 'rebound' inrease post-study. The 95% C for the hanges in hormones and binding Results OXC and metabolites The onentration-time urves for OXC and 1-OH- CZ following a single dose of the parent drug, using the mean of eight results at eah time point, are shown in Figure 2. Conentrations of the trans-diol were generally undetetable. The omparable urves following the 29th dose are given in Figure 3. All subjets demonstrated a higher AUC (-12 h) at steady state (395 ± 59,umol 1-1 h) for 1-OH-CZ than the equivalent AUC (-oo) following the single dose (255 ± 59,umol 1-1 h, P <.5). Elimination half-lives of 1-OH-CZ did not \ E E 22. Figure Time (h) Serum onentration-time urves for oxarbazepine (--*) and its metabolite 1-OH-CZ ( *) following 3 mg oxarbazepine by mouth in eight male subjets (o mean + s.e. mean) O 2 - o E \ E E: 1 _ Oxarbazepine Trans-diol Time (h) Figure 3 Serum onentration-time urves for oxarbazepine (D - -*) and its metabolites 1-OH-CZ (e- *) and the transdiol () following the 29th dose of oxarbazepine 3 mg twie daily by mouth in eight male subjets (o mean + s.e. mean) a)._ o 2r- 16.k 12. f Single 29th dose Figure 4 Elimination half-lives of 1-OH-CZ following a 3 mg single dose of oxarbazepine and after 2 weeks' therapy with 3 mg twie daily in eight male subjets (@ mean + s.e. mean)

4 68 J. G. Larkin et al. E = C.)_ E q) 4r ,>- o----o o-o-- Observed Predited protein between baseline and day 15 were: T (-5.9 to +2.3 nmol l-1), SHBG (-9.6 to +5.6 nmol l-1), A (-4.1 to +4.5 nmol l-1), DHAS (-3.1 to + 1.9,umol [-1), and FA (-14.9 to +1.7%). Table 2 also shows the hanges in FSH (-2.3 to +5.6 u l-1), LH (-1.7 to +3.6 u 1-1) and prolatin (-19 to +44 mu 1-1) after 15 days' OXC therapy. Disussion o The enzyme-induing linial use of properties CBZ is (Editorial, often ompliated 1989). n by the its Dose number present study, its analogue, OXC, appeared to be 5Mean atual and predited pre-dosing (trough) devoid of any auto-induing effets, as Figure S the half-life of serum onentrations of 1-OH-CZ in eight male subjets the ative metabolite remained unhanged after 2 taking oxarbazepine 3 mg twie daily weeks' administration, a time period suffiient for nearmaximum indution by equivalent doses of CBZ (Mikati et al., 1989; Rapeport et al., 1983). The onfidene interval 'exludes' a fall of 26% as opposed to previously Table 1 Antipyrine kinetis and urinary 6-13-hydroxyortisol exretion before, during and after 2 weeks' treatment with oxarbazepine in eight male subjets. Values are mean (s.d.) Baseline Day 8 Day 15 Post-study Antipyrine half-life (h) 1.6 (3.3) 1.3 (3.) 1.4 (1.7) 9.3 (3.) Antipyrine learane (ml kg-' min-1).88 (.2).86 (.2).98 (.15).96 (.23) 6-3-hydroxyortisol (pg 24 h-1) (18) (129) (149) (129) Table 2 Mean (s.d.) irulating hormones, sex hormone binding globulin onentrations and free androgen index before, during and after 2 weeks' treatment with oxarbazepine in eight male subjets Baseline Day 8 Day 15 Post-study Testosterone (nmol -1') (3.8) (2.4) (3.8) (2.4) Sex hormone binding globulin (nmol l-') 24.9 (7.5) 25.4 (9.1) 22.9 (6.6) 22.4 (7.2) Androstenedione ** 7.5# 6.7 (nmol l1) (3.7) (2.8) (4.2) (2.2) Dehydroepiandrosterone sulphate (jxmol l') 8.3 (2.6) 8.1 (2.5) 7.7 (2.) 9.9## (2.3) Free androgen index (%) 58.8 (1.5) 56.1 (16.6) 56.6 (13.) 65.4## (15.3) Luteinising hormone * (u l-l) (2.2) (1.7) (2.7) (2.5) Follile stimulating hormone (u 1-) 3.2 (2.7) 4.2** (3.) 4.6 (4.1) 3.7* (2.7) Prolatin (mu 1-1)' ** ** (28) (41) (28) (64) Friedman's analysis of variane + P <.5 Wiloxon mathed pairs * P <.5 vs baseline, ** P <.1 vs baseline, #P<.O5vsday8, ##P<.5 vs day 15

5 Lak of indution with oxarbazepine 69 demonstrated redutions in CBZ half-life on hroni therapy of 38% (Rapeport et al., 1983) and 4% (Larkin et al., 1989a). The standard markers of ytohrome P45 indution - antipyrine metabolism and 6-,-hydroxyortisol exretion (Park, 1982; Rimmer et al., 1986; Roots et al., 1979) - were also unaffeted by OXC therapy. Confidene intervals were against the likelihood of a redution of 25% in antipyrine half-life [previously shown falls with CBZ - 33% (Connell et al., 1984), 35% (Larkin et al., 1989a)], an inrease of 33% in antipyrine learane [CBZ - 39% (Connell et al., 1984)], and a rise in 6-,B-hydroxyortisol exretion of 79% [CBZ - 178% (Rapeport et al., 1983)]. These differenes are illustrated graphially in Figure 6, whih also ompares hanges in sex hormone and binding protein onentrations. The 95% Cs of these measurements in the present study approximated the magnitude of hanges previously shown with CBZ in SHBG, FA and DHAS (Connell et al., 1984). Thus, there was no evidene of OXC aelerating its own metabolism nor that of any of the other indies of indution. After 2 weeks treatment with OXC, the dosage interval AUC of 1-OH-CZ was signifiantly larger than that to infinity following a single dose and the observed steady-state onentration profile was also higher than predited. Nevertheless, the time to reah steady-state was not affeted, and the AUC ratio of 1-OH-CZ/OXC (where alulable) showed no overall hange after repeated dosing. The elimination half-life of OXC (where alulable) was also unaffeted by repeated dosing, giving support to a lak of auto-indution. The higher than predited steady-state values for 1- OH-CZ require some omment. A reent study has shown a 17% inrease in the systemi availability of 1- OH-CZ when OXC is given after a meal (P. Lloyd, personal ommuniation). n the present study, the single dose and steady-state profiles were determined in fasted subjets and steady-state trough onentrations were most likely monitored under non-fasting onditions. This may aount, at least in part, for the observed inrease in serum onentrations of 1-OH-CZ. Another possible explanation is a putative 'biphasi' elimination half-life for 1-OH-CZ. t has been suggested that the metabolism of OXC is saturable and so the elimination half-life may be prolonged at higher onentrations (Theisohn & Heimann, 1982). This ould explain our findings, although analysis of the individual onentration-time urves showed only two whih might be better fitted by a biphasi model. The issue, therefore, remains unlear. Of the hormones, only serum prolatin onentrations varied signifiantly during the study (Friedman's twoway analysis of variane P <.5). This differene is likely to be due to the use of indwelling annulae for obtaining blood for baseline and day 15 samples, whih were the days when multiple sampling was performed. While none of the other hormones showed a signifiant variation, it would be impreise to ignore the trends for a rebound inrease in A, DHAS and FA after an initial -E 5 a). N 3 m mn 1 5 -r N., ** ) C-)- x- a) _ 5 r 31- o5 q -4 1 /7 /-O // /L /- - x a1) / C 5 a) acd 3 LL - 7n _ - T 9% V+Ei~~ Q1) T 1 *\ \ ** \i 1.5 E 12r 8 E 4 3?- T. 4-4 n 4 m (n 21_ 5th day l 5th day Time 1 5th day Figure 6 Comparison ofthe effets of treatment for 2 weeks with oxarbazepine (@- ) on various markers of enzyme indution with previously shown effets following a omparable dose of arbamazepine (.- -*). (O mean + s.e. mean). * P <.5, ** P <.1. Carbamazepine data taken from Rapeport et al. (1983) and Connell et al. (1984). 1-OH CBZ = 1- hydroxyarbazepine, CBZ = arbamazepine, DHAS = dehydroepiandrosterone sulphate, SHBG = sex hormone binding globulin

6 7 J. G. Larkin et al. small fall - sine they are at variane with our hypothesis of lak of indution with OXC. These trends would be 'statistially signifiant' if diret Mann-Whitney U tests were performed without the initial assessment by analysis of variane. While this may well be an effet of multiple analyses, we have not exluded some slight alteration of endogenous hormone metabolism aused by OXC. Sine redution is the first step in the metabolism of T, A and DHAS (Bentley, 198) it is oneivable that OXC might indue reduing enzymes, although suh an effet is unusual and unlikely (Bahur, 1976). Overall, we found no evidene of any major induing effet of OXC on its own metabolism or those of other endogenous or exogenous markers of oxidation. By neessity, the dose of OXC was low and we annot exlude at this stage a small indution effet in patients reeiving a higher dose of the drug (Patsalos etal., 199). OXC is a ompound with similar antionvulsant effiay to CBZ, but whih appears to have improved patient tolerability both with regard to allergi reations and psyhomotor impairment (Bulau etal., 1987; Dam etal., 1989; Houtkooper etal., 1987; Reinikainen etal., 1987). The latter potential advantage may be due to its lak of an epoxide metabolite, as this plays a major role in the neurotoxi side-effets assoiated with CBZ (Gillham et al., 1988; Patsalos et al., 1985). t is this differene in metabolism whih may also be responsible for the lak of monooxygenase indution with OXC demonstrated in the present study. This may give OXC an advantage over CBZ in patients taking other drugs, partiularly the oral ontraeptive pill. The dosage of onomitant drugs needs to be reappraised if OXC is substituted for CBZ e.g. in patients with an allergi rash, as toxi onentrations of other antionvulsants (Bulau et al., 1987; Houtkooper et al., 1987) ould our. 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