Pharmacokinetics, safety, and tolerability of the new antiepileptic carisbamate in the elderly

Epilepsy Research (2008) 79, 22—30

journal homepage: www.elsevier.com/locate/epilepsyres

Pharmacokinetics, safety, and tolerability of the new antiepileptic carisbamate in the elderly Rene Levy a,∗, Isabelle Ragueneau-Majlessi a, Bhavna Solanki b, Peter Zannikos c, Caiping Yao c, Gerald Novak c a

Department of Pharmaceutics, University of Washington, H-272, Health Science Building, Box 357610, Seattle, WA 98195-7610, USA b Johnson & Johnson PRD, LLC, 1000 Route 202 South, Raritan, NJ 08869, USA c Johnson & Johnson PRD, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, USA Received 17 September 2007; received in revised form 10 December 2007; accepted 23 December 2007 Available online 14 February 2008

KEYWORDS Carisbamate (RWJ-333369); Pharmacokinetics; Epilepsy; Elderly

Summary Purpose: To evaluate the effect of age on the disposition of two different oral formulations of carisbamate (RWJ-333369), a novel neuromodulator under investigation. Methods: The disposition of carisbamate was studied in eight men and eight women in each of the three age groups: 18—55, 65—74, and ≥75 years (N = 48). Subjects received single (100 mg immediate-release [IR] tablets or 250 mg controlled-release [CR] tablets) or repeated administration (up to 500 mg IR BID or 1250 mg CR QD) of carisbamate in a randomized, double-blind, placebo-controlled, parallel-group, single-center study. Results: After either single or repeated IR administration, no apparent differences were observed between the two elderly and the non-elderly groups. Following single-dose CR administration, the two elderly age groups had higher exposure compared with non-elderly subjects, but the difference decreased for all doses tested after repeated administration. There was no effect of age on plasma protein binding of carisbamate. Renal clearance decreased with age for both formulations, but this decrease had no effect on the total clearance of the drug because of its limited renal elimination. Conclusion: Age had no effect on pharmacokinetics of carisbamate IR formulation. The small effect observed after single-dose CR carisbamate diminished after repeated dosing. The drug was generally safe and well tolerated. © 2008 Published by Elsevier B.V.

∗

Corresponding author. Tel.: +1 206 685 8319; fax: +1 206 543 3204. E-mail addresses: [email protected] (R. Levy), [email protected] (I. Ragueneau-Majlessi), [email protected] (B. Solanki), [email protected] (P. Zannikos), caiping [email protected] (C. Yao), [email protected] (G. Novak). 0920-1211/$ — see front matter © 2008 Published by Elsevier B.V. doi:10.1016/j.eplepsyres.2007.12.013

Antiepileptic carisbamate in the elderly groups

Introduction The elderly are a substantial and rapidly increasing proportion of the population. Approximately one third of patients with newly diagnosed epilepsy are older than 60 years, and one half of all adult patients with known epilepsy are beyond the age of 60 (Trinka, 2003). Clinical management of epilepsy in the elderly is often challenging due to an increase in the likelihood of adverse treatment events and a higher prevalence of concomitant diseases requiring nonanticonvulsant comedications that can cause significant drug interactions. Alterations in drug disposition that occur with aging have been widely recognized for drugs from several therapeutic classes (Kinirons and O’Mahony, 2004), including antiepileptic drugs (AEDs). For example, a recent population pharmacokinetic study showed statistically significant differences in carbamazepine pharmacokinetics between elderly and relatively young epileptic patients (Bondareva et al., 2006). For new-generation AEDs, a review of the available evidence (Perucca, 2006) indicates that the apparent oral clearance is almost invariably reduced in the elderly (on average by 10—50%). Carisbamate, or RWJ-333369 (S-2-O-carbamoyl-1-ochlorophenyl-ethanol), is a novel neuromodulator under investigation for the adjunctive treatment of epilepsy. The efficacy, safety, and tolerability of carisbamate as adjunctive treatment in partial-onset seizures were examined in two randomized, controlled phase II studies (Bialer et al., 2007); pivotal phase III studies are under way. The drug is extensively metabolized (<2% of dose excreted unchanged in urine), has a low oral clearance (CL/F ∼4 l/h), and has a good oral bioavailability (∼94%) (Yao et al., 2006). Its half-life (t1/2 ) is in the range of 10.6—12.8 h. The primary routes of metabolism include O-glucuronidation, accounting for 44% of the dose, and carbamate ester hydrolysis, accounting for 36% of the dose, with subsequent oxidation of the aliphatic side chain (Mannens et al., 2007). Minor routes include chiral inversion to the R-enantiomer followed by O-glucuronidation (11% of the dose) and hydroxylation of the aromatic ring followed by sulfation (5% of the dose) (Mannens et al., 2007). With the use of very sensitive liquid chromatography-tandem mass spectroscopy (LC—MS/MS) techniques, only traces of aromatic (pre) mercapturic acid conjugates were detected in urine (each <0.3% of the dose), suggesting a low potential for reactive metabolite formation. Following single and repetitive (q12h) doses (100—750 mg), carisbamate exhibited linear pharmacokinetics, and food did not alter pharmacokinetics to a clinically relevant extent (Yao et al., 2006). Carisbamate clearance is increased by carbamazepine (Chien et al., 2006) and to a lesser extent by oral contraceptives (Novak et al., 2007), consistent with induction of glucuronidation. Carisbamate slightly increases the clearance of valproic acid and lamotrigine (Chien et al., 2007), but conversely, the two drugs had no effect on carisbamate pharmacokinetics. Even though glucuronidation is considered to be less affected by aging compared with P450-mediated drug oxidation (Liston et al., 2001; Perucca, 2006), formal pharmacokinetic studies with two glucuronidated substrates, lamotrigine (Posner et al., 1991) and the active monohydroxy derivative of oxcarbazepine (Van Heiningen et al., 1991), have demonstrated that on average, CL/F values are

23 reduced by about one-third in elderly patients relative to non-elderly adults. The present study was designed to determine whether carisbamate displays clinically significant differences between non-elderly and elderly individuals in pharmacokinetics, safety, or tolerability. The effect of age was evaluated using two different oral formulations, an immediate-release (IR) formulation and a controlled-release (CR) formulation that uses an osmotic controlled-release oral delivery system (OROS® ) technology. As modifications in drug absorption have been described in the elderly (Gidal, 2006), it became relevant to evaluate the effect of age on the new CR formulation of carisbamate.

Materials and methods Study population The study was performed in accordance with the Declaration of Helsinki and its amendments and in compliance with the guidelines of Good Clinical Practice. The study protocol and informed consent form were approved by an Institutional Review Board before recruitment of any subjects. Written informed consent was obtained from each subject prior to participation in the study. International Conference on Harmonization (ICH) guidelines (ICH E7, 1994) define the age range of the geriatric population as 65 years and above, and the inclusion of subjects 75 years and older is recommended. A total of 48 subjects were to be enrolled: 16 elderly subjects aged 65—74 years (eight men and eight women), 16 elderly subjects aged ≥75 years (eight men and eight women), and 16 non-elderly healthy adults aged 18—55 years (eight men and eight women), who served as a control group. Eligibility was determined on the basis of medical history, physical examination, body mass index (BMI), clinical laboratory test results, 12-lead electrocardiogram (ECG) findings, and review of inclusion/exclusion criteria. Elderly subjects had to be considered healthy for their age and were excluded if they had any degree of hepatic impairment or a severe renal dysfunction (defined as a serum creatinine clearance below 30 ml/min). Subjects with certain chronic conditions could be included, as long as they were under stable medical control. In the control group of non-elderly subjects, female subjects of childbearing potential had to use an acceptable non-hormonal method of birth control before study entry and throughout the study and had to have a negative serum pregnancy test (beta human chorionic gonadotropin [␤-hCG]) at screening and a negative urine ␤-hCG test within 24 h of the first dose on day 1. Smoking was not allowed in all groups.

Study protocol and clinical procedures This was a randomized, double-blind, placebo-controlled, parallelgroup, single-center study. Subjects were randomized and stratified so that 24 subjects received the IR formulation or matching placebo and 24 subjects received the CR formulation or matching placebo (both CR and IR formulation were tablets). In each age group, subjects were randomly assigned to carisbamate or placebo and randomly assigned to the IR or CR groups. Within each age group and formulation group, three men and three women were to receive carisbamate, and one man and one woman were to receive placebo (i.e. a 3:1 ratio). Because the two formulations (and their respective placebos) differed in appearance, no blinding occurred between the two treatment formulations, but there was double-blinding between active drug and placebo within each formulation group. Subjects received a single dose of carisbamate (100 mg IR or 250 mg CR) or matching placebo on day 1. Starting on day 5, placebo or increasing doses of carisbamate were administered to subjects in both formulation treatment groups. Subjects in the IR treatment

24 group (hereafter referred to as the IR group) received placebo or doses of 100 mg, increasing to 500 mg IR every 12 h (q12h), and subjects in the CR treatment group (CR group) received placebo or doses of 250 mg, increasing to 1250 mg CR every 24 h (q24h). Within each treatment group, each escalating dose level was to be administered for 6 days. The total study duration was approximately 6—7 weeks, consisting of a 3-week screening phase, a double-blind treatment phase of 3 weeks (IR group) or 4 weeks (CR group), and a post treatment assessment on the day after the last morning dose. Subjects who could not tolerate the third dose level (500 mg IR q12h, 1000 mg CR q24h) could have the dosage reduced once only. To ensure that subjects who received a dosage reduction attained steady state by the time of the steady-state pharmacokinetics evaluation, these subjects received the reduced dosage for at least 3 days. Subjects were confined to the study unit from the morning of day 1 until the morning of day 23 (IR group) or day 29 (CR group). Subjects had to take their study medications orally at the same time of day each morning and evening at 12-h intervals for the IR group and in the morning at 24-h intervals for the CR group. Study drug was taken with 240 ml (eight oz) of water, with or without food. However, on days 1, 10, 16, and 22 for all subjects and on day 28 for subjects in the CR group (and if necessary on additional days for those subjects who reduced their dosage), when frequent blood samples were collected for pharmacokinetic evaluations, subjects were required to fast for 2 h before and 2 h after study drug administration. No liquids, including water (other than that taken with the study drug), were permitted during that period. Standardized meals were provided for all subjects throughout their stay at the study site. High-fat, high-calorie, aged, and fermented foods were to be avoided during the treatment phase. Foods containing methylxanthine (e.g. caffeine, cola, chocolate) were not to be consumed at any time during the treatment phase. For both IR and CR formulations, the pharmacokinetics of carisbamate were evaluated following the first dose and at steady state. Following the first dose on day 1, blood samples (2 ml each) were collected for 96 h, immediately before dosing and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 24, 48, 72, and 96 h after dosing. At steady state, samples were collected for 12 h in the IR group (before dosing and 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after dosing) or for 24 h in the CR group (before dosing and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, and 24 h after dosing), beginning with the last dose on days 10, 16, and 22 for all subjects and also on day 28 for subjects in the CR group. Urine samples were collected from 0 through 12 h following the morning dose on days 10, 16, and 22 in the IR group and from 0 through 24 h following the morning dose on days 10, 16, 22, and 28 in the CR group.

Safety and compliance Safety evaluations consisted of vital sign measurements, clinical laboratory testing, 12-lead ECGs, physical examinations, and monitoring of adverse events. The study medication was administered under the direct supervision of the investigator or designated staff member. The time of administration and number of tablets administered were recorded in the case report form. For the elderly subjects who were under stable medical treatment, concomitant medications were recorded at baseline and throughout the study.

Analytical procedures Unchanged carisbamate in plasma and urine Plasma samples were analyzed for carisbamate concentrations by using a validated LC—MS/MS method (Mannens et al., 2007). Briefly, 100-␮l aliquots of plasma were spiked with 200 ng of the stable isotope-labeled internal standard (containing 2 13 C and 2 2 H isotope labels carisbamate), and 100 ␮l of methanol was added. The

R. Levy et al. samples were buffered by adding 1 ml of a 0.1 M phosphate buffer (pH 7) and extracted with 3 ml of methyl-tert-butyl ether. The organic solvent was transferred and evaporated under nitrogen at 65 ◦ C and the residue dissolved in 500 ␮l of injection solvent (0.01 M ammonium acetate/methanol; 70/30). Forty-microliter aliquots of these extracts were analyzed by LC—MS/MS. Chromatography was on a 5 cm × 4.6 mm I.D. Hypersil BDS C18 (5 ␮m) column (Alltech Assoc., Columbia, Maryland, USA) with an isocratic mobile phase (0.01 M ammonium acetate/methanol; 55/45). One hundred microliters per min of the column effluent was directed to an API3000 triple quadrupole mass spectrometer (Applied Biosystems, Foster City, California, USA), with a turbo ionspray source running at 350 ◦ C, operated in the positive ion mode (ionspray voltage, 4500 V). The analyte and its internal standard were monitored at transitions m/z 216.0 → 155.0 and m/z 220.0 → 159.0, respectively. The validated calibration range was 0.1—50 ␮g/ml, and the lower limit of quantitation (LLOQ) was 0.1 ␮g/ml. The performance of the method during the analysis of the study samples was monitored by analyzing independently prepared quality-control samples at three concentrations in duplicate along with the study samples. Urine concentrations of carisbamate were determined by a validated LC—MS/MS method with a range of quantitation of 0.1—50 ␮g/ml and the LLOQ was 0.1 ␮g/ml. Sample preparation and analysis was similar to the method used for plasma. Carisbamate glucuronides in urine Two glucuronide metabolites, R289876 (glucuronide of RWJ-333369) and R382574 (glucuronide of the R-enantiomer of RWJ-333369), were quantitated in urine. The analytical procedure was: 100␮l aliquots of urine were mixed with 1 ml of ammonium acetate and transferred to an injection vial. Of these solutions, 10-␮l aliquots were analyzed by LC—MS/MS. Chromatography was on a 5 cm × 4.6 mm I.D. Symmetry Shield RP18 (3.5 ␮m) column (Waters, Millford, Pennsylvania, USA). Elution was with an isocratic mobile phase (0.01 M ammonium acetate/methanol; 85/15) at a flow rate of 1.5 ml/min during the first 5 min, followed by an increase of the methanolic content of the mobile phase to 90% during the next 1.5 min to wash late-eluting compounds off the column. One hundred microliters/min of the column effluent was directed to an API3000 triple quadrupole mass spectrometer (Applied Biosystems), with a turbo ionspray source running at 350 ◦ C, operated in the negative ion mode (ionspray voltage, 3500 V). Both analytes 347.0. The range of were monitored at transitions m/z 390.0 quantitation was 1.00—2000 ␮g/ml, and the LLOQ was 1.00 ␮g/ml.

Pharmacokinetic and statistical analysis Pharmacokinetic parameters Pharmacokinetic analysis was conducted using a noncompartmental method based on statistical moment theory (Gibaldi and Perrier, 1982; Rowland and Tozer, 1995; Yamaoka et al., 1978). For each subject, the following parameters were estimated for carisbamate following morning doses: • Cmax , maximum observed plasma concentration following the morning doses; • Cavg , average plasma concentration over a dose interval, calculated as AUC /, where  is the time (in hours) of dosing interval; • Ctrough , plasma concentration at the end of dosing interval; • tmax , time of maximum observed plasma concentration following the morning dose; • t1/2 , apparent terminal half-life, computed as (ln 2)/ke; apparent rate constant (ke) computed as the magnitude of the terminal log-linear phase of the plasma concentration-time curve (single dose/day 1 only); • AUC* , area under the plasma concentration-time curve using linear trapezoidal summation:

Antiepileptic carisbamate in the elderly groups

• • • •

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◦ AUC∞ from time 0 extrapolated to infinity following the single dose on day 1; ◦ AUC12 from time 0—12 h following the morning dose on days 10, 16, and 22 of the IR q12h dosing; ◦ AUC24 from time 0—24 h following the morning dose on days 10, 16, 22, and 28 of the CR q24h dosing. CL/F, oral clearance calculated as dose/AUC∞ for day 1 and as dose/AUC for days 10, 16, 22, and 28; Vd /F, volume of distribution calculated as CL/F/ke (single dose/day 1 only); Ae%, amount excreted in urine, expressed as percent of dose; Dose-normalized AUC ratio, steady-state AUC collected on days 10, 16, 22, and 28 versus single-dose AUC∞ collected on day 1, normalized by dose.

Statistical methods Pharmacokinetics. Statistical analysis was performed separately for each formulation and separately for single-dose and multipledose steady-state data. Steady-state achievement was evaluated by visual inspection of the Ctrough values. An analysis of variance (ANOVA) was performed on log-transformed dose-normalized Cmax and/or AUC as the dependent variable and age group and sex as fixed effects, and the 90% confidence intervals (CIs) for the ratio of means were calculated. Statistical significance was assigned at a p-value of <0.05. The pharmacokinetic parameters were compared between the IR and CR formulations using descriptive statistics. Safety. Treatment-emergent adverse events were summarized by body system and preferred terms, severity, and relationship to study drug. Descriptive statistics and changes from baseline were used to summarize clinical laboratory data and vital signs. Physical examination and body weight data were listed.

Results Disposition of subjects Forty-seven of the 48 subjects who were enrolled in the study completed the study and were considered evaluable for pharmacokinetic evaluations. One elderly (≥75 years age group) female subject in the IR group withdrew consent (not treatment-related) and was discontinued from the study after receiving the morning dose on day 21. All 48 subjects were considered evaluable for safety. All subjects achieved the highest scheduled dose, and there were no dose reductions for any subjects. The demographic and baseline characteristics for all subjects are summarized by treatment group and age group in Table 1.

Fig. 1 Mean plasma carisbamate concentration-time profiles following oral administration of single-dose (SD) 100 mg immediate-release (IR) formulation (upper panel) and SD 250 mg controlled-release (CR) formulation (lower panel).

al., 2006). There was no statistically significant difference (p ≥ 0.05) for any of the age-group pairwise comparisons for AUC∞ and Cmax . After single dose of the CR formulation, the time to reach the Cmax of carisbamate was approximately 20—24 h (Fig. 1), illustrating the CR properties of the formulation. Cmax values after adjustment for dose and body weight were 45.3—65.0% lower than those observed after administration of the IR formulation. Cmax and AUC values tended to increase with age: Cmax and AUC values for the two elderly age groups were 17% and 25% (65—74 years and ≥75 years, respectively, for Cmax ) and 24% and 40% (65—74 years and ≥75 years, respectively, for AUC) higher than those obtained for the young age group based on geometric means (Table 2). Similarly, CL/F and Vd /F decreased in the elderly age groups in comparison with the younger age group. The elimination t1/2 was approximately 12—14 h across all age groups. After pairwise comparison, AUC∞ and Cmax values were significantly different (p < 0.05) between the ≥75 years and the 18- to 55-year-old age group, and the 90% CIs for the ratios of geometric means for AUC∞ and Cmax fell outside of 80—125% of the bioequivalence range for all age-group comparisons.

Pharmacokinetics Single-dose pharmacokinetics Mean values of carisbamate plasma concentration-time curves following single oral administration of the 100 mg IR formulation and the 250 mg CR formulation are illustrated in Fig. 1 for each age group. For the IR formulation, the disposition of carisbamate was similar across all age groups, with rapid absorption reaching maximum concentrations within 1—2 h post dose (mean tmax 1.00—1.77 h). The other mean pharmacokinetic parameters ranged as follows among the three age groups: CL/F 2.40—2.58 l/h, Vd /F 41.7—47.5 l, AUC∞ 39.7—44.1 ␮g h/ml, Cmax 2.32—2.61 ␮g/ml, and t1/2 12.4—13.3 h. These findings are consistent with results from previous clinical studies in young healthy subjects (Yao et

Multiple-dose pharmacokinetics After administration of the IR formulation, steady state appeared to have been reached in all age groups within 4 days after dose escalation. Mean (S.D.) pharmacokinetic parameters are presented in Table 3. As shown in Fig. 2, the disposition of carisbamate was similar among the three age groups. No statistically significant differences were observed for any of the age-group pairwise comparisons for steady-state AUC12 and Cmax values. All carisbamate pharmacokinetic parameters were similar to those obtained previously in a population of young (18—40 years) healthy men (Yao et al., 2006) and confirmed the known linearity of carisbamate pharmacokinetics in the dose range of 100—750 mg BID.

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Table 1

Demographic characteristics by treatment group and age group (means ± S.D.)

Immediate-release (IR) formulation

Placebo IR

Carisbamate IR

Non-elderly subjects

Elderly subjects

18—55 years

65—74 years

N (male/female) Age (y) Weight (kg) Height (cm) BMI (kg/m2 )

2 (1/1) 39; 41 76; 80 163; 173 27; 29

2 (1/1) 68; 72 57; 65 150; 165 24; 26

Controlled-release (CR) formulation

Placebo CR

N (male/female) Age (y) Body weight (kg) Height (cm) BMI (kg/m2 )

Non-elderly subjects

Elderly subjects

≥75 years

18—55 years

65—74 years

≥75 years

2 (1/1) 78; 78 56; 79 152; 163 24; 30

6 (3/3) 47.0 ± 4.05 70.3 ± 8.04 162.7 ± 8.87 26.5 ± 2.29

6 (3/3) 70.7 ± 2.94 67.3 ± 7.15 160.7 ± 7.74 26.4 ± 4.63

6 (3/3) 77.5 ± 1.87 62.8 ± 8.54 159.3 ± 6.83 24.6 ± 2.00

Carisbamate CR

Non-elderly subjects

Elderly subjects

18—55 years

65—74 years

2 (1/1) 33; 46 64; 76 165; 168 23; 28

2 (1/1) 65; 74 54; 80 155; 163 22; 30

Non-elderly subjects

Elderly subjects

≥75 years

18—55 years

65—74 years

≥75 years

2 (1/1) 76; 77 63; 81 147; 170 28; 29

6 (3/3) 41.8 ± 14.77 63.3 ± 3.98 159.8 ± 9.56 25.0 ± 2.89

6 (3/3) 67.8 ± 1.83 79.5 ± 8.53 163.3 ± 8.14 29.7 ± 2.57

6 (3/3) 78.7 ± 3.33 78.0 ± 10.83 162.7 ± 6.38 29.4 ± 3.06

BMI, body mass index.

R. Levy et al.

Antiepileptic carisbamate in the elderly groups Table 2

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Carisbamate pharmacokinetic parameters following single oral dose of 250 mg controlled-release (means ± S.D.)

(n = 6 per age group)

tmax a (h) Cmax (␮g/ml) AUC24 (␮g h/ml) AUC∞ (␮g h/ml) t1/2 (h)

Non-elderly subjects

Elderly subjects

18—55 years

65—74 years

≥75 years

20.00 2.29 ± 0.421 36.7 ± 7.44 78.5 ± 22.3 12.3 ± 2.7

20.00 2.66 ± 0.426 41.2 ± 6.56 95.4 ± 19.4 13.6 ± 2.8

24.00 2.87 ± 0.565 43.1 ± 7.25 108 ± 20.7 13.8 ± 2.2

tmax , time of maximum observed plasma concentration; Cmax , maximum observed plasma concentration; AUC, area under the plasma-concentration time cure; t1/2 , apparent terminal half-life. a Median.

Fig. 2 Mean plasma carisbamate concentration-time profiles following oral administration of multiple doses of 100 mg q12h, 250 mg q12h, and 500 mg q12h immediate-release formulation.

Mean steady-state plasma carisbamate concentrationtime profiles following multiple doses of the CR formulation are presented based on age groups in Fig. 3. These profiles were almost flat for all subjects at steady state. Mean (S.D.) pharmacokinetic parameters are presented in Table 4. There were no statistically significant differences in steady-state AUC24 and Cmax values for any of the age-group pairwise comparisons. However, the 90% CIs for the ratios of the geometric means of the AUC24 fell slightly outside of 80—125% of the bioequivalence range in several instances: (1) for all age-group comparisons for the 250 and 1250 mg q24h dose levels and (2) for the ≥75 years versus 18—55 years and the ≥75 years versus 65—74 years age-group comparisons for the 1000-mg dose level. Similarly, the 90% CIs for the ratios of geometric means of Cmax fell slightly outside of 80—125% of the bioequivalence range for all age-group comparisons for

Table 3 Carisbamate pharmacokinetic parameters following repeated oral administration of immediate-release formulation 100 mg q12h, 250 mg q12h, and 500 mg q12h (means ± S.D.) Non-elderly subjects

Elderly subjects

18—55 years

65—74 years

≥75 years

Day 10: 100 mg q12h (n = 6 per age group) tmax a (h) 2.00 Cmax (␮g/ml) 4.69 ± 0.840 AUC12 (␮g h/ml) 40.0 ± 4.89 CL/F (l/h) 2.53 ± 0.322 CLr (l/h) 0.0946 ± 0.0431

1.50 4.81 ± 1.04 39.9 ± 7.55 2.60 ± 0.637 0.106 ± 0.0545

1.50 5.33 ± 1.06 45.1 ± 10.1 2.32 ± 0.586 0.0704 ± 0.0150

Day 16: 250 mg q12h (n = 6 per age group) tmax a (h) 1.50 Cmax (␮g/ml) 12.1 ± 0.654 AUC12 (␮g h/ml) 104 ± 10.6 CL/F (l/h) 2.43 ± 0.247 CLr (l/h) 0.0912 ± 0.0312

2.00 11.7 ± 1.53 104 ± 14.6 2.46 ± 0.405 0.0693 ± 0.0254

2.00 12.5 ± 2.30 112 ± 24.0 2.34 ± 0.611 0.0609 ± 0.0265

Day 22: 500 mg q12h (n = 6 per age group) tmax a (h) 1.00 Cmax (␮g/ml) 22.9 ± 3.07 AUC12 (␮g h/ml) 198 ± 26.2 CL/F (l/h) 2.57 ± 0.338 CLr (l/h) 0.0765 ± 0.0282

1.75 22.9 ± 2.74 199 ± 27.2 2.56 ± 0.394 0.0620 ± 0.0122

4.00 24.8 ± 4.51 216 ± 29.4 2.35 ± 0.348 0.0610 ± 0.0222

tmax , time of maximum observed plasma concentration; Cmax , maximum observed plasma concentration; AUC, area under the plasma-concentration time cure; CL/F, oral clearance; CLr, renal clearance. a Median.

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R. Levy et al. years age-group comparisons for the 500-mg dose level. Mean CL/F values (Table 4) appeared similar in the four dose groups, showing linearity of carisbamate pharmacokinetics with the CR formulation. Plasma carisbamate protein binding The mean percent free carisbamate was similar across all age groups, ranging from 56.8% to 59.8%. Therefore, pharmacokinetic parameters based on the free fraction were not estimated or compared across age groups.

Fig. 3 Mean plasma carisbamate concentration-time profiles following oral administration of multiple doses of 250, 500, 1000, and 1250 mg once-daily controlled-release formulation.

the 1000- and 1250-mg dose levels, for the ≥75 years versus 18—55 years and 65—74 years versus 18—55 years age-group comparisons for the 250-mg dose level, and for the 65—74 years versus 18—55 years and the ≥75 years versus 65—74

Disposition of carisbamate and metabolites in urine The fraction of dose of carisbamate excreted in urine was <4.5% for the IR formulation and <2.1% for CR formulation. Similarly, for glucuronide metabolites (R289876 and R382574), the fractions of dose excreted in urine appeared greater for the IR formulation than for the CR formulation. There was a general trend toward greater percent dose excreted of unchanged carisbamate in urine for the younger age group for both the IR and CR formulations, which was consistent with the renal clearance calculations. Renal clearance In general, renal clearance decreased with age for the two formulations (Tables 3 and 4), likely due to a decreased

Table 4 Carisbamate’s pharmacokinetic parameters following repeated oral administration of controlled-release formulation 250, 500, 1000, and 1250 mg once daily (means ± S.D.) Non-elderly subjects

Elderly subjects

18—55 years

65—74 years

≥75 years

Day 10: 250 mg q24h (n = 6 per age group) tmax a (h) 12.00 Cmax (␮g/ml) 3.89 ± 0.704 AUC24 (␮g h/ml) 79.4 ± 18.4 CL/F (l/h) 3.34 ± 1.01 CLr (l/h) 0.0635 ± 0.0397

10.00 4.15 ± 0.755 88.3 ± 17.8 2.92 ± 0.527 0.0513 ± 0.0153

13.97 4.06 ± 0.615 84.0 ± 18.6 3.10 ± 0.666 0.0586 ± 0.0288

Day 16: 500 mg q24h (n = 6 per age group) tmax a (h) 4.00 Cmax (␮g/ml) 7.78 ± 1.59 AUC24 (␮g h/ml) 168 ± 34.6 CL/F (l/h) 3.08 ± 0.614 CLr (l/h) 0.0516 ± 0.0175

6.00 8.61 ± 2.00 175 ± 38.7 2.96 ± 0.524 0.0491 ± 0.0116

12.00 7.89 ± 1.12 170 ± 22.0 2.99 ± 0.368 0.0584 ± 0.0408

Day 22: 1000 mg q24h (n = 6 per age group) tmax a (h) 11.00 Cmax (␮g/ml) 14.4 ± 2.73 AUC24 (␮g h/ml) 312 ± 67.7 CL/F (l/h) 3.34 ± 0.758 CLr (l/h) 0.0608 ± 0.0234

4.00 17.0 ± 4.29 314 ± 60.6 3.26 ± 0.529 0.0534 ± 0.0273

4.00 15.7 ± 2.31 334 ± 50.7 3.05 ± 0.429 0.0467 ± 0.0252

Day 28: 1250 mg q24h (n = 6 per age group) tmax a (h) 9.99 Cmax (␮g/ml) 17.4 ± 5.21 AUC24 (␮g h/ml) 358 ± 103 CL/F (l/h) 3.71 ± 0.974 CLr (l/h) 0.0569 ± 0.0135

4.00 18.0 ± 4.08 375 ± 84.9 3.49 ± 0.848 0.0496 ± 0.0143

5.00 17.7 ± 2.39 380 ± 49.2 3.33 ± 0.407 0.0415 ± 0.0256

tmax , time of maximum observed plasma concentration; Cmax , maximum observed plasma concentration; AUC, area under the plasma-concentration time cure; CL/F, oral clearance; CLr, renal clearance. a Median.

Antiepileptic carisbamate in the elderly groups renal function in elderly subjects, as shown by a decrease in creatinine clearance in the two elderly age groups. As for the urinary excretion of carisbamate and its metabolites, it appeared that renal clearance of the IR formulation was also higher than that for the CR formulation. This difference could be the result of a diurnal effect, with a higher renal excretion of carisbamate during daytime versus nighttime. Compared with the total clearance of carisbamate, the renal clearance generally accounted for 2.5—4.5% of total clearance for the IR formulation and 1.3—2% of total clearance for the CR formulation, confirming earlier studies showing that <5% of drug is eliminated through renal clearance (Yao et al., 2006). As expected from the limited renal elimination of the drug, the total CL/F for both the IR and CR formulations did not change with creatinine clearance.

Safety Overall, 56% (27/48) of subjects reported at least one adverse event during the study. The most commonly reported adverse events were headache (29%), influenzalike illness (25%), and dizziness (13%). All adverse events were mild or moderate in severity. The adverse event profiles were comparable among the treatment groups, except for a higher incidence of dizziness in the IR group (33%) compared with no reports of dizziness in the CR or placebo groups. Most cases of the frequently reported adverse events were assessed by the investigator to be at least possibly related to the study medication. All of the more common adverse events were seen in all age groups, without any apparent differences. There were no serious adverse events or events that led to discontinuation of treatment. There were no clinically important findings in clinical laboratory measurements, vital signs, physical examinations, body weight, or ECG measurements.

Discussion The primary objective of this study was to evaluate the pharmacokinetics, safety, and tolerability of both IR and CR formulations of carisbamate as a function of age. The doses tested in the present study were chosen based on findings of early phase I studies in healthy volunteers where doses of carisbamate IR formulation up to 750 mg BID were administered. Based on recently completed phase II trials, the doses selected for phase III studies are 200 mg and 400 mg/day with the IR formulation. The IR formulation behaved in a similar and consistent manner across all age groups, with rapid absorption reaching maximum concentrations within 1—2 h post dose, which is consistent with results of previous studies in young adults (Yao et al., 2006). Pharmacokinetic parameters such as AUC, CL/F, Vd /F, and t1/2 of carisbamate confirmed the linearity of carisbamate pharmacokinetics in the dose range studied and were similar among all age groups, indicating that age does not affect the pharmacokinetics of carisbamate IR formulation. Based on the disposition of carisbamate and its metabolites in urine, there was no effect of age on carisbamate glucuronidated metabolism. To date, there have been few studies examining the effect of age on glucuronidation pathways, and much of the current database is old

29 (Kinirons and O’Mahony, 2004). Lorazepam and oxazepam are eliminated primarily by glucuronidation UGT 2B15 for lorazepam (Chung et al., 2005) and UGTs 2B15, 1A9, and 2B7 for oxazepam (Court et al., 2002), and their clearances were not significantly reduced in the elderly (Greenblatt et al., 1991; Kraus et al., 1978). Pharmacokinetic studies with lamotrigine (metabolized by UGT1A4) (Rowland et al., 2006) and the active monohydroxy derivative of oxcarbazepine (UGT isoform unknown) have shown that, on average, CL/F values were reduced by about one-third in elderly patients relative to non-elderly adults (Posner et al., 1991; Van Heiningen et al., 1991). After administration of the CR formulation, linearity of carisbamate pharmacokinetics was preserved, and the concentration-time profiles were almost flat at steadystate. Cmax values were consistently 50—60% lower across age groups in comparison with those obtained for the IR formulation, and tmax values increased from 1—2 h to 20—24 h post dose. These results are in line with the known properties of the osmotic controlled-release oral delivery system (OROS® ) technology (Conley et al., 2006). Regarding the effect of age on CR treatments, there was an increase in drug exposure in the two elderly age groups after a single dose; Cmax and AUC values were 17% and 25%, and 24% and 40% higher, respectively, than those obtained for the younger age group. However, after repeated administration, these differences tended to decrease for all doses tested (Table 4). Because age does not influence carisbamate metabolism based on the results with the IR formulation, this increased exposure is likely to be due to an increased absorption of the CR formulation in elderly subjects, perhaps as a result of slower gastrointestinal motility, allowing the CR formulation to remain in the gastrointestinal tract for a longer period before excretion in feces. This result is consistent with the known variations in drug absorption observed in the elderly (Gidal, 2006). In one evaluation of an osmotically controlled-release formulation of carbamazepine, systemic exposure varied substantially as a function of the transit time from stomach and small intestine (Wilding et al., 1991). Overall, drug release was greatest in subjects with the longest transit times, while up to 30% of the drug was not released in the subjects with the fastest transit times. For both formulations, the renal clearance of carisbamate was slightly higher in the younger age group and progressively decreased with increasing age for both formulations. However, as expected from the limited renal elimination of carisbamate, the total CL/F from both the IR and CR formulations did not change with creatinine clearance. Carisbamate showed moderate binding (40—43%) to plasma proteins across all age groups, which is consistent with earlier findings (Chien et al., 2006; Yao et al., 2006). All adverse events were mild or moderate in severity. The adverse event profiles were comparable among the treatment groups, except for a higher incidence of dizziness in the IR group (33%) compared with no reports of dizziness in the CR or the placebo groups. The incidence of dizziness was similar to what has been observed previously with comparable doses of the IR formulation in small populations of healthy volunteers (Chien et al., 2006; Yao et al., 2006). However, at the doses selected for phase III studies (200 and 400 mg/day), the incidence of dizziness is less than 10%. The

30 absence of report of dizziness in the CR group may be related to the more favorable pharmacokinetic profile of the CR formulation but needs to be confirmed in a larger population. Also, the incidence of adverse events may be different in elderly patients exposed to different comedications.

Conclusion No apparent differences in the pharmacokinetic parameters of carisbamate were observed between elderly and nonelderly subjects after administration of the IR formulation (for both single and multiple dosing). Following oral administration of the CR formulation, a small increase in exposure was observed in the two elderly age groups compared with non-elderly subjects after single-dose administration. However, after repeated administration, these differences tended to be even smaller for all doses tested. The drug was generally safe and well tolerated during the study.

Acknowledgement Editorial support provided by Maria Soushko, PhD, Phase Five Communications, Inc. with funding provided by Johnson & Johnson Research and Development, LLC.

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