Immediate-release topiramate (TPM-IR, Topamax; Janssen Pharmaceuticals, Inc., Titusville, NJ, U.S.A.) is approved in many countries for both adjunctive and monotherapy treatment of epilepsy as well as for migraine prophylaxis (Maryanoff et al., 1987; Doose et al., 1996). The recommended total adult TPM-IR dose for adjunctive treatment of partial onset seizures is 200–400 mg/day administered as two divided doses (Topamax Prescribing Information, 2012). TPM-IR displays a linear and dose-proportional pharmacokinetic (PK) profile from 200 to 800 mg with an elimination half-life (t1/2) of 19–25 h (Doose et al., 1996; Garnett, 2000; Doose & Streeter, 2002; Gidal, 2002; Sachdeo et al., 2002; Bialer et al., 2004; Britzi et al., 2005; Mimrod et al., 2005; Topamax Prescribing Information, 2012).
Maintenance of stable and effective antiepileptic drug (AED) plasma concentrations to prevent seizures is the overall treatment objective for patients with epilepsy. Compliance with the AED prescribed dosage routine is essential for the maintenance of therapeutic plasma concentrations. Unfortunately, noncompliance with AED treatment regimens is common and negatively affects management of epilepsy (Syed & Sajatovic, 2010). Extended-release (ER) AED formulations aim to reduce the frequency of dosing, thereby improving patient compliance (Bialer, 2007). ER formulations can maintain relatively flat drug plasma concentrations during the dosing interval, thereby providing less fluctuation in drug plasma concentrations. These fluctuations in AED plasma concentration may lead to adverse events (AEs) at maximum concentrations (Cmax) or breakthrough seizures at trough concentrations (Cmin) (Bialer, 2007). Because the TPM-IR formulation requires twice-daily dosing in patients with epilepsy, a once-daily formulation might be clinically advantageous if it maintains a more consistent (“flatter”) TPM plasma profile with less fluctuations following multiple dosing, thereby minimizing concentration-related AEs (Bialer, 2007) while consistently maintaining equivalent TPM exposure.
USL255, a once-daily ER formulation of TPM, is currently being developed by Upsher-Smith Laboratories, Inc. (Minneapolis, MN, U.S.A.) for the treatment of epilepsy (Lambrecht et al., 2011a). Single-dose PK data modeled to steady state suggest once-daily USL255 200 mg (USL255 200 mg QD) may provide TPM plasma exposure equivalent to TPM-IR 100 mg dosed every 12 h (TPM-IR 100 mg Q12h) with an improved PK profile (e.g., lower Cmax, higher Cmin, and reduced fluctuation index [FI]) (Lambrecht et al., 2011b).
The objectives of this study were to compare steady-state PK profiles and evaluate the tolerability of USL255 200 mg QD and TPM-IR 100 mg Q12h in healthy subjects. The major PK parameters used to assess rate of absorption (e.g., Cmax and tmax [time to Cmax]) are not ideal in cases of flat concentration-time curves obtained after oral dosing of ER formulations such as USL255 (Lambrecht et al., 2011a). Therefore, multiple PK parameters were evaluated to assess steady-state performance of USL255 compared with TPM-IR in vivo, which included both standard parameters (i.e., AUC0–24 [AUC at steady state], Cmax, Cmin, Cavg [average TPM plasma concentration at steady state], tmax) and less common PK criteria – FI, peak occupancy or plateau time (POT), and percent coefficient of variation of the TPM steady-state plasma concentration (%CV) – that estimate the flatness of the TPM plasma concentration-time curves (Caldwell et al., 1981; Silber et al., 1987; Pollak et al., 1988; Bialer et al., 1998a). In addition, comparative analyses using the metric partial area under the concentration–time curve (AUCp) were conducted on TPM steady-state PK data. Partial AUC analyses evaluate systemic exposure at any sampling time point, which allows for relative comparisons between AUC profiles over a predetermined window of clinical importance to more accurately assess similarity of PK profiles between formulations (Chen et al., 2010).
Furthermore, when switching AED formulations, exposure to the drug may be altered (Krauss et al., 2011). This change in exposure may lead to potential problems such as varied treatment response, breakthrough seizures, and/or increased AEs (Crawford et al., 2006). Therefore, this study also evaluated the effects of switching TPM formulations (TPM-IR to USL255; USL255 to TPM-IR) on the maintenance of TPM steady-state plasma concentrations both immediately after the switch and following repeated dosing. The preliminary results of this investigation were reported recently in brief abstracts (Braun et al., 2012; Lambrecht et al., 2012) and the final, more detailed, analyses are presented here.
- Top of page
The primary objective of this study was to evaluate the steady-state PK profile of USL255 and determine its equivalence to TPM-IR. Standard steady-state PK parameters (AUC, Cmax, Cmin, Cavg) demonstrated that USL255 provided equivalent TPM plasma exposure with an extended absorption profile when compared to TPM-IR. Additional PK parameters (POT, FI, %CV) provided even greater insight into the in vivo performance of USL255.
Due to concerns that traditional PK metrics such as Cmax and tmax may not fully correspond to therapeutic equivalence for a modified-release formulation, additional analyses using the metric AUCp were conducted to further evaluate the similarity of the steady-state PK profiles between USL255 QD and TPM-IR Q12h. As depicted in Table 3, all USL255/TPM-IR AUCp GLSM ratios were within the acceptable 90% CI values for pharmacokinetic equivalence. Therefore, these data suggest the topiramate exposure was equivalent between formulations across the two TPM-IR dosing intervals (0–12 h; 12–24 h), the interval associated with the median steady state USL255 tmax (0–6 h), and the longer intervals (0–18 h; 0–24 h). Together with the two primary metrics, AUC and Cmax, AUCp provides a robust assessment of equivalence between formulations (Chen et al., 2010).
Differences in the shape of the topiramate plasma concentration-time curve and/or tmax of USL255 QD and TPM-IR Q12h should not result in differences in pharmacodynamic responses. Sensitivity to differences in the shape of the PK curve depends on the rapidity of onset and where clinical doses fall on the dose-response (or concentration-response) curve (Chen et al., 2010). Overall, if a drug does not have rapid therapeutic effects and is not dosed on the steep part of the dose–response curve, differences in the rate of drug release and/or shape of the PK curve should not result in clinical differences. The time to Cmax and/or shape of the plasma concentration-time curve is critical for drugs with a rapid onset of effect (minutes to hours), such as medications for pain relief (e.g., hydromorphone) or sleep aids (e.g., zolpidem). However, for drugs that take days to weeks to elicit efficacy, such as TPM, changes in efficacy/effectiveness due to the differences in tmax or shape of the plasma concentration-time profile is highly unlikely. In addition, clinical dosages of TPM (200–400 mg/day) do not fall within the steep portion of the PK-PD dose–response curve. This is demonstrated clinically by the lack of increased efficacy at doses above 400 mg/day (Faught et al., 1996; Privitera et al., 1996) as well as by modeling the TPM exposure–response relationships for monotherapy and adjunctive treatment of epilepsy (Girgis et al., 2010). Therefore, because TPM does not have a rapid therapeutic effect and is not dosed on the steep part of the PK-PD response curve, differences in rate of drug release and/or shape of the PK curve should not result in clinical differences.
Steady-state PK parameters obtained in the current study were compared with data obtained in a previous single-dose study (Lambrecht et al., 2011a). Systemic exposure of TPM provided by a single 200 mg dose of USL255 (170 mg h/L) was comparable to the TPM systemic exposure after USL255 200 mg was administered once-daily for 14 days (158 mg h/L). In addition, the calculated USL255 POT values after a single dose and at steady state were not different (12 and 13 h, respectively). Similarly, no differences in systemic exposure or POT were observed with TPM-IR 100 mg Q12h after single- and multiple-dose administration. Predicted values for steady-state Cmax and Cmin were calculated from the product of the mean single-dose Cmax or Cmin values and the accumulation ratio (Rac) for both USL255 and TPM-IR. Rac was estimated by the single-dose AUC0–inf/AUC0–τ quotient as depicted in eqn (3). Keff is the disposition rate constant, and the effective half-life (t1/2,eff) is equal to the quotient ln2/Keff as depicted in eqn (4) (Kwan et al., 1984; Boxenbaum and Battle, 1995; Sahin & Benet, 2008).
The predicted USL255 200 mg values (9.2 mg/L [Cmin] and 10.8 mg/L [Cmax]) were higher than observed values (5.3 mg/L [Cmin] and 7.9 mg/L [Cmax]). Predicted Cmin and Cmax values for TPM-IR 100 mg Q12h were also higher than observed values (data not shown). Unlike Cmax and Cmin, which are difficult to accurately predict for drugs with a flat PK profile like USL255, USL255 200 mg Cavg values were nearly identical (predicted = 6.6 mg/L; observed = 6.3 mg/L). Cavg is a more robust PK parameter than the empirical, single-point parameters of Cmax and Cmin. This, coupled with the fact these studies were conducted in different subject groups, may help explain why predicted Cmax and Cmin were higher than the actual observed values. In addition, steady-state tmax is shorter than the tmax after a single-dose administration. This is not unexpected as single-dose tmax is a function of the absorption and elimination rate constants, whereas steady-state tmax is also affected by τ. Consequently, the steady-state tmax is shorter than the single-dose tmax as the numerator of the single-dose tmax is multiplied by a repetitive-dosing factor smaller than 1 (Gibaldi & Perrier, 1977). As such, these data suggest a linear PK profile of TPM at the clinically relevant dose range, when given either as an IR or ER formulation. This is supported by the ability of robust PK parameters (e.g., AUC0–24, Cavg, POT) calculated after a single-dose study to accurately predict TPM steady-state PK parameters after multiple dosing.
A population exposure–response (PK-PD) model for TPM has recently been developed, which includes data from a total of 11 clinical studies in both adults and pediatrics for both monotherapy and adjunctive treatment of epilepsy (Girgis et al., 2010). For monotherapy, steady-state Cmin was related to the time-to-first-seizure; as an adjunctive therapy, both percent reduction in seizure frequency from baseline and responder rate (defined as a ≥50% seizure reduction of baseline seizure frequency) were related to steady-state minimum TPM concentrations. Because therapeutic effects of TPM, in both monotherapy and adjunctive treatment of epilepsy, are related to TPM Cmin, subtherapeutic concentrations of TPM could lead to lack of efficacy. The results from this study demonstrate that steady-state Cmin after administration of USL255 QD was slightly higher (5.3 mg/L) than Cmin values achieved after TPM-IR Q12h (5.0 mg/L). In addition, when the effects of switching between formulations were evaluated, no significant difference in minimum TPM concentrations was identified in the 24 h after the switch. This indicates switching from TPM-IR to USL255 provides immediate maintenance of minimum therapeutic concentrations and equivalent exposure. Together, these data provide evidence that at equivalent daily doses, USL255 QD will consistently maintain TPM concentrations at, or above, minimum concentrations provided by TPM-IR Q12h.
USL255, administered as once-daily doses of 200 mg for 14 days, was generally well tolerated. All observed TEAEs were mild in intensity and were consistent with those generally seen with TPM-IR. Furthermore, the proportion of subjects and the incidences of TEAEs were similar between the two formulations.
The current study demonstrates that USL255 is pharmacokinetically equivalent to TPM-IR in systemic exposure, yet displays an improved TPM PK profile (e.g., lower Cmax, higher Cmin) with decreased fluctuations in TPM steady-state plasma concentrations. Coupled with the ability to maintain steady-state TPM concentrations after switching from TPM-IR and the PK results of a previous single dose study (Lambrecht et al., 2011a), these data suggest USL255 may offer a once-daily alternative to TPM-IR.
- Top of page
Dr. Meir Bialer is a consultant to Upsher-Smith Laboratories, Inc. In addition, within the last 3 years, he has received speakers or consultancy fees from BIAL, BioAvenir, CTS Chemicals, Desitin, Janssen-Cilag, Rekah, Sepracor, Tombotech, and UCB Pharma. Dr. Meir Bialer has been involved in the design and development of new antiepileptics and CNS drugs as well as new formulations of existing drugs. Drs. Braun and Halvorsen are employees of Upsher-Smith Laboratories, Inc. T. Shekh-Ahmad has no conflict of interest to disclose. We, the authors, confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.