The Application of Half-Life in Clinical Decision Making: Comparison of the Pharmacokinetics of Extended-Release Topiramate (USL255) and Immediate-Release Topiramate

Objective: For extended-release drugs with multi-compartment kinetics, such as topiramate, effective half-life (t1/2eff) may be a more clinically relevant parameter than elimination half-life (t1/2z). Using topiramate as a real-life example, the objective was to compare these half-life values for immediate- and extended-release topiramate (TPM-IR and USL255, respectively) to understand how drug pharmacokinetics may impact drug dosing recommendations. Methods: The t1/2z and t1/2eff for USL255 and TPM-IR were compared using data from a phase I study (N = 36) of 200 mg USL255 administered once daily (QD) or TPM-IR twice daily (BID); effect of sampling duration on t1/2z was investigated. To further explore the relationship between half-life and dosing, steady-state PK was simulated for USL255 and TPM-IR. Results: As previously reported, mean t1/2z was similar between USL255 (80.2 h) and TPM-IR (82.8 h); TPM-IR t1/2z was ∼4 times longer than reported in the Topamax label (21 h). In contrast, USL255 displayed a 1.5 fold longer t1/2eff (55.7 vs 37.1 h for TPM-IR). When t1/2z was calculated from 48 to 336 h, values ranged from 28.8 to 82.8 h. Simulated steady-state PK profiles of USL255 QD exhibited reduced plasma fluctuations during a dosing interval vs TPM-IR QD or BID. Significance: As expected for the same moiety, t1/2z of USL255 and TPM-IR were similar; however, the longer t1/2eff for USL255 better approximates differences in recommend dosing (QD USL255 vs BID TPM-IR). Further, sampling duration impacted t1/2z, diminishing its predictive value for determining dose regimens; sampling-time differences may also explain t1/2z discrepancy between TPM-IR here versus Topamax label. As expected, steady-state simulations confirm that although TPM-IR has a long t1/2z, taking TPM-IR QD would lead to large plasma fluctuations. These data demonstrate that t1/2z may be less clinically meaningful than t1/2eff, and using t1/2z for some drugs may lead to erroneous conclusions regarding dosing regimens

Effects of adjunctive eslicarbazepine acetate on serum lipids in patients with partial-onset seizures: Impact of concomitant statins and enzyme-inducing antiepileptic drugs.

PURPOSE: To evaluate the effects of eslicarbazepine acetate (ESL) on lipid metabolism and to determine whether reduced statin exposure during ESL therapy has clinical consequences. SUBJECTS AND METHODS: We conducted a post-hoc analysis of pooled data for serum lipids (laboratory values) from three phase III, multicenter, randomized, double-blind, placebo-controlled trials of adjunctive ESL therapy (400, 800, or 1200 mg once daily) in patients with treatment-refractory partial-onset seizures. Changes from baseline in serum lipid levels were analyzed according to use of statins and/or enzyme-inducing antiepileptic drugs (EIAEDs) during the baseline period. KEY FINDINGS: In total, 426 and 1021 placebo- and ESL-treated patients, respectively, were included in the analysis. With regard to the changes from baseline in serum concentrations, there were statistically significant differences between the placebo and ESL 1200 mg QD groups, for both total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), but the effect sizes were small (+4.1 mg/dL and +1.8 mg/dL, respectively). A small but significant difference in low-density lipoprotein cholesterol (LDL-C; -5.0 mg/dL) was observed between the ESL 400 mg QD group and the placebo group. In patients not taking a concomitant EIAED, there were no changes with ESL 400 mg QD, but modest and statistically significant increases in cholesterol fractions (TC, LDL-C and HDL-C) with ESL 800 mg QD (/dL) and ESL 1200 mg QD (/dL). ESL had no consistent effect on lipids in patients taking a concomitant EIAED. In patients taking statins during baseline, there were no clinically relevant changes in serum lipids during use of ESL, although the subgroups were small. SIGNIFICANCE: These results suggest that ESL does not appear to have clinically significant effects on serum lipids, nor does the pharmacokinetic interaction between ESL and statins have an impact on serum lipid concentrations

Search for the Lepton-Number-Violating Decay Ξ−→pμ−μ−\Xi^- \to p \mu^- \mu^-

A sensitive search for the lepton-number-violating decay $\Xi^-\to p \mu^-\mu^-$ has been performed using a sample of $\sim10^9$ $\Xi^-$ hyperons produced in 800 GeV/$c$ $p$-Cu collisions. We obtain $\mathcal{B}(\Xi^-\to p \mu^-\mu^-)< 4.0\times 10^{-8}$ at 90% confidence, improving on the best previous limit by four orders of magnitude.Comment: 9 pages, 5 figures, to be published in Phys. Rev. Let

Evidence for the Decay Sigma+ -> p mu+ mu-

We report the first evidence for the decay Sigma+ -> p mu+ mu- from data taken by the HyperCP experiment(E871) at Fermilab. Based on three observed events, the branching ratio is B(Sigma+ -> p,mu+,mu-) = [8.6 +6.6,-5.4(stat) +/-5.5(syst)] x 10**-8. The narrow range of dimuon masses may indicate that the decay proceeds via a neutral intermediate state, Sigma+ -> p P0, P0 -> mu+ mu-, with a P0 mass of 214.3 +/- 0.5 MeV/c**2 and branching ratio B(Sigma+ -> p P0; P0 -> mu+ mu-) = [3.1 +2.4,-1.(stat) +/-1.5(syst)] x 10**-8.Comment: As published in PR

Measurement of the Alpha Asymmetry Parameter for the Omega- to Lambda K- Decay

We have measured the alpha parameter of the Omega- to Lambda K- decay using data collected with the HyperCP spectrometer during the 1997 fixed-target run at Fermilab. Analyzing a sample of 0.96 million Omega- to Lambda K^-, Lambda to p pi- decays, we obtain alpha_Omega*alpha_Lambda = [1.33+/-0.33(stat)+/-0.52(syst)] x 10^{-2}. With the accepted value of alpha_Lambda, alpha_Omega is found to be [2.07+/-0.51(stat)+/-0.81(syst)] x 10^{-2}.Comment: 5 pages, 4 figures, to be appeared as a Rapid Communication in Phys. Rev.

Study of the J/ψ→ϕ(ω)f2(1270)J/\psi \to \phi (\omega) f_2(1270), J/ψ→ϕ(ω)f2′(1525)J/\psi \to \phi (\omega) f'_2(1525) and J/ψ→K∗0(892)Kˉ2∗0(1430)J/\psi \to K^{*0}(892) \bar{K}^{* 0}_2(1430) decays

We present an approach to study the decay modes of the $J/\psi$ into a vector meson and a tensor meson, taking into account the nature of the $f_2(1270)$, $f'_2(1525)$, $\bar{K}^{* 0}_2(1430)$ resonances as dynamically generated states from the vector meson-vector meson interaction. We evaluate four ratios of partial decay widths in terms of a flavor dependent OZI breaking parameter and the results obtained compare favorably with experiment. The fit to the data is possible due to the particular strength and sign of the couplings of the resonances to pairs of vector mesons given by the theory, thus providing a nontrivial test for the idea of these tensor states as dynamically generated from the vector-vector interaction.Comment: published versio

Search for flavor-changing neutral currents and lepton-family-number violation in two-body D0 decays

Results of a search for the three neutral charm decays, D0 -> mu e, D0 -> mu mu, and D0 -> e e, are presented. This study was based on data collected in Experiment 789 at the Fermi National Accelerator Laboratory using 800 GeV/c proton-Au and proton-Be interactions. No evidence is found for any of the decays. Upper limits on the branching ratios, at the 90% confidence level, are obtained.Comment: 28 pages, 18 figures. Submitted to Physical Review

Study of the Ds+→π−π+π+D^+_s \to \pi^- \pi^+ \pi^+ decay and measurement of f0f_0 masses and widths

From a sample of 848 $\pm$ 44 $D_s^+ \to \pi^- \pi^+ \pi^+$ decays, we find $\Gamma(D_s^+ \to \pi^- \pi^+ \pi^+) / \Gamma(D_s^+ \to \phi \pi^+) = 0.245 \pm 0.028^{+0.019}_{-0.012}$. Using a Dalitz plot analysis of this three body decay, we find significant contributions from the channels $\rho^0(770)\pi^+$, $\rho^0(1450)\pi^+$, $f_0(980)\pi^+$, $f_2(1270)\pi^+$, and $f_0(1370)\pi^+$. We present also the values obtained for masses and widths of the resonances $f_0(980)$ and $f_0(1370)$.Comment: 10 pages, 3 eps figure