Isabelle Ragueneau-Majlessi

New Antiepileptic Drugs: Review on Drug Interactions

During the Past decade, nine new antiepileptic drugs (AEDs) namely, Felbamate, Gabapentin, Levetiracetam, Lamotrigine, Oxcarbazepine, Tiagabine, Topiramate, Vigabatrin and Zonisamide have been marketed worldwide. The introduction of these drugs increased appreciably the number of therapeutic combinations used in the treatment of epilepsy and with it, the risk of drug interactions. In general, these newer antiepileptic drugs exhibit a lower potential for drug interactions than the classic AEDs, like phenytoin, carbamazepine and valproic acid, mostly because of their pharmacokinetic characteristics. For example, vigabatrin, levetiracetam and gabapentin, exhibit few or no interactions with other AEDs. Felbamate, tiagabine, topiramate and zonisamide are sensitive to induction by known anticonvulsants with inducing effects but are less vulnerable to inhibition by common drug inhibitors. Felbamate, topiramate and oxcarbazepine are mild inducers and may affect the disposition of oral contraceptives with a risk of failure of contraception. These drugs also inhibit CYP2C19 and may affect the disposition of phenytoin. Lamotrigine is eliminated mostly by glucuronidation and is susceptible to inhibition by valproic acid and induction by classic AEDs such as phenytoin, carbamazepine, phenobarbital and primidone.

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

Modeling and simulation of drug disposition has emerged as an important tool in drug development, clinical study design and regulatory review, and the number of physiologically based pharmacokinetic (PBPK) modeling related publications and regulatory submissions have risen dramatically in recent years. However, the extent of use of PBPK modeling by researchers, and the public availability of models has not been systematically evaluated. This review evaluates PBPK-related publications to 1) identify the common applications of PBPK modeling; 2) determine ways in which models are developed; 3) establish how model quality is assessed; and 4) provide a list of publically available PBPK models for sensitive P450 and transporter substrates as well as selective inhibitors and inducers. PubMed searches were conducted using the terms “PBPK” and “physiologically based pharmacokinetic model” to collect published models. Only papers on PBPK modeling of pharmaceutical agents in humans published in English between 2008 and May 2015 were reviewed. A total of 366 PBPK-related articles met the search criteria, with the number of articles published per year rising steadily. Published models were most commonly used for drug-drug interaction predictions (28%), followed by interindividual variability and general clinical pharmacokinetic predictions (23%), formulation or absorption modeling (12%), and predicting age-related changes in pharmacokinetics and disposition (10%). In total, 106 models of sensitive substrates, inhibitors, and inducers were identified. An in-depth analysis of the model development and verification revealed a lack of consistency in model development and quality assessment practices, demonstrating a need for development of best-practice guidelines.

Quantitative Evaluation of Pharmacokinetic Inhibition of CYP3A Substrates by Ketoconazole : A Simulation Study

The US Food and Drug Administration draft drug interaction guidance recommends that 400 mg ketoconazole (KTZ) be administered once daily for several days (QD400) for maximal CYP3A inhibition. Some investigators suggest that a single dose of 400 mg (SD400) KTZ is sufficient given its short half‐life (t1/2 ∼ 3–5 hr). To determine the impact of KTZ regimens on CYP3A inhibition, we simulated AUC fold‐change (AUCR) in the presence of SD400, QD400, or 200 mg twice‐daily (BID200) KTZ for theoretical CYP3A substrates. Ratios of AUCR (AUCRQD400/AUCRSD400 and AUCRBID200 AUCRQD400) increase with increasing bioavailability and increasing substrate t1/2. The SD400 KTZ regimen may provide maximal inhibition only for a subset of substrates (ie, low bioavailability and short t1/2). For substrates with t1/2 longer than that of KTZ, multiple KTZ dosing is critical and BID200 appears to provide greater inhibition than QD400. Also, timing of KTZ administration should be optimized to allow maximal presystemic enzyme inhibition prior to substrate administration.

Levetiracetam Does Not Alter the Pharmacokinetics of an Oral Contraceptive in Healthy Women

Summary:  Purpose: This study was designed to evaluate whether levetiracetam, a novel antiepileptic drug (AED), influences the pharmacokinetics of steroid oral contraceptives.

Lack of effect of repeated administration of levetiracetam on the pharmacodynamic and pharmacokinetic profiles of warfarin

The objective of this study was to determine if repeated administration of levetiracetam alters the pharmacokinetics or the pharmacodynamics of warfarin. Forty-two healthy subjects (18-50 years old) were recruited into the study. After a dose-finding phase and a stabilization phase, during which a warfarin treatment was introduced and the dose maintained stable for at least 5 days, 18 male and 8 female subjects were eligible and enrolled. Subjects received warfarin (2.5, 5 or 7.5 mg/day) plus levetiracetam 1000 mg bid, and warfarin plus placebo. The treatment periods were 7 days long and were separated by a 3-day wash-out period. The protein binding and the pharmacokinetic profiles of R- and S-warfarin were assessed at steady state by analysis of blood samples, and the anticoagulant effect was measured using the international normalized ratio (INR). The ratios of the geometric means for AUC(ss) (90% confidence interval) between coadministration of warfarin with levetiracetam or with placebo were 97.17% (92.85%, 101.68%) for R-warfarin and 100.16% (96.43%, 104.02%) for S-warfarin. Results for C(max), C(min) and oral clearance were consistent with those of AUC(ss). In addition, the protein binding of warfarin was not affected by the concomitant treatment. The INR values measured the last 5 days of each period were not statistically altered by the concomitant administration of levetiracetam or placebo: 1.59+/-0.18 for warfarin alone, 1.49+/-0.21 when coadministered with placebo, and 1.55+/-0.23 with levetiracetam (means+/-S.D.). The frequency and profile of adverse events under the concomitant therapy of warfarin and levetiracetam were expected for subjects receiving these drugs, and the coadministration was safe. Moreover, levetiracetam pharmacokinetics after repeated warfarin administration did not differ from those previously reported in healthy volunteers. At the doses administered, there is no evidence of a pharmacokinetic or pharmacodynamic interaction between warfarin and levetiracetam.

Breast Cancer Resistance Protein (ABCG2) in Clinical Pharmacokinetics and Drug Interactions: Practical Recommendations for Clinical Victim and Perpetrator Drug-Drug Interaction Study Design

Breast cancer resistance protein (BCRP; ABCG2) limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Based on clinical evidence of BCRP-mediated drug-drug interactions (DDIs) and the c.421C>A functional polymorphism affecting drug efficacy and safety, both the US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment of BCRP-mediated DDIs. Although many BCRP substrates and inhibitors have been identified in vitro, clinical translation has been confounded by overlap with other transporters and metabolic enzymes. Regulatory recommendations for BCRP-mediated clinical DDI studies are challenging, as consensus is lacking on the choice of the most robust and specific human BCRP substrates and inhibitors and optimal study design. This review proposes a path forward based on a comprehensive analysis of available data. Oral sulfasalazine (1000 mg, immediate-release tablet) is the best available clinical substrate for intestinal BCRP, oral rosuvastatin (20 mg) for both intestinal and hepatic BCRP, and intravenous rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000 mg) and lapatinib (250 mg) are the best available clinical BCRP inhibitors. To interrogate the worst-case clinical BCRP DDI scenario, study subjects harboring the BCRP c.421C/C reference genotype are recommended. In addition, if sulfasalazine is selected as the substrate, subjects having the rapid acetylator phenotype are recommended. In the case of rosuvastatin, subjects with the organic anion–transporting polypeptide 1B1 c.521T/T genotype are recommended, together with monitoring of rosuvastatins cholesterol-lowering effect at baseline and DDI phase. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design.

Repeated administration of the novel antiepileptic agent levetiracetam does not alter digoxin pharmacokinetics and pharmacodynamics in healthy volunteers

OBJECTIVE This study was undertaken to determine whether levetiracetam (Keppra) affected the pharmacokinetic or pharmacodynamic profile of digoxin in healthy adults. METHODS Seven men and four women (19-48 years old) completed this double-blind, placebo-controlled study. Each received digoxin 0.25 mg once daily (0.5 mg on day 1) during the 1-week run-in period, followed by two 1-week periods of coadministration of digoxin with levetiracetam (2000 mg/day) or placebo in a two-way crossover design. The pharmacokinetics of digoxin and levetiracetam were assessed by analysis of blood samples. ECG recordings were taken to monitor effects of levetiracetam on digoxin pharmacodynamics. RESULTS The ratios of geometric means, using a 90% confidence interval, between coadministration of digoxin with levetiracetam or placebo were 103.96% (99.18%, 108.95%) for AUC(ss), 100.87% (89.52%, 113.66%) for C(max), 97.67% (82.76%, 115.26%) for PTF, and 99.04% (90.98%, 109.00%) for C(min). Although digoxin produced predictable changes in ECG, its pharmacodynamic parameters did not differ significantly between levetiracetam and placebo administration. Furthermore, the pharmacokinetics of levetiracetam were not altered in the presence of digoxin. Co-administration of levetiracetam and digoxin was well tolerated. CONCLUSION At the doses administered, there was no pharmacokinetic interaction and no evidence of a pharmacodynamic interaction between digoxin and levetiracetam.

Evaluation of various static in vitro-in vivo extrapolation models for risk assessment of the CYP3A inhibition potential of an investigational drug

Nine static models (seven basic and two mechanistic) and their respective cutoff values used for predicting cytochrome P450 3A (CYP3A) inhibition, as recommended by the US Food and Drug Administration and the European Medicines Agency, were evaluated using data from 119 clinical studies with orally administered midazolam as a substrate. Positive predictive error (PPE) and negative predictive error (NPE) rates were used to assess model performance, based on a cutoff of 1.25‐fold change in midazolam area under the curve (AUC) by inhibitor. For reversible inhibition, basic models using total or unbound systemic inhibitor concentration [I] had high NPE rates (46–47%), whereas those using intestinal luminal ([I]gut) values had no NPE but a higher PPE. All basic models for time‐dependent inhibition had no NPE and reasonable PPE rates (15–18%). Mechanistic static models that incorporate all interaction mechanisms and organ specific [I] values (enterocyte and hepatic inlet) provided a higher predictive precision, a slightly increased NPE, and a reasonable PPE. Various cutoffs for predicting the likelihood of CYP3A inhibition were evaluated for mechanistic models, and a cutoff of 1.25‐fold change in midazolam AUC appears appropriate.

Carbamazepine pharmacokinetics are not affected by zonisamide: in vitro mechanistic study and in vivo clinical study in epileptic patients

Carbamazepine is metabolized by CYP3A4 and several other cytochrome P450 enzymes. The potential effects of zonisamide on carbamazepine pharmacokinetics (PK) have not been well characterized, with contradictory literature reports. Hence, an in vitro study was designed to evaluate the cytochrome P450 inhibition spectrum of zonisamide using human liver microsomes. Further, an in vivo steady-state study was performed to measure the effect of zonisamide on carbamazepine PK in epileptic patients, and monitor zonisamide PK. In vitro human liver microsomes were incubated with zonisamide (200, 600 or 1000 microM) in the presence of appropriate probe substrates to assess selected cytochrome P450 activities. In vivo, the effect of zonisamide, up to 400 mg/day, on the steady-state PK of carbamazepine and carbamazepine-epoxide (CBZ-E) was studied in 18 epileptic patients. In vitro, zonisamide did not inhibit CYP1A2 and 2D6, and only weakly inhibited CYP2A6, 2C9, 2C19, and 2E1. The estimated Ki for zonisamide inhibition of CYP3A4 was 1076 microM, 12 times higher than typical unbound therapeutic serum zonisamide concentrations. In vivo, no statistically significant differences were observed for mean Cmax, Tmax, and AUC0-12 of total and free carbamazepine and CBZ-E measured before and after zonisamide administration (300-400 mg/day for 14 days). However, CBZ-E renal clearance was significantly (p < 0.05) reduced by zonisamide. The observed mean zonisamide t1/2 (36.3h), relative to approximately 65 h reported in subjects on zonisamide monotherapy, reflects known CYP3A4 induction by carbamazepine. Based on the lack of clinically relevant in vitro and in vivo effects, adjustment of carbamazepine dosing should not be required with concomitant zonisamide administration.

Lack of pharmacokinetic interactions between steady-state zonisamide and valproic acid in patients with epilepsy

ObjectivesThis study evaluated the effect of the addition of zonisamide on valproic acid (valproate sodium) pharmacokinetics under steady-state conditions in patients with epilepsy. A second aim was to characterise zonisamide pharmacokinetics in the presence of valproic acid.MethodsTwenty-two patients (males and females, 18–55 years of age) with their seizure disorder stabilised on valproic acid monotherapy were included in a two-centre, open-label, one-way drug-interaction trial. The zonisamide dose was gradually increased from 100 mg/day to 400 mg/day. Three pharmacokinetic profiles were obtained: on days −7 and −1, to assess pharmacokinetic parameters of oral valproic acid administered alone, and on day 35, after 14 days of zonisamide treatment at the maximal tolerated dose, to evaluate the effect of zonisamide on valproic acid pharmacokinetics and to characterise zonisamide pharmacokinetics in the presence of valproic acid.ResultsSeventeen patients completed the study, with 16 patients contributing to the pharmacokinetic analyses. Coadministration of zonisamide and valproic acid appeared reasonably well tolerated. Steady-state dosing of zonisamide (200mg twice daily) had no statistically significant effect on the mean (± SD) maximum observed plasma concentration (Cmax) [70.8 ± 20.5 vs 69.2 ± 27.0 μg/mL], area under the plasma concentration-time curve from the time of dosing to 12 hours post-dose (AUC12) [689.3 ± 250.4 vs 661.8 ± 251.3 μg · h/mL] or other evaluated pharmacokinetic parameters for valproic acid measured before and after zonisamide administration. Furthermore, 90% confidence intervals for the ratio of the geometric means (day 35/day −1) of valproic acid pharmacokinetic exposure measures fell only slightly outside the ‘no effect’ range of 0.80–1.25. In the presence of valproic acid, mean zonisamide oral clearance (1.23 L/h) and elimination half-life (52.5 hours) are generally consistent with values reported for healthy volunteers receiving zonisamide monotherapy.ConclusionThere is no apparent clinically significant effect of steady-state dosing of zonisamide on valproic acid pharmacokinetics, and valproic acid did not appear to affect the pharmacokinetics of zonisamide, indicating that no dosage adjustment of either drug should be required when they are used in combination in patients with epilepsy.