Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects

Almeida L, Nunes T, Sicard E, Rocha J‐F, Falcão A, Brunet J‐S, Lefebvre M, Soares‐da‐Silva P. Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects.
Acta Neurol Scand: 2010: 121: 257–264.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – Anti‐epileptic drugs are often used in combination. Both eslicarbazepine (main metabolite of eslicarbazepine acetate, ESL) and lamotrigine undergo conjugation with glucuronic acid, and both eslicarbazepine and its glucuronide and lamotrigine glucuronide undergo extensive renal elimination; therefore, there is a potential for interaction. This study investigated the interaction between ESL and lamotrigine in healthy subjects. Methods – Open‐label study in two parallel groups of 16 healthy volunteers each. After an 8‐day treatment with ESL or lamotrigine, ESL (1200 mg once‐daily) and lamotrigine (150 mg once‐daily) were co‐administered for 19 days. Geometric mean ratios (GMR) and 90% confidence intervals (90% CI) for maximum plasma concentration (C_max) and area under the plasma concentration–time curve in the dosing interval (AUC_0–24) were calculated for eslicarbazepine (ESL active metabolite) and lamotrigine. Results – The C_max and AUC_0–24 GMR (90% CI) were, respectively, 95% (87–102%) and 96% (91–102%) for eslicarbazepine, and 88% (82–94%) and 86% (81–92%) for lamotrigine. The 90% CI of the C_max and AUC_0–24 GMR fell within the prespecified acceptance interval (80–125%) both for eslicarbazepine and lamotrigine. Conclusion – There was no significant pharmacokinetic interaction between ESL and lamotrigine in healthy subjects. Therefore, no dosage adjustment appears to be usually required in either lamotrigine or ESL when the drugs are co‐administered.     

Extended‐release antiepileptic drugs: A comparison of pharmacokinetic parameters relative to original immediate‐release formulations

Many antiepileptic drugs (AEDs) have short half‐lives with large fluctuations in peak‐to‐trough plasma concentrations. Consequences of these pharmacokinetic (PK) properties may include adverse events (AEs) and breakthrough seizures, potentially leading to poor adherence. To address these challenges, newer formulations of these AEDs have been developed using unique extended‐release (ER) technologies. These technologies extend the dosing interval such that dosing frequency can be minimized, which may improve patient adherence. Available ER formulations have the potential to minimize the spikes in maximum plasma concentrations (C_max) at steady‐state that often contribute to AEs during treatment with immediate‐release (IR) products. In so doing, tolerability advantages may lead to increased AED effectiveness by improving adherence and allowing higher doses if clinically indicated. Direct PK comparison studies of IR and ER formulations (e.g., carbamazepine, divalproate sodium, lamotrigine, oxcarbazepine, levetiracetam, and phenytoin) have found that dose‐normalized ER formulations may or may not be bioequivalent to their IR counterparts, but most ER formulations have a lower fluctuation index ([C_max–C_min]/C_avg) compared with the IR versions. This results in flatter concentration‐time plots. Not all ER preparations improve the various PK parameters to the same extent, and PK nuances may impact the effectiveness, tolerability, and adherence rates of various ER formulations.     

Tolerability,pharmacokinetics, and bioequivalence of the tablet and syrup formulations of lacosamide in plasma,saliva, and urine: Saliva as a surrogate of pharmacokinetics in the central compartment

Purpose: To test for bioequivalence of 200 mg lacosamide oral tablet and syrup formulations. Additional objectives were to compare the pharmacokinetic profile of lacosamide in saliva and plasma, and to evaluate its tolerability. Methods: This open‐label, randomized, two‐way crossover trial was conducted in 16 healthy Caucasian male participants in Germany. The bioequivalence of 200 mg lacosamide tablet and syrup was evaluated using plasma to determine maximum measured concentration (C_max) and area under the curve from zero to the last time point (AUC)_(0–tz). Plasma and saliva samples for evaluation of pharmacokinetic parameters of lacosamide and the major metabolite O‐desmethyl lacosamide (SPM 12809) were taken over 15 time points (0.5–72 h) and used to statistically compare bioavailability of the two. Urine samples were collected predose and over five time points (0–48 h) to evaluate the cumulative amount of unchanged drug and metabolite. Key Findings: Lacosamide median time to reach C_max (t_max) was 1 h for tablet and 0.5 h for syrup in plasma and saliva. Mean terminal half life (t_½) for tablet and syrup was 12.5 and 12.4 h in plasma, and 13.1 and 13.3 h in saliva, respectively. Tablet and syrup mean plasma AUC_(0–tz) was 84.5 and 83.3 μg/mL*h, respectively. Mean AUC_(0–tz) in saliva was 93.2 μg/mL*h for tablet and syrup. Mean C_max for tablet was 5.26 μg/mL in plasma and 5.63 μg/mL in saliva. Syrup mean C_max was 5.14 and 8.32 μg/mL in plasma and saliva, respectively. Within 2 h of syrup administration, elevated lacosamide concentration in saliva compared to plasma was observed. The ratio of lacosamide syrup to tablet was 0.98 for C_max and 0.99 for AUC_(0–tz) in plasma, and 1.00 for AUC_(0–tz) in saliva; the 90% confidence intervals (CIs) for these parameters were within the range of 0.80–1.25, which meets accepted bioequivalence criteria. The syrup‐to‐tablet ratio for C_max in saliva was 1.48, and the 90% CIs exceeded the accepted upper boundary for bioequivalence (1.32–1.66). Both formulations were well tolerated. Metabolite concentration versus time profiles for saliva were similar to plasma following tablet and syrup administration. Significance: The tablet and syrup formulations of lacosamide 200 mg were bioequivalent and well tolerated. Saliva samples were demonstrated to be a suitable surrogate to evaluate lacosamide tablet pharmacokinetics in the central compartment. Due to residual syrup in the buccal cavity, limitations exist when using saliva to evaluate the pharmacokinetics of lacosamide syrup <2 h after administration.     

Steady-State Pharmacokinetics of Topiramate and Carbamazepine in Patients with Epilepsy During Monotherapy and Concomitant Therapy

Summary: Purpose: We studied the steady-state pharmacokinetic profile of topiramate (TPM) as a function of dose and the effects of comedication with carbamazepine (CBZ). Methods: We enrolled 12 patients with partial epilepsy receiving chronic stable doses of CBZ 300–800 mg every 8 h. In a 6-week period, TPM was added and doses were increased at -2-week intervals from 100 to 200 to 400 mg every 12 h and stabilized at the highest tolerated dose to as high as 400 mg every 12 h. CBZ was tapered in the next 4 weeks when possible, and TPM was maintained as monotherapy at the highest stabilized dose for 2 more weeks. Plasma and urine samples were collected before TPM dosing, after each TPM dose increase, and during TPM monotherapy. Results: Dose-normalized results (n = 10) for TPM area under the curve from 0 to 12 h (AUC_(0–12)), C_min(0), and C_avg indicated that TPM exhibits linear plasma pharmacokinetics over the dose range of 100- to 400-mg every 12 h when administered with CBZ. Mean TPM AUC_(0–12)) C_max, C_min(0), and C_avg values were -40% lower during CBZ treatment as compared with those during TPM monotherapy (n = 3). TPM oral and nonrenal clearance rates were approximately two- to threefold higher, whereas TPM renal clearance was unchanged during concomitant CBZ treatment (n = 3). There were no significant changes in total and unbound CBZ and CBZ-epoxide (CBZ-E) pharmacokinetics during TPM administration (n = 10). TPM pharmacokinetics during concomitant CBZ treatment were significantly different from those during TPM monotherapy, suggesting that metabolic clearance of TPM increases when CBZ is coadministered. Conclusions: When CBZ is reduced or discontinued, TPM doses may need to be lowered to maintain equivalent plasma concentrations. Adjusting the CBZ dose for pharmacokinetic reasons when TPM is administered as adjunctive treatment does not appear to be necessary.     

Comparative pharmacokinetic analysis of USL255, a new once‐daily extended‐release formulation of topiramate

Purpose: To compare the pharmacokinetics of USL255, a once‐daily extended‐release (ER) formulation of topiramate (TPM), with Topamax (immediate‐release TPM) in healthy subjects after oral dosing and evaluate the effect of food on USL255 bioavailability and pharmacokinetics. Methods: This randomized, single‐center, open‐label, cross‐over design study had three dosing periods separated by 21 days of washout between treatments. Thirty‐six volunteers received single doses of USL255 (200 mg) in fasted and fed conditions and two doses of Topamax (100 mg) administered 12 h apart. TPM plasma samples were analyzed by liquid chromatography–mass spectroscopy. Pharmacokinetic parameters were calculated by noncompartmental methods. Key Findings: USL255 fasted pharmacokinetic parameters [point estimate (90% confidence interval, CI) compared to Topamax] were: relative bioavailability (F´) 91.2% (84–99%), peak plasma concentration (C_max) USL255/Topamax‐ratio 59% (53–65%), time to reach C_max (t_max) 19.5 ± 7.2 h, accumulation ratio (R_ac) 3.9 ± 1.2, effective half‐life (t_1/2,eff) 55.7 ± 19.9 h, terminal half‐life (t_1/2,z) 80.2 ± 14.2 h, and peak‐occupancy‐time (POT) 12.1 ± 4.0 h. Although the F´ and C_max were unaffected by food, R_ac and t_1/2,eff increased to 4.9 ± 0.9, and 72.5 ± 15.4 h, respectively. In contrast to t_1/2,z, t_1/2,eff reflects absorption rate; therefore, USL255’s t_1/2,eff was significantly longer than Topamax’s t_1/2,eff (37.1 ± 6.5 h). Significance: Although bioequivalent to Topamax in extent of absorption, USL255 had a slower absorption rate as reflected in its lower C_max and longer t_max, larger POT and longer t_1/2,eff, and similar R_ac values to that of Topamax (q12 h). This relative flat plasma profile allows for once‐daily dosing with diminished fluctuations in TPM plasma levels. In addition, neither USL255’s peak nor extent of plasma exposure of TPM was affected by food.     

Genetic Polymorphism of NAT2 Metabolizing Enzymes on Phenytoin Pharmacokinetics in Indian Epileptic Patients Developing Toxicity

SUMMARY Objective: To investigate the effects of NAT2 metabolizing enzymes on the pharmacokinetics of antiepileptic drug phenytoin in the epileptic patients showing toxicity. Methods: Fifty epileptic individuals who had developed toxicity to phenytoin and 50 control epileptic subjects who had not developed toxicity to phenytoin were genotyped for NAT2 (NAT2*5A, NAT2*5C, NAT2*7, NAT2*6) polymorphisms by polymerase chain reaction–restriction fragment length polymorphisms (PCR–RFLP method). Phenytoin plasma levels were analyzed by reversed phase HPLC method and pharmacokinetic parameters such as area under the concentration curve (AUC), maximum concentration (C_max), time to C_max (t_max) and half‐life (t_1/2) were estimated by noncompartmental analysis using PK Solutions® software. Results : The NAT2 polymorphism was seen to be in Hardy–Weinberg equilibrium and showed significant genotypic as well as allelic association with phenytoin toxicity for NAT2*5A (481C>T) and NAT2*5C (803A>G). Pharmacokinetic parameters for phenytoin in toxicity group of poor metabolizers showed a longer elimination half‐life of a drug (t_1/2= 35.3 h) and less clearance rate (CL = 468 mL/h) compared to intermediate metabolizers (t_1/2= 33.2 h, CL = 674 mL/h) and extensive metabolizer (t_1/2= 20.7 h, CL = 977 mL/h) in NAT2*5A polymorphism. Conclusion: Our findings suggest that the NAT2*5A genetic polymorphisms plays a significant role in the steady‐state concentrations of phenytoin and thereby have impact on toxicity in epileptic patients.     

Tolerability and Pharmacokinetics of Monotherapy Felbamate Doses of 1,200–6,000 mg/day in Subjects with Epilepsy

: Purpose: Felbamate (FBM) pharmacokinetic parameters, safety and tolerability in the dose range of 1,200–6,000 mg/day were assessed in two open-label studies with similar designs. Methods: In study A, newly diagnosed subjects with epilepsy receiving FBM monotherapy at a starting dose of 1,200 mg/day (400 mg/three times daily, t.i.d.) and increased 1,200 mg/day, if tolerated, at 14-day intervals to 3,600 mg/day were investigated. In study B, epilepsy subjects with prior FBM monotherapy exposure received ascending FBM doses in five consecutive 14-day periods with a starting dose of 3,600 mg/day (1,200 mg t.i.d.) FBM. In each successive period, if FBM was well tolerated, the dose was increased by 600 mg/day to a maximum of 6,000 mg/day (2,000 mg t.i.d.). Results: The pharmacokinetic parameter estimates maximum observed concentration (C_max), area under the concentration–time curve (AUCτ) C_trough, and C_av showed a linear dependence to dose above the 1,200–6,000 mg/day FBM dose range (F-tests; p <0.0001) with apparent clearance (Cl/kg) and T_max (time to C_max) independent of dose. When AUCτ, C_maxand C_troughwere adjusted for dose, there were no significant differences between the dosing periods. Conclusions: The data establish that plasma concentrations of FBM are linear with respect to dose to 6,000 mg/day. In addition, FBM was safely administered at these doses for periods as long as 14 days to epileptic subjects with prior exposure to FBM. FBM-naive subjects appeared to report more adverse experiences (generally of mild to moderate severity) than did subjects with prior FBM exposure.     

Interaction between brivaracetam (100 mg/day) and a combination oral contraceptive: A randomized,double‐blind,placebo‐controlled study

This randomized, double‐blind, placebo‐controlled, two‐way crossover study aimed to assess the pharmacokinetic interactions between brivaracetam 100 mg/day and a combination oral contraceptive (OC) containing 30 μg ethinylestradiol and 150 μg levonorgestrel. The study was performed in 28 healthy women over five 28‐day menstrual cycles: baseline (OC only), two treatment cycles with brivaracetam (50 mg b.i.d.) or placebo coadministered with OC separated by a wash‐out cycle (OC only), and a follow‐up cycle (OC only). The OC was administered on days 1–21 of each cycle, and brivaracetam or placebo on days 1–28 of the treatment cycles. Pharmacokinetics of ethinylestradiol and levonorgestrel were determined on day 20; brivaracetam morning trough levels on days 20 (with OC) and 29 (without OC) were compared. C_max (maximum plasma concentration) and AUC (area under the plasma concentration versus time curve) ratios for brivaracetam versus placebo (90% confidence interval [CI]) were 0.96 (0.88–1.04) and 0.90 (0.86–0.95) for ethinylestradiol, and 0.95 (0.91–0.99) and 0.92 (0.88–0.97) for levonorgestrel, within predefined bioequivalence limits (0.80–1.25). Brivaracetam trough levels were similar on days 20 and 29 (ratio 1.08; 90% CI 0.98–1.18). No differences in breakthrough bleeding were seen across the five cycles. It was concluded that there were no interactions between brivaracetam 100 mg/day and the OC. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Validation of [11C]ORM‐13070 as a PET tracer for alpha2c‐adrenoceptors in the human brain

This study explored the use of the α_2C‐adrenoceptor PET tracer [¹¹C]ORM‐13070 to monitor α_2C‐AR occupancy in the human brain. The subtype‐nonselective α₂‐AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (E_max and EC₅₀) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound‐to‐free ratio measured during 5–30 min post injection. Based on extrapolation of one‐site binding, the maximal extent of inhibition of striatal [¹¹C]ORM‐13070 uptake (E_max) achievable by atipamezole was 78% (95% CI 69–87%) in the caudate nucleus and 65% (53–77%) in the putamen. The EC₅₀ estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α_2C‐ARs. These findings represent clear support for the use of [¹¹C]ORM‐13070 for monitoring drug occupancy of α_2C‐ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10–16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin‐induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α_2C‐AR ligands in human subjects. [¹¹C]ORM‐13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies. Synapse 69:172–181, 2015. © 2014 Wiley Periodicals, Inc.     

Fosphenytoin dosing regimen including optimal timing for the measurement of serum phenytoin concentration in pediatric patients

IntroductionWe aimed to evaluate the pediatric fosphenytoin dosing regimen, including optimal timing for the measurement of total serum phenytoin concentration (C_PHT).MethodsWe retrospectively investigated pediatric patients with status epilepticus or seizure clusters treated with fosphenytoin between April 2013 and March 2018. Two C_PHT measurements were analyzed, one 2–4 h after the loading dose and another before the second dose. Individual pharmacokinetic parameters were estimated using the Bayesian method and were used to simulate C_PHT.ResultsThe present study involved 12 pediatric patients; the loading dose of fosphenytoin was 22.1 (17.2–27.2) mg/kg. The C_PHT was 13.4 (8.6–18.9) μg/mL 2–4 h after the loading dose. The C_PHT estimated from individual pharmacokinetic parameters 12 and 24 h after the loading dose was 9.5 (6.7–14.2) and 5.8 (3.7–10.0) μg/mL, respectively. If fosphenytoin was administered at a loading dose of 22.5 mg/kg and a maintenance dose of 5 or 7.5 mg/kg (administered every 12 h, starting 12 h after the loading dose), then the C_PHT on day 8 was estimated to be 5.74 (2.6–15.4) μg/mL at 5 mg/kg and 13.9 (5.7–31.0) μg/mL at 7.5 mg/kg.ConclusionsIn pediatric patients, a maintenance dose of fosphenytoin should be started 12 h after the loading dose, and a maintenance dose of 5–7.5 mg/kg/dose every 12 h may be better than every 24 h. We recommend measuring C_PHT at 2 and 12 h after the loading dose to simplify and safely adjust the dosage in clinical practice.     

Comparison of the Steady-State Pharmacokinetics of Topiramate and Valproate in Patients with Epilepsy During Monotherapy and Concomitant Therapy

Summary: Purpose: The steady-state pharmacokinetics of valproate (VPA) and topiramate (TPM) were compared during VPA monotherapy, concomitant VPA and TPM therapy, and TPM monotherapy to evaluate pharmacokinetic interactions. Methods: After a 3-week baseline period, 12 patients receiving VPA monotherapy (500 to 2,250 mg every 12 h) received TPM at three escalating doses (from 100 to 200 to 400 mg every 12 h), each for 2 weeks. Thereafter, the VPA dose was tapered by 25% weekly. Blood and urine samples were collected over 12-h intervals during VPA monotherapy and at the end of each stage of TPM dose escalation and TPM monotherapy. Results: All patients reached TPM monotherapy, and nine achieved satisfactory seizure control for 2 weeks without VPA. TPM plasma peak concentration (C_max) and area under the concentration-versus-time curve during a 12–h dosing interval (AUC_0–12) were slightly higher (17%; n = 8) during TPM monotherapy than during concomitant VPA therapy. TPM oral and renal clearances (n = 8) were 25.9 ± 4.6 and 11.6 ± 3.2 ml/min during TPM monotherapy and were 29.8 ± 4.2 and 12.4 ± 2.7 ml/min during VPA concomitant therapy. VPA AUC_(0–12) decreased (11.3%; n = 10) with the addition of TPM 400 mg every 12 h. VPA oral clearance was 12.8 ± 4.1 ml/min during monotherapy and was 13.8 ± 4.0,14.1 ± 3.9, and 14.5 ± 5.2 ml/min during coadministration of TPM 100, 200, and 400 mg every 12 h, respectively. Cognitive dysfunction, observed in some patients receiving high doses of VPA with TPM, reversed or improved with VPA dose reduction and discontinuation. The lower-than-normal prestudy platelet count measured in one patient increased to normal levels when VPA was discontinued. Conclusions: Because changes in TPM and VPA pharmacokinetics were small, it is unlikely that their concomitant use will have a significant impact on the clinical condition of the patient.     

Lamotrigine monotherapy compared with carbamazepine, phenytoin, or valproate monotherapy in patients with epilepsy

OBJECTIVE: This open-label study evaluated the efficacy and tolerability of lamotrigine monotherapy compared with monotherapy with conventional antiepileptic drugs in patients converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. METHODS: This study was conducted in 26 neurology clinics and epilepsy centers throughout the United States. The study enrolled 115 patients with epilepsy converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Patients were randomized 1:1 to receive 24 weeks of lamotrigine monotherapy or monotherapy with a conventional antiepileptic drug (carbamazepine, phenytoin, or valproate based on physician's choice). Patients were converted during an 相似文献   

Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson's disease

The objective of the study was to compare the pharmacokinetics, motor effects, and safety of IPX066, a novel extended‐release formulation of carbidopa‐levodopa, with an immediate‐release carbidopa‐levodopa formulation in advanced Parkinson's disease. We performed an open‐label crossover study in 27 subjects with advanced Parkinson's disease experiencing motor fluctuations on levodopa therapy. Subjects were randomized 1:1 to 8 days' treatment with either immediate‐release carbidopa‐levodopa followed by IPX066 or IPX066 followed by immediate‐release carbidopa‐levodopa. Pharmacokinetic and motor assessments were undertaken on day 1 for 8 hours (following a single dose) and on day 8 for 12 hours (during multiple‐dose administration). Following a single dose of IPX066 or immediate‐release carbidopa‐levodopa, plasma levodopa concentrations increased at a similarly rapid rate and were sustained above 50% of peak concentration for 4 hours with IPX066 versus 1.4 hours with immediate‐release carbidopa‐levodopa (P < .0001). Multiple‐dose data showed IPX066 substantially reduced variability in plasma levodopa concentrations despite a lower dosing frequency (mean, 3.5 vs 5.4 administrations per day). In addition, total levodopa exposure during IPX066 treatment was approximately 87% higher, whereas the increase in levodopa C_max was approximately 30% compared with immediate‐release carbidopa‐levodopa. Both products were well tolerated. IPX066 provided more sustained plasma levodopa concentrations than immediate‐release carbidopa‐levodopa. Larger, longer‐term, well‐controlled studies should be conducted to provide rigorous assessment of the clinical effects of IPX066. © 2011 Movement Disorder Society     

Pharmacokinetics of pitolisant in children and adolescents with narcolepsy

ObjectiveTo evaluate the pharmacokinetic profile and tolerability of pitolisant, a selective histamine 3 (H₃)−receptor antagonist/inverse agonist, in children and adolescents with narcolepsy.MethodsThis multicenter, open-label, single-dose study of pitolisant 17.8 mg enrolled patients aged 6 through 17 years with a diagnosis of narcolepsy. Blood samples were collected at prespecified time points for analysis of pharmacokinetic parameters, including maximum serum concentration (C_max) and area under the serum concentration–time curve from time 0–10 h (AUC_0–10h). Pharmacokinetic parameters were compared across three prespecified age groups: younger pediatric patients (aged 6 to <12 years), older pediatric patients (aged 12 to <18 years), and a historical comparison group of young adults (aged 18 to <45 years).ResultsOf the 25 enrolled patients, 24 were included in the pharmacokinetic analysis. Pitolisant C_max and AUC_0–10h were greater (by 52% and 73%, respectively) in the younger (n = 12) versus older (n = 12) pediatric subgroup. These parameters were lower in the young adult group (n = 13) by 51% and 48%, respectively, compared with the older pediatric patients, and by 68% and 70%, respectively, compared with the younger pediatric patients. There were six treatment-emergent adverse events: headache (three), dizziness (one), diarrhea (one), and vomiting (one).ConclusionsAfter single-dose administration, the exposure parameters of pitolisant were significantly greater in the younger compared with older pediatric patients with narcolepsy. Pitolisant doses up to 17.8 mg/d (in children with body weight <40 kg) or 35.6 mg/d are appropriate for further evaluation in pediatric patients.Trial registrationEudraCT Number: 2013-001505-93.     

Phenytoin intoxication during concurrent diazepam therapy

Phenytoin elimination is a saturable process obeying Michaelis-Menten kinetics. Plasma phenytoin levels are not related linearly to dose, and small changes in enzyme activity produced by concurrent drug therapy could alter plasma levels. Two cases of phenytoin intoxication associated with simultaneous administration of diazepam are reported. Intravenous phenytoin infusions were given and the apparent K_m and V_max computed from the resulting plasma phenytoin levels. In one case `K<sub>m</sub>' and `V_max' were 0.8 μmol/1 and 1.3 μmol/1/hour respectively during concurrent diazepam administration, and 50.3 μmol/1 and 4.4 μmol/1/hour after discontinuation of diazepam. In the second case phenytoin infusion with diazepam gave `K<sub>m</sub>' and `V_max' values of 0.012 μmol/1 and 0.95 μmol/1/hour. Without diazepam these were 28.8 μmol/1 and 0.92 μmol/1/hour respectively.     

Pharmacokinetic-pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to <10 years of age

Purpose: To identify and validate the efficacious monotherapy dosing regimen for topiramate in children aged 2 to <10 years with newly diagnosed epilepsy using pharmacokinetic–pharmacodynamic (PK–PD) modeling and simulation bridging. Methods: Several models were developed in pediatric and adult populations to relate steady‐state trough plasma concentrations (C_min ) of topiramate to the magnitude of clinical effect in monotherapy and adjunctive settings. These models were integrated to derive and support the monotherapy dosing regimen for pediatric patients. Key Findings: A two‐compartmental population PK model with first‐order absorption described the time course of topiramate C_min as a function of dosing regimen. Disposition of topiramate was related to age, body weight, and use of various concomitant antiepileptic drugs. The PK–PD model for monotherapy indicated that the hazard of time to first seizure decreased with increasing C_min and time since randomization. Higher baseline seizure frequency increased risk for seizures. Age did not significantly influence hazard of time to first seizure after randomization to monotherapy. For adjunctive therapy, the distribution of drug and placebo responses was not significantly different among age groups. Based on the available PK–PD modeling data, the dosing regimen expected to achieve a 65–75% seizure freedom rate after 1 year for pediatric patients age 2–10 years is approximately 6–9 mg/kg per day. Significance: This analysis indicated no difference in PK–PD of topiramate between adult and pediatric patients. Effects of indication and body weight on PK were adequately integrated into the model, and monotherapy dosing regimens were identified for children 2–10 years of age.     

Criteria to Assess In Vivo Performance and Bioequivalence of Generic Controlled-Release Formulations of Carbamazepine

Summary: Purpose: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled-release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (C_max), and time to reach C_max (t_max), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time-concentration curve. They include mean residence time (MRT), C_max/AUC, plateau time or POT (the time span associated with the concentrations within 25% of C_max), t_apical, and C_apical, (the arithmetic mean of the POT times and concentrations within 25% of C_max respectively). Additional parameters for multiple-dose studies include the percentage fluctuation and the flatness of the steady state-concentration curve. Methods: These proposed parameters were used in two recent (single and multiple dose) two-way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab. Results: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time-concentration curves as assessed by visual inspection and the proposed parameters. Conclusions: The additional parameters examined may supplement the traditional single-point parameters, C_max and t_max for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption-rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.     

Clinical and pharmacy utilization outcomes with brand to generic antiepileptic switches in patients with epilepsy

Purpose: To determine if switching from select branded to generic equivalent antiepileptic drugs (AEDs) in patients with epilepsy is associated with adverse outcomes. Methods: A retrospective cohort study using a large health insurance plan claims database comparing patients with epilepsy who switched from brand to generic equivalent phenytoin, lamotrigine, or divalproex after 6 months (switch cohorts) to matched patients who remained on the brand (nonswitch cohorts). Primary outcomes measured include the incidence rate ratio (IRR) of discontinuation of the index AED; change in dose of index AED or addition of another AED; and the event rate ratio (ERR) of the composite of all‐cause emergency department (ED) visits or hospitalizations. Key Findings: Lamotrigine and divalproex showed no differences in AED utilization changes between the switchers and nonswitchers [IRR for lamotrigine 1.00, 95% confidence interval (CI) 0.84–1.19; IRR for divalproex 1.02, 95% CI, 0.88–1.42]. Compared with nonswitchers, the phenytoin switch cohort had greater incidence of AED utilization changes (IRR 1.85, 95% CI 1.50–2.29). The switch versus nonswitch cohorts did not demonstrate differences in ED visits or hospitalizations for the studied AEDs (ERR for phenytoin 0.96, 95% CI 0.80–1.16; ERR for lamotrigine 0.97, 95% CI 0.80‐1.17; ERR for divalproex 0.83, 95% CI 0.66–1.06). Significance: Brand to generic switching of phenytoin was not associated with more clinical events but was associated with increased index drug discontinuations, dose changes, or therapy augmentations. Lamotrigine or divalproex brand to generic switching was not associated with increased incidence of events or utilization changes compared with patients remaining on the branded product. Changes in AED utilization may be more sensitive than ED visits and hospitalizations for detecting adverse outcomes.     

Effect of antiepileptic drug comedication on lamotrigine clearance

OBJECTIVE: To investigate the effect of antiepileptic drug (AED) comedication, including all newer AEDs, on lamotrigine clearance (CL). DESIGN: We reviewed 570 medical charts of outpatients 12 years and older seen at the Columbia Comprehensive Epilepsy Center who received lamotrigine as monotherapy or adjunctive therapy. We investigated whether a given comedication contributed to the lamotrigine serum concentration. In addition, we examined whether the mean lamotrigine CL during comedication with each AED differed from the lamotrigine CL during monotherapy. Finally, we examined whether individuals had significantly different lamotrigine CLs when taking or not taking a particular comedication. RESULTS: Comedication with phenytoin, carbamazepine, and valproate sodium were the major AED predictors of lamotrigine serum concentration. Comedication regimens with felbamate, oxcarbazepine, and phenobarbital were small but significant predictors. The mean lamotrigine CL was 43.2 mL/h per kilogram of body weight with lamotrigine monotherapy, significantly higher with comedication with phenytoin (101.3 mL/h per kilogram) and carbamazepine (59.5 mL/h per kilogram) and significantly lower with valproate (16.9 mL/h per kilogram). Patients had significantly higher lamotrigine CL when taking phenytoin, carbamazepine, and phenobarbital than when not taking those comedications and had significantly lower lamotrigine CL when taking valproate. The mean lamotrigine CL was significantly lower than that associated with monotherapy in patients comedicated with valproate plus phenytoin (22.0 mL/h per kilogram) but not in patients comedicated with valproate plus carbamazepine (33.3 mL/h per kilogram). No other AEDs affected lamotrigine CL. CONCLUSION: Phenytoin increases lamotrigine CL by approximately 125%, carbamazepine increases lamotrigine CL by approximately 30% to 50%, and valproate decreases lamotrigine CL by approximately 60%. No newer AED, with the possible exception of oxcarbazepine, has a major impact on lamotrigine CL.