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OBJECTIVE This post hoc analysis evaluated whether continued treatment with perampanel monotherapy beyond initial titration may be appropriate for patients with focal-onset seizures (FOS) with currently untreated epilepsy to achieve seizure freedom with an effective dose. METHODS Study 342 (NCT03201900; FREEDOM) is a single-arm, open-label, Phase III study of perampanel monotherapy. Patients aged ≥12 years with untreated FOS received perampanel 4 mg/d in a 32-week Treatment Phase (6-week Titration and 26-week Maintenance Periods); in case of seizure(s) during Maintenance Period, patients could enter a 30-week Treatment Phase (4-week Titration and 26-week Maintenance Periods) to be up-titrated to perampanel 8 mg/d. The primary endpoint was seizure-freedom rate during Maintenance Period in the modified Intent-to-Treat (mITT) Analysis Set (patients who had ≥1 post-dose efficacy measurement during Maintenance Period); safety was monitored. This analysis of 4-mg/d efficacy data assessed the proportion of patients achieving seizure freedom during the Maintenance Period (responders) relative to patients with an early/later response (depending on seizure status during the Titration Period). RESULTS In the mITT population (n = 73), 46 patients were 4-mg/d responders; of whom, 37 (80.4%) were early responders and nine (19.6%) were later responders. The mean (standard deviation) percent reductions in FOS frequency from baseline at the end of the 4-mg/d Titration Period were 100.0% (0.0%; early responders) and 46.3% (97.3%; later responders). Among the 27 4-mg/d nonresponders, nine (33.3%) patients who had an early response experienced seizure(s) during the subsequent 4-mg/d Maintenance Period. Safety outcomes were similar, regardless of responder status, without new safety concerns. SIGNIFICANCE Some patients with untreated FOS may benefit from continued treatment beyond initial titration of perampanel monotherapy to achieve seizure freedom, suggesting that it may not be appropriate to make treatment decisions to discontinue or switch from perampanel monotherapy solely based on seizure response before an effective dose has been reached.

To evaluate the exploratory time to exceed pre-randomization seizure count (T-PSC) in the determination of efficacy of adjunctive perampanel in participants with primary generalized tonic-clonic (PGTC) seizures in generalized-onset epilepsy.In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743), participants ≥12 years of age with treatment-resistant idiopathic generalized epilepsy were randomized to receive placebo or adjunctive perampanel (≤8 mg/day) across a 17-week double-blind treatment phase (4-week titration; 13-week maintenance). We evaluated the pre-planned exploratory end point of the T-PSC using a Kaplan-Meier analysis. We also re-evaluated the correspondence of the primary end points of median percent seizure frequency change (MPC) and 50% responder rate (50RR) calculated at T-PSC and at the end of the trial.The exploratory end point of median T-PSC on placebo was 43 days and120 days on perampanel (log-rank p .001). The primary end points calculated at T-PSC did not differ significantly from the end points at the end of the trial (MPC -31% vs -42% at T-PSC; 50RR 32% vs 51% at T-PSC). After T-PSC was reached, participants had a median (interquartile range) of 5 (3-13) additional seizures on placebo and 5 (2-10) on perampanel.The exploratory end point of T-PSC demonstrated the effectiveness of perampanel despite a shorter duration of monitoring. The seizures that occurred after T-PSC did not influence the conclusions of the trial; therefore, T-PSC may be a viable alternative to traditional trial end points that reduces the risk to participants.

Intravenous (IV) drug administration enables treatment of epilepsy when oral administration is temporarily not feasible. Perampanel is a once-daily antiseizure medication currently available as oral formulations. Study 050 (NCT03376997) was an open-label, randomized, single-dose, crossover study to evaluate the interchangeability of oral and IV perampanel in healthy subjects (N = 48). Bioequivalence of single 12-mg doses of IV (30-, 60-, or 90-minute infusion) and oral perampanel, ≥6 weeks apart, was assessed. Analyses indicated bioequivalence of area under the plasma concentration-time curve extrapolated to infinity for 30- and 60-minute IV infusions and oral perampanel doses (geometric mean ratio [90% confidence interval], 0.93 [0.84-1.02] and 1.03 [0.97-1.09], respectively); however, IV maximum observed drug concentration (C

BackgroundWe report data from three Phase IV, observational studies (Studies 506 [US;NCT03208660], 508 [India;NCT03836924] and 501 [Italy;NCT04257604]), which assessed real-world safety and efficacy of adjunctive perampanel across different regions.MethodsStudy 506 included patients with any seizure type. Studies 508/501 included patients with focal- onset seizures.Endpoints included: retention rate (Studies 506/501), median percent reduction in seizure frequency/28 days, seizure-freedom rates and safety.ResultsIn Study 506, the 12-month retention rate was 58.5% (n=876/1498). At Months 10–12, the median percent reduction in seizure frequency/28 days was 75.0% (n=123) and the seizure-freedom rate was 30.9% (n=38/123). In Study 508, the 6-month median percent reduction in seizure frequency/28 days was 100.0% (n=174) and seizure-freedom rate was 49.4% (n=86/174). In Study 501, the 6-month median percent reduction in seizure frequency/28 days, retention rate and seizure-freedom rate were 55.4% (n=198), 72.6% (n=170/234) and 18.0% (n=36/200), respectively. Treatment-emergent adverse events occurred in 704/1703 (41.3%; Study 506), 36/199 (18.1%; Study 508) and 132/234 (56.4%; Study 501) patients; the most common was dizziness/vertigo.ConclusionsPerampanel is efficacious and well tolerated during real-world use regardless of geographi- cal region; no unexpected safety signals emerged.FundingEisai Inc., Eisai Pharmaceuticals India Pvt., Ltd., and Eisai s.r.l.

BackgroundThis post hoc analysis assessed the efficacy and safety of adjunctive perampanel in adult/adolescent/paediatric patients with myoclonic and absence seizures during Phase II/III clinical studies.MethodsDuring Study 332 (NCT01393743), patients aged ≥12 years with generalised tonic-clonic seizures (GTCS) received placebo/adjunctive perampanel 8-mg/day. In Study 311 (NCT02849626), patients aged 4–NCT01527006), patients aged 2–ResultsOverall, 66/393 patients had myoclonic seizures (placebo, n=23; perampanel, n=43) and 72/393 had absence seizures (placebo, n=33; perampanel, n=39); patients with both seizure types are counted twice. Reductions in seizure frequency/28 days were observed with placebo and perampanel: myoclonic, 52.5% and 24.6%; absence, 7.6% and 25.1%, respectively. TEAEs with placebo and perampanel occurred in 18 (78.3%) and 36 (83.7%) patients with myoclonic seizures, and 25 (75.8%) and 34 (87.2%) patients with absence seizures, respectively; most common TEAEs with perampanel were dizziness and fatigue.ConclusionThese data suggest adjunctive perampanel does not worsen myoclonic/absence seizures in adult/adolescent/paediatric patients.FundingEisai Inc. stella_ngo@eisai.com32

BackgroundThe long-term (≤1-year) effects of adjunctive perampanel on cognition, behaviour and growth/development were assessed in paediatric patients aged 4–NCT02849626).MethodsCore Study (4-week pretreatment/23-week treatment) completers could enter the Extension (29-week maintenance/4-week follow-up). Assessments included: change from baseline at Week 52 for cognition (Aldenkamp-Baker Neuropsychological Assessment Schedule [ABNAS]), behavioural/emotional problems (Child Behaviour Checklist [CBCL]), visuomotor skills (Lafayette Grooved Pegboard Test [LGPT]) and growth/development.ResultsMean standard deviation (SD) change from baseline to Week 52 in total ABNAS score was -3.3 (16.6) (n=112). Mean (SD) change from baseline at Week 52 in CBCL total problems was -6.0 (14.0) and-1.6 (14.7) for patients aged 1.5–5 (n=17) and 6–18 years (n=102), respectively; for time to complete the LGPT, this was 5.3 (48.0) seconds for patients aged ≤8 years (n=33) and 0.4 (23.2) for patients aged >8 years (n=51). No significant impact on growth/development observed.ConclusionNo clinically significant changes were observed in cognition, behaviour or growth/devel- opment parameters following long-term (≤1 year) adjunctive perampanel in paediatric patients (aged 4–manoj_malhotra@eisai.com

BackgroundLong-term (1-year) seizure-freedom rates with adjunctive perampanel were assessed in paediatric patients aged 4–NCT02849626).MethodsSeizure-freedom rates (FOS, FBTCS, GTCS) were assessed in patients who achieved seizure freedom during the Core Study Maintenance Period and then remained seizure free for up to 12 months (calculated from the start of their seizure-free period). Data were stratified by concomitant enzyme- inducing anti-seizure medications (EIASMs) (with and without) and age (4–ResultsFor FOS, 6/11 (54.5%) patients remained seizure free for 12 months (with EIASMs, n=2/5 [40.0%]; without EIASMs, n=4/6 [66.7%]; 4–ConclusionDespite small patient numbers, seizure-freedom rates are maintained during long-term (1-year) perampanel treatment in paediatric patients, consistent with analyses in adolescents/adults.Funding.Eisai Inc. stella_ngo@eisai.com

BackgroundThe long-term efficacy and safety of adjunctive perampanel was evaluated in patients aged≥60 years with focal-onset seizures (FOS) with/without focal to bilateral tonic-clonic seizures (FBTCS) who participated in open-label extension Studies 307 (NCT00735397) and 335 (NCT01618695).MethodsPatients received perampanel 2–12 mg/day during Studies 307 (16-week blinded Conversion; 256-week Maintenance) and 335 (4-week Pre-conversion; 6-week Conversion; ≥46-week Maintenance). Assessments included median per cent reduction in seizure frequency/28 days vs pre-perampanel baseline, 50% responder rates and treatment-emergent adverse events (TEAEs).ResultsThe Safety Analysis Set included 71 patients (mean age, 64.0 years). Seizure frequency reductions during Years 1 and 2 were 31.7% (n=71) and 44.5% (n=38) (total FOS), and 95.5% (n=19) and 100.0% (n=9) (FBTCS), respectively. Seizure frequency reductions were observed during Years 3/4 (low patient numbers); over one-third of patients achieved a ≥50% seizure reduction each year. During Years 1, 2, 3 and 4, TEAE incidence was 87.3% (n=62/71), 60.4% (n=29/48), 47.4% (n=9/19) and 57.1% (n=8/14), respectively; most common were dizziness and fall during Years 1/2 and 3/4, respectively.ConclusionPerampanel was associated with reductions in seizure frequency over 4 years in elderly patients. The safety profile was consistent with the overall populations.FundingEisai Inc. stella_ngo@eisai.com33

BackgroundThe long-term (≤1-year) effects of adjunctive perampanel on cognition by responder status and modal dose were assessed in paediatric patients (aged 4–NCT02849626).MethodsCore Study (4-week pretreatment/23-week treatment) completers could enter the Extension (29-week maintenance/4-week follow-up). The Aldenkamp-Baker Neuropsychological Assessment Schedule [ABNAS] was used to assess cognition (change from baseline, Weeks 23/52) by total seizure response category (ResultsMean (standard deviation) change from baseline in total ABNAS for Weeks 23 and 52 by response category was: (14.8); 100%, -1.6 (18.3) and -0.6 (20.6), respectively; and by modal dose was: -2.0 (7.2); 4 mg/day, -4.8 (22.4) and -10.4 (25.6); >4–6 mg/day, 1.3 (8.3) and -1.3 (10.2); >6–8 mg/day, -0.5(10.7) and 1.9 (9.4); >8–12 mg/day, -0.1 (12.8) and -7.4 (20.2); >12–16 mg/day, 2.2 (12.4) and 1.1 (14.8), respectively.ConclusionAdjunctive perampanel had few long-term effects on cognition in paediatric patients, regard- less of responder status and modal dose.FundingEisai Inc.11m2anoj_malhotra@eisai.com

Purpose This post hoc analysis assessed the effects of adjunctive perampanel on myoclonic and absence seizure outcomes in patients (aged ≥12 years) with idiopathic generalized epilepsy (IGE) and generalized tonic-clonic seizures during the double-blind (up to 8 mg/day) and open-label extension (OLEx; up to 12 mg/day) phases of Study 332. Methods Patients experiencing myoclonic and/or absence seizures during study baseline were included. Assessments for myoclonic and absence seizures included: median percent change in seizure frequency, number of seizure days and seizure-free days (all per 28 days), 50 % and 75 % responder rates, seizure-freedom rates, seizure worsening, and monitoring of treatment-emergent adverse events (TEAEs). Results During the double-blind phase, myoclonic and/or absence seizures were reported in 47/163 and 60/163 patients, respectively. Median percent reductions in seizure frequency per 28 days from study baseline were 52.5% and 24.5% (myoclonic seizures) and 7.6 % and 41.2 % (absence seizures) for placebo and perampanel, respectively; seizure-freedom rates were 13.0 % and 16.7 % (myoclonic seizures) and 12.1 % and 22.2 % (absence seizures), respectively. During the OLEx phase, 46/138 and 52/138 patients experienced myoclonic and/or absence seizures, respectively. Responses during the double-blind phase were maintained during long-term (>104 weeks) adjunctive perampanel treatment. The frequency/type of TEAEs was consistent with the known safety profile of perampanel. Conclusion In this post hoc analysis, adjunctive perampanel was not associated with any overall worsening of absence seizures. Further research is needed to investigate the effect of adjunctive perampanel in IGE patients with myoclonic and/or absence seizures.

Objective Study 311 (NCT02849626) was a global, multicenter, open‐label, single‐arm study that assessed safety, tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamics of once‐daily adjunctive perampanel oral suspension in pediatric patients (aged 4 to

Study 311 (E2007-G000-311; NCT02849626) was a Phase 3, multicenter, open-label single-arm study of adjunctive perampanel oral suspension in pediatric patients (aged 4 to12 years) with partial-onset seizures (POS) (with/without secondarily generalized tonic-clonic seizures [SGTCS]) or primary generalized tonic-clonic seizures (PGTCS). Health-related quality of life (HRQoL) was an exploratory endpoint initially analyzed through simple descriptive summaries. The aim of this post hoc analysis was to provide a more thorough assessment of HRQoL.This analysis focused on EQ-5D-Y data collected at Baseline, Week 23, and Week 52. Individual dimensions, visual analog scale (VAS) and summed misery index (MI) were evaluated at all visits and compared by seizure type (POS versus SGTCS versus PGTCS), age (4 to7 versus 7 to12), and use of concomitant enzyme-inducing antiepileptic drugs (EIAEDs) (yes versus no). Paretian Classification of Health Change (PCHC) analysis summarized the proportion of patients who showed improvement or deterioration in HRQoL. Waterfall plots assessed changes in EQ-5D-Y scores by treatment-emergent adverse events (TEAEs) and by reduction in seizure frequency. Health state utility values associated with differing seizure frequency states were estimated using a linear mixed model.One hundred and fifteen patients completed EQ-5D-Y at relevant study visits (Seizure type: POS n = 84 [of which 21 had SGTCS], PGTCS n = 31; Age: 4 to7 years n = 30, 7 to12 years n = 85; Concomitant EIAEDs: Yes n = 35, No n = 80). Completion rates out of those expected to complete EQ-5D-Y were high at both timepoints (84.4% at Week 23 and 97.2% at Week 52). Overall, VAS/MI remained stable over time (did not exceed minimal important difference); this was similar according to seizure type, age, and EIAED usage. In patients with 'no problems' on any EQ-5D-Y dimension at Baseline, nearly all retained their full health at Week 23 (94.7%), and all retained it at Week 52 (100.0%). PCHC analysis showed fewer patients with POS experienced deterioration in EQ-5D-Y than patients with PGTCS at Week 23 (24.1% versus 42.1%). Not experiencing a TEAE, or remaining seizure-free, was associated with improvements in VAS score at Week 23 compared to those experiencing TEAEs or seizures, respectively. Health state utility values (HSUVs) were estimated as follows: seizure free (LS Mean 0.914 [95% CIs 0.587, 1.240]), ≥1 seizure per year (0.620 [0.506, 0.734]), ≥1 seizure per month (0.596 [0.338, 0.855]), ≥1 seizure per week (0.284 [-0.014, 0.582]).An in-depth analysis of EQ-5D-Y data allowed for a more nuanced exploration of HRQoL than previous descriptive summaries. Our findings provide evidence that perampanel as adjunctive therapy did not result in deterioration of patient HRQoL. The association between TEAEs or remaining seizure-free and HRQoL warrants further exploration. Increasing seizure frequency was associated with decreasing HSUVs; these can inform cost-effectiveness modeling of perampanel and other therapies aiming to reduce seizure frequency in pediatric patients.

Introduction Prothrombin complex concentrates (PCCs) are a common treatment option for the reversal of oral anticoagulation with vitamin K antagonists (VKAs). This study assessed efficacy and safety of Prothromplex Total®. Materials and Methods Patients (≥ 18 years) with acquired prothrombin complex coagulation factor deficiency (international normalized ratio [INR] ≥ 2 at screening) due to oral VKAs, requiring reversal of anticoagulation, were treated with 25, 35, or 50 IU/kg BW PCC. After infusion, efficacy was assessed for 72 ± 4 hours. Adverse events (AEs) were captured for 15 days. Results Sixty-one subjects, 48 requiring interventional procedures and 13 with acute bleeds, received a single infusion of PCC. Of 59 subjects analyzed, all achieved normalization of INR (≤ 1.3) within 30 ± 5 minutes of infusion, demonstrating effective anticoagulant reversal. IVRs of factors II, VII, IX, and X ranged from 1.12-2.03 IU/dL:IU/kg. Median INRs remained between 1.00 and 1.18 for up to 6 hours. Overall efficacy of treatment was rated “excellent” for 60 subjects. Three AEs were deemed possibly related to treatment: 1 serious AE (SAE) of acute myocardial infarction (rated severe), 1 SAE of deep vein thrombosis (rated mild), and 1 AE of pyrexia (rated mild). Thrombotic adverse events (2/61, 3.3%) reported here are comparable to rates observed in other PCC studies. Conclusions While there is a risk of thromboembolic events following treatment with PCC products, the number of events reported here was low and could have occurred without PCC treatment. The individualized, INR-based dosing of PCC used here for VKA anticoagulant reversal produces rapid normalization of INR to ≤ 1.3 within 30 minutes.

Leock Y Ngo,1 Adam Haeberle,1 Jacqueline Dyck-Jones,1 David Gelmont,1 Leman Yel11Baxter Healthcare Corporation, Westlake Village, CA, USAPurpose: Alpha1-proteinase inhibitor (A1PI) is indicated for chronic augmentation therapy in adults with emphysema due to congenital deficiency of A1PI. An intravenous infusion rate of 0.04 mL/kg/minute is currently recommended for the A1PI product, Glassia®. This randomized, placebo-masked, rate-controlled, crossover study was designed to evaluate the safety and tolerability of A1PI administration at an increased infusion rate.Patients and methods: A total of 30 healthy male and female subjects aged 19–61 years were enrolled. Each subject received simultaneous intravenous infusions of A1PI (Glassia®) and placebo (human albumin 2.5%) administered through a single infusion site on two separate treatment periods. Subjects were randomized in a 1:1 ratio to receive either test treatment (A1PI 0.2 mL/kg/minute + placebo 0.04 mL/kg/minute), or reference treatment (A1PI 0.04 mL/kg/minute + placebo 0.2 mL/kg/minute) on Day 1. On Day 15, subjects received the other treatment regimen in a crossover sequence.Results: A total of 36 adverse events (AEs), regardless of causality, were reported; all were non-serious and of mild intensity, with headaches and dizziness occurring most frequently (12 [33.3%] and three [8.3%] of 36 AEs, respectively). Only seven AEs in six subjects were assessed as related to study treatment: with two AEs reported in two subjects treated with the 0.2 mL/kg/minute rate compared with five AEs in four subjects treated with the 0.04 mL/kg/minute rate.Conclusions: This study demonstrated the safety and tolerability of an A1PI product at an increased infusion rate (0.2 mL/kg/minute) resulting in a shorter infusion duration in healthy subjects.Keywords: A1PI, Glassia, administration rate, Alpha-1 antitrypsin, ATT

The objectives of our study were to identify the types of nucleoside transporters present in the human fetal small intestine and to characterize their developmental activity, longitudinal distribution, and transport kinetics compared with those present in the adult intestine. Nucleoside uptake by intestinal brush-border membrane vesicles was measured by an inhibitor-stop rapid filtration technique. Only the purine-specific (N1; hCNT2) and the pyrimidine-specific (N2; hCNT1) Na+-dependent nucleoside transporters were found to be present on the brush-border membranes of the enterocytes along the entire length of the fetal and adult small intestines. The activity of these transporters was higher in the proximal than in the distal small intestine. Both the N1 and N2 transporters found in the fetal intestine shared similar kinetic properties (Michaelis-Menten constant and Na+-nucleoside stoichiometry) to those in the adult intestine. During the period of rapid morphogenesis (11–15 wk gestation), no temporal differences were apparent in the activity of the N1 and N2 transporters in the fetal small intestine. These findings have implications for the absorption of drugs from the amniotic fluid by the fetus after maternal drug administration of nucleoside drugs such as the antivirals zidovudine and didanosine.

Purpose: To determine the structure-inhibitory profiles of nucleosides for the N1 and N2 Na+-nucleoside transporters of the human intestine. Methods: The uptake of 3H-labeled prototypic substrates of the N1 (inosine) and N2 (thymidine) transporters into human intestinal brush border membrane vesicles was measured by a rapid filtration technique in the presence and absence of various uridine and adenosine analogs and antiviral and anticancer nucleoside drugs (100 and 1000 μM). Results: In the ribose ring, the 3′-oxygen is required for inhibition of uptake of nucleosides by both the N1 and N2 transporters. The structural requirements for such inhibition differ with respect to modifications on the 5′ position of the sugar ring or on the base. The N2 transporter is more tolerant to these substitutions than is the N1 transporter. The 6 position on uracil and the 8 position on adenine are critical for inhibition of uptake of nucleosides by both the N1 and N2 nucleoside transporters. Conclusions: These data are the first evidence that the binding site(s) of the human N1 and N2 transporters differ in their interaction with analogs of their common substrates, uridine and adenosine. Such studies can provide insight into the critical structural determinants of the substrate necessary for recognition by the Na+-nucleoside transporters of the human intestine.

Purpose: To clone and sequence the equilibrative nitrobenzylthioinosine (NBMPR)-sensitive nucleoside transporter (es) from the human small intestine and to examine the capacities of nucleosides and nucleoside analogs to inhibit the uptake of uridine by this transporter. Methods: Using PCR, es was cloned from a cDNA library of the human small intestine. The uptake of 3H-uridine (10 μM) by the recombinant es, expressed in Xenopus oocytes, was measured in the presence (2 mM) and absence of nucleosides and nucleoside analogs. Results: The amino acid sequence of this es transporter was identical to that of the human placental es transporter. Uptake of 3H-uridine by this es transporter was inhibitable by 1 μM NBMPR. Removal of the oxygen from the 3′ position or from both the 2′ and 3′ positions, but not from 2′ or 5′ position, resulted in a partial or total loss of the capacity of the nucleosides to inhibit 3H-uridine uptake. No modifications of the adenosine base or of the uridine base (except for 3 and 6 positions on uracil) affected nucleoside inhibitory capacity. Conclusions: The es transporters of the human intestine and placenta are identical in their amino acid sequences. Moreover, the inhibitory profiles of various nucleoside analogs in inhibiting the uptake of uridine by the intestinal es transporter are similar to those obtained with the as-yet-uncloned human erythrocyte es transporter. Collectively, these findings suggest that the es transporter does not appear to be functionally variant in the human placenta, small intestine or erythrocytes.

Intravenous immunoglobulin (IVIG) has become the standard treatment for multifocal motor neuropathy (MMN) based on limited data. To critically assess the efficacy, safety, and tolerability of 10% liquid IVIG (IVIG), 44 adults with MMN were randomized 1 : 1 to either double-blind treatment of IVIG followed by placebo for 12 weeks each or the reverse. Open-label IVIG was administered for 12 weeks at the beginning and end of the study for clinical stabilization, and between double-blinded periods to prevent a carry-over effect. To avoid potential worsening, switching to open-label IVIG was permitted if deterioration occurred during blinded treatment. Mean maximal grip strength of the more affected hand declined 31.38% during placebo and increased 3.75% during IVIG (p = 0.005). In 35.7% of participants, Guy's Neurological Disability scores for upper limbs worsened during placebo and not during IVIG, whereas the converse was true in 11.9% (p = 0.021). Sixty-nine percent (69.0%) switched prematurely from placebo to open-label IVIG and 2.4% switched from blinded to open-label IVIG (p

Concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs) are important in physiological and pharmacological activity and disposition of nucleosides and nucleoside drugs. A better understanding of the structural requirements of inhibitors for these transporters will aid in designing therapeutic agents. To define the relative and unified structural requirements of nucleoside analogs for interaction with hCNT1, hCNT2, and hENT1, we applied an array of structure-activity techniques. Unique pharmacophore models for each respective nucleoside transporter were generated. These models reveal that hCNT2 affinity is dominated by hydrogen bonding features, whereas hCNT1 and hENT1 displayed mainly electrostatic and steric features. Hydrogen bond formation over 3′-OH is essential for all nucleoside transporters. Inhibition of nucleoside transporters by a series of uridine and adenosine analogs and a variety of drugs was analyzed by comparative molecular field analysis. Cross-validated r2 (q2) values were 0.65, 0.52, and 0.74 for hCNT1, hCNT2, and hENT1, respectively. The predictive quality of the models was further validated by successful prediction of the inhibition of a set of test compounds. Addition of a hydroxyl group around the 2-position of purine (or 3-position of pyrimidine) may increase inhibition to hCNT2 transporter; addition of hydroxyl group around the 2,7-position of purine (or the 3,5-position of pyrimidine) would increase the inhibition to hENT1 transporter. Utilization of these models should assist the design of high-affinity nucleoside transporter inhibitors and substrates for both anticancer and antiviral therapy.

To evaluate if atovaquone (ATQ) interacts pharmacokinetically with azithromycin (AZ) in human immunodeficiency virus-infected children, 10 subjects (ages, 4 to 13 years) were randomized in a crossover study to receive AZ (5 mg/kg/day) alone (ALONE) or AZ (5 mg/kg/day) and ATQ (30 mg/kg/day) simultaneously (SIM) prior to receiving AZ and ATQ staggered by 12 h. Despite a lack of significant difference in the mean AZ pharmacokinetic parameters, the steady-state values of AZ’s area under the concentration-time curve from 0 to 24 h and maximum concentration in serum were consistently lower ( n = 7 of 7) for the SIM regimen than they were for the ALONE regimen. A larger study will be required to determine if ATQ affects AZ pharmacokinetics and efficacy in a clinically significant manner.

In this study, potential alterations in hepatic blood flow, plasma protein binding, hepatic tissue binding, and enzyme activities induced by LD iv infusion of lidocaine (LD) were evaluated using a chronically instrumented dog model. Four conscious female mongrel dogs (19.0-23.5 kg) were each given, on days 1 and 10, a 5-min infusion of a mixture of unlabeled LD at approximately 2 mg/kg and 14C-labeled LD at approximately 25 microCi and, on day 8, a 12-h constant rate iv infusion of LD (approximately 76 microg/kg/min). During LD infusion, there was a 11-79% increase in total hepatic blood flow, mainly due to a 1.6-9.2-fold increase in hepatic arterial flow. Despite similar blood clearance (27.5 +/- 6.0 mL/min/kg vs 27.5 +/- 3.5 mL/min/kg), volume of distribution at steady state (1.38 +/- 0.08 L/kg vs 1.36 +/- 0.17 L/kg), and free fraction values of LD between days 1 and 10 (p > 0.05), intrinsic clearance values were consistently reduced (1224 +/- 859 mL/ min/kg vs 285 +/- 104 mL/min/kg; p = 0.034). Furthermore, hepatic tissue uptake of LD and/or its metabolites was less on day 10 than on day 1 (39.7 +/- 14.5 micromol vs 30.1 +/- 15.1 micromol; p = 0.072). The extent of N-dealkylation of LD to MEGX was unaltered, whereas sequential biotransformation of MEGX was impaired. Hence, these findings suggested that LD infusion led to a reduction of hepatic intrinsic clearance, although the change was not significant enough to alter its conventional kinetic parameters.