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N‐methyl‐D‐aspartate ionotropic glutamatergic receptor (NMDAR) modulators, including rapastinel and ketamine, elicit rapid and sustained antidepressant responses in patients with treatment‐resistant major depressive disorder. This phase I, randomized, multicenter, placebo‐controlled, five‐period, crossover, single‐dose study evaluated simulated driving performance of healthy participants (N = 107) after single doses of rapastinel slow intravenous (i.v.) bolus 900 and 1800 mg, alprazolam oral 0.75 mg (positive control), ketamine i.v. infusion 0.5 mg/kg (clinical comparator), and placebo ~ 45 min before driving. The primary end point was SD of lateral position (SDLP) during the 60‐min 100‐km simulated driving scenario. Additional measures of driving performance, sleepiness, and cognition were also evaluated. To assess effects over time, mean SDLP was calculated for each 10‐min interval of driving. Sensitivity of the assays was confirmed with alprazolam (all placebo comparisons p 0.5). Both rapastinel doses resulted in significantly less impaired driving compared to alprazolam or ketamine (all p

Atogepant is a selective, oral calcitonin gene–related peptide receptor antagonist in development for preventive treatment of migraine. This randomized, double‐blind, phase 1 crossover study evaluated the cardiac repolarization effect of a single supratherapeutic (300 mg) atogepant dose vs placebo in healthy adults. Moxifloxacin 400 mg was the open‐label active control. The primary end point was a change from baseline in Fridericia‐corrected QT intervals (ΔQTcF). Sixty participants were randomized to atogepant 300 mg, placebo, and moxifloxacin; 59 (98.3%) completed all interventions. Assay sensitivity was confirmed: lower 90% confidence interval limit for QTcF interval change from baseline (ΔΔQTcF) for moxifloxacin was >5 millisecond vs placebo at prespecified 2‐, 3‐, and 4‐hour time points. Following single‐dose atogepant 300 mg, mean atogepant ΔΔQTcF and upper 90% confidence interval limits were lower than the 10‐millisecond threshold at all time points. Atogepant mean peak plasma concentration was 3197 ng/mL, area under the concentration‐time curve from time 0 to time t was 16 640 ng • h/mL, area under the concentration‐time curve from time 0 to 24 hours was 16 607 ng • h/mL, and median time to peak plasma concentration was 2.1 hours. The incidence of adverse events was low; no serious adverse events or elevations of liver enzymes were reported. Overall, a single supratherapeutic dose of atogepant was safe and did not impact cardiac repolarization in healthy participants.

Objective To evaluate the impact of two calcitonin gene–related peptide (CGRP)‐targeted monoclonal antibodies (mAbs), erenumab and galcanezumab, on the pharmacokinetic (PK) profile, safety, and tolerability of ubrogepant. Background People taking CGRP‐targeted mAbs for migraine prevention sometimes take ubrogepant, an oral small‐molecule CGRP receptor antagonist, for acute treatment of breakthrough migraine attacks. Design In this two‐arm, multicenter, open‐label, phase 1b trial, adults with migraine were randomized to arm 1 (ubrogepant ± erenumab) or arm 2 (ubrogepant ± galcanezumab). The PK profile of ubrogepant was characterized for administration before and 4 days after CGRP‐targeted mAb injection. Participants received single‐dose ubrogepant 100 mg on day 1, subcutaneous erenumab 140 mg (arm 1) or galcanezumab 240 mg (arm 2) on day 8, and ubrogepant 100 mg once daily on days 12–15. In each study arm, serial blood samples were drawn on days 1 and 12 for measurement of plasma ubrogepant concentrations. The primary outcomes were area under the plasma ubrogepant concentration–time curve (AUC) from time 0 to t post‐dose (AUC0– t) and from time 0 to infinity (AUC0–inf), and maximum plasma concentration (C max) of ubrogepant when ubrogepant was administered before or after a single dose of erenumab or galcanezumab. Vital signs and laboratory parameters were monitored. Results Forty participants enrolled (20 per arm; mean [standard deviation] ages, 32.2 [8.9] and 38.4 [8.8] years; 50% [10/20] and 60% [12/20] female in arms 1 and 2, respectively). There were no significant differences in ubrogepant C max after versus before erenumab administration (geometric least‐squares mean [LSM] ratio, 1.04 [90% CI, 0.93–1.16]), and no significant differences in AUC0– t (1.06 [0.96–1.16]) or AUC0–inf (1.05 [0.96–1.15]). Similarly, ubrogepant C max (1.00 [90% CI, 0.82–1.20]), AUC0– t (1.05 [0.90–1.23]), and AUC0–inf (1.05 [0.90–1.22]) geometric LSM ratios were statistically equivalent after galcanezumab versus ubrogepant alone. Treatment‐emergent adverse events (TEAEs) were similar to those reported with each treatment alone. No serious TEAEs, TEAEs leading to discontinuation, or clinically relevant changes in laboratory parameters or vital signs were reported. Conclusions The PK profile of ubrogepant was not significantly changed and no safety concerns were identified when ubrogepant was coadministered with erenumab or galcanezumab.

Background and Objectives Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, is approved for the treatment of adults with schizophrenia (1.5–6 mg/day) and manic/mixed (3–6 mg/day) episodes associated with bipolar I disorder. This population pharmacokinetic analysis describes the concentration-time profiles of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Additionally, the potential impact of patient characteristics, creatinine clearance, and cytochrome P450 2D6 (CYP2D6) metabolizer status on the pharmacokinetics of cariprazine and its metabolites was evaluated. Methods Data from three phase 1 and ten phase 2/3 studies in adult patients with schizophrenia or bipolar mania were included. Nonlinear mixed-effects pharmacokinetic modeling was performed using the NONMEM software package. Compartmental modeling was performed sequentially with the cariprazine elimination rate used as the DCAR formation rate and likewise the elimination rate of DCAR used with a delay as the DDCAR formation rate. Results Cariprazine pharmacokinetics were described by a three-compartment model with zero-order input of the dose to a depot compartment followed by first-order absorption and first-order elimination. DCAR and DDCAR pharmacokinetics were described by two-compartment models with linear elimination. Statistically significant predictors of pharmacokinetic parameters included weight, sex, and race, though differences in exposures were not large enough to require an adjustment in dose. Creatinine clearance was not a statistically significant predictor of drug clearance, and a post hoc analysis found that CYP2D6 metabolizer status was not associated with changes in exposure levels for cariprazine, DCAR, or DDCAR. The median time to 90% of steady state was approximately 1 week for cariprazine and DCAR and 3 weeks for DDCAR. Conclusions Population pharmacokinetic modeling provided a quantitative description of the concentration-time profile of cariprazine and its metabolites. Electronic supplementary material The online version of this article (10.1007/s13318-020-00650-4) contains supplementary material, which is available to authorized users.

Objective To evaluate the potential for pharmacokinetic interaction and the safety and tolerability when ubrogepant and sumatriptan are coadministered in a Phase 1 study in healthy participants, and to inform the safety and tolerability of ubrogepant alone and in combination with triptans in Phase 3 trials in participants with migraine. Background Calcitonin gene-related peptide is a potent vasodilatory neurotransmitter believed to play a key role in the pathophysiology of migraine. Ubrogepant (UBRELVY™) is a potent and selective antagonist of the human calcitonin gene-related peptide receptor approved for the acute treatment of migraine. Sumatriptan is a serotonin receptor agonist and the most commonly used triptan for the acute treatment of migraine. Ubrogepant could be prescribed with triptans. Design The Phase 1 study was a single-center, open-label, randomized, 3-way crossover, single-dose, pharmacokinetic interaction study, where participants received each of 3 oral treatments with a 7-day washout period between treatments: single dose of ubrogepant 100 mg, single dose of sumatriptan 100 mg, and ubrogepant 100 mg plus sumatriptan 100 mg. Pharmacokinetic parameters were calculated using a model-independent approach. The ACHIEVE I and II trials were 2 multicenter, single-attack, randomized, Phase 3 trials in adults with a history of migraine with or without aura. Participants had the option to take a second dose of study medication or rescue medication to treat a nonresponding migraine or a migraine recurrence from 2 to 48 hours after the initial dose of study medication. Rescue medication options included acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, anti-emetics, or triptans. Treatment-emergent adverse events were evaluated up to 30 days after the last dose in the Phase 1 and Phase 3 studies. Results Ubrogepant median time to maximum plasma concentration was delayed (3 hours [range: 1-5 hours] vs 1.5 hours [range: 1-4 hours]), mean maximum plasma concentration was reduced by 24% (coefficient of variation: 37.4%) when ubrogepant was coadministered with sumatriptan (n = 29) compared with ubrogepant administered alone (N = 30). No significant effect was observed on the area under the plasma concentration-time curve of ubrogepant. Sumatriptan area under the curve and maximum plasma concentration showed no significant change when sumatriptan was coadministered with ubrogepant (n = 29), but the sumatriptan time to maximum plasma concentration was delayed (1 hour [range: 0.5-5 hours] vs 3 hours [range: 0.5-6 hours]. No treatment-emergent adverse events were reported with the coadministration of ubrogepant 100 mg and sumatriptan 100 mg in the Phase 1 study. The pooled safety data from ACHIEVE trials (N = 1938) showed similar rates of treatment-related treatment-emergent adverse events between participants who took ubrogepant alone and participants who took ubrogepant and a triptan as a rescue medication (14.9% [53/355] vs 12.8% [5/39] in the ubrogepant 100 mg treatment group, respectively). Conclusions Although there were slight alterations in ubrogepant pharmacokinetic parameters when coadministered with sumatriptan, such changes are expected to have minimal clinical relevance, especially because no changes were seen in sumatriptan area under the curve and maximum plasma concentration when coadministered with ubrogepant. Coadministration of ubrogepant with sumatriptan was well tolerated in healthy participants in the Phase 1 study, and coadministration of ubrogepant with triptans was well tolerated in participants with migraine in the Phase 3 trials. No new safety concerns for ubrogepant were identified across all trials.

Population pharmacokinetic/pharmacodynamic modeling (via NONMEM) was used to describe longitudinal exposure-response relationships for total cariprazine (sum of cariprazine and its major active metabolites) in 2,558 patients with schizophrenia or bipolar mania. Drug exposure metrics were explored for potential relationships with efficacy and safety end points. Total cariprazine exposures were significantly related to reductions in Positive and Negative Syndrome Scale (PANSS) or Young Mania Rating Scale (YMRS) total scores in schizophrenia or bipolar mania, respectively, via a maximum effect (Emax )-type relationship. Typical steady-state plasma concentrations after 3 and 4.5 mg/day were associated with 50% of maximum typical reductions in PANSS and YMRS total scores, respectively. Time-weighted cariprazine exposures had significant relationships with the probability of common adverse events (AEs). Dose increase was associated with increased efficacy but was also associated with an increase in AEs. Results of these pharmacokinetic/pharmacodynamic analyses support that the recommended dose range (1.5-6 mg/day for schizophrenia and 3-6 mg/day for bipolar mania) provides an appropriate benefit-risk balance between cariprazine efficacy and safety.

Ubrogepant is a novel, oral calcitonin gene-related peptide receptor antagonist currently under US Food and Drug Administration (FDA) review for the acute treatment of migraine attacks. This double-blind, four-period crossover study compared the cardiac repolarization effect of therapeutic (100 mg) and supratherapeutic (400 mg) ubrogepant doses vs. placebo in healthy adults. Moxifloxacin 400 mg was used as an open-label active control, and the primary end point was change from baseline in Fridericia-corrected QT intervals (ΔQTcF). Assay sensitivity was demonstrated via statistically significant QTcF prolongation with moxifloxacin vs. placebo. After single oral doses of ubrogepant, the least squares mean placebo-corrected ΔQTcF (ΔΔQTcF) and 90% confidence intervals (CIs) did not exceed the 10-millisecond regulatory threshold at any timepoint. The 90% CI upper bounds were 2.46 milliseconds and 2.69 milliseconds for ubrogepant 100 and 400 mg, respectively. Categorical and concentration-based analyses were consistent with the primary result, showing no significant impact of ubrogepant on cardiac repolarization.

Aim: To evaluate pharmacokinetic interactions of atogepant with sumatriptan, an open-label, randomized, crossover study was conducted. Patients & methods: Thirty healthy adults received atogepant 60 mg, sumatriptan 100 mg, or coadministered drugs. Primary end point was geometric mean ratios (GMRs) and 90% CIs of interventions for area under the plasma concentration–time curve from time 0 to t (AUC0-t) or infinity (AUC0-∞) and peak plasma concentration (Cmax). Results: Atogepant GMRs for AUC0-t and AUC0-∞ versus with sumatriptan were within 90% CI 0.80–1.25, indicating no interaction; atogepant Cmax was reduced by 22% (GMR: 0.78; 90% CI: 0.69–0.89) with sumatriptan. Sumatriptan GMRs for AUC0-t, AUC0-∞ and Cmax versus with atogepant were within 90% CI 0.80–1.25. Conclusion: Atogepant with sumatriptan had no clinically relevant pharmacokinetic interactions.

Christoph U Correll,1–3 Rakesh Jain,4 Jonathan M Meyer,5 Antonia Periclou,6 Timothy Carrothers,6 Ágota Barabássy,7 Mehul Patel,8 Willie Earley91Department of Psychiatry, Northwell Health, The Zucker Hillside Hospital, Glen Oaks, NY, USA; 2Hofstra Northwell School of Medicine, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; 3Charité Universitätsmedizin, Department of Child and Adolescent Psychiatry, Berlin, Germany; 4Texas Tech University School of Medicine – Permian Basin, Department of Psychiatry, Midland, TX, USA; 5University of California, San Diego School of Medicine, Department of Psychiatry, La Jolla, CA, USA; 6Allergan, Department of Clinical Pharmacology, Madison, NJ, USA; 7Department of Medical Affairs, Gedeon Richter Plc, Budapest, Hungary; 8Department of Medical Affairs, Allergan, Madison, NJ, USA; 9Department of Clinical Development, Allergan, Madison, NJ, USACorrespondence: Christoph U CorrellThe Zucker Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, NY 11004, USATel +1 718 470 4812Email ccorrell@northwell.eduObjective: To explore the timing of relapse following drug discontinuation and its relationship to estimated plasma levels and elimination half-life by comparing data from a randomized, placebo-controlled discontinuation study of cariprazine with those from similarly designed and conducted randomized control trials of other oral atypical antipsychotics (AAPs).Methods: Data from a long-term, randomized, double-blind, placebo-controlled relapse prevention study in participants with schizophrenia (NCT01412060) were analyzed. Similarly designed, published studies of other AAPs were used for comparison. Time to drug-placebo relapse separation and relapse rates were estimated from Kaplan–Meier curves and evaluated descriptively. Separation was defined as a sustained difference of ≥5% incidence of relapse between the AAP and placebo curves.Results: The Kaplan–Meier curve for cariprazine showed a time to drug-placebo relapse separation at 6–7 weeks after randomization, compared to the Kaplan–Meier curves for the other AAPs, which showed earlier separation at 1–4 weeks. The placebo relapse rates at 4 weeks after randomization were 5% for cariprazine and 8–34% for other AAPs. Geometric mean values of model-predicted plasma concentrations for total active cariprazine moieties (sum of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine) were 20.0 and 6.1 nM at 2 and 4 weeks after discontinuation, respectively. Elimination half-lives of other AAPs and their active metabolites (

Atogepant is a selective oral calcitonin gene‐related peptide receptor antagonist in development for migraine prevention. Here, we report the pharmacokinetics (PK) and safety of single‐dose 60 mg atogepant in participants with severe, moderate, or mild hepatic impairment and matched participants with normal hepatic function from an open‐label, parallel‐group, single‐dose phase 1 trial. Thirty‐two participants aged 45 to 72 years were enrolled, which included 8 each with severe, moderate, mild, or no hepatic impairment. All participants completed the study. Atogepant was rapidly absorbed (median time to maximum plasma concentration, ∼2 hours) with an apparent terminal elimination half‐life of ∼11 hours. Compared with participants with normal hepatic function, the change in maximum plasma concentrations of atogepant were –4%, –12%, and +9% in participants with severe, moderate, or mild hepatic impairment, respectively. Overall systemic exposures to atogepant were 15% to 38% higher in participants with hepatic impairment compared with those with normal hepatic function, but these differences are not expected to be clinically relevant given the established safety profile of atogepant. Only 1 adverse event was reported: mild rhinorrhea in a participant with moderate hepatic impairment. Overall, atogepant was safe and not associated with any clinically relevant change in PK in participants with severe, moderate, or mild hepatic impairment.

Rationale Second-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia. Objective The purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia. Methods Using [11C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations. Results A monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing. Conclusion This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.

Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor with balanced potency for the reuptake inhibition of norepinephrine and serotonin, approved in the USA for the treatment of major depressive disorder (MDD) in adults. We conducted studies in healthy human subjects to investigate pharmacokinetic interactions when levomilnacipran extended-release (ER) is administered in combination with an inhibitor (ketoconazole), an inducer (carbamazepine), or a substrate (alprazolam) of cytochrome P450 (CYP) 3A4. Randomised, open-label studies were conducted in healthy volunteers (n = 34 ketoconazole, n = 34 carbamazepine, n = 30 alprazolam) and pharmacokinetic parameters were determined when levomilnacipran was administered alone or together with the relevant study drug. Co-administration of ketoconazole with levomilnacipran ER increased levomilnacipran maximum concentration (C max) by 39 % [90 % confidence interval (CI) 31–47 %] and area under the concentration–time curve (AUC) by 57 % (90 % CI 47–67 %), whereas carbamazepine reduced the C max and AUC of levomilnacipran by 26 % (90 % CI 22–30 %) and 29 % (90 % CI 26–32 %), respectively. Levomilnacipran at steady state had no significant effect on the pharmacokinetics of a single 1 mg dose of alprazolam extended release (XR); neither did single-dose alprazolam XR affect the steady-state pharmacokinetics of levomilnacipran. No new safety concerns were noted in these studies. Based on these results, the levomilnacipran ER dose should not exceed 80 mg once daily when used with ketoconazole, compared to 120 mg once daily in the absence of ketoconazole. No dose adjustment for levomilnacipran is suggested when levomilnacipran ER is co-administered with carbamazepine or other CYP3A4 inducers. Co-administration with levomilnacipran of drugs metabolised by CYP3A4, such as alprazolam, requires no dose adjustment due to pharmacokinetic considerations.

BACKGROUND: Relapse prevention remains an important treatment goal in schizophrenia, and oral atypical antipsychotics (AAPs) with long half-lives may confer continued treatment effects in cases of partial adherence or after drug discontinuation. Cariprazine, an oral dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist with a relatively long half-life, is approved for the treatment of schizophrenia in the US and Europe. Cariprazine forms 2 major metabolites, desmethyl cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), which are pharmacologically equipotent to cariprazine; half-lives are 2–4 days for cariprazine, 1–2 days for DCAR, and 1–3 weeks for DDCAR. Here, we conducted a post hoc analysis of published relapse prevention clinical studies to explore the timing of relapse following drug discontinuation and its relationship to predicted plasma levels. METHODS: Data from a long-term, randomized, double-blind (DB), fixed-dose, placebo (PBO) controlled cariprazine relapse prevention study in patients with schizophrenia (NCT01412060) were analyzed. Patients were stabilized with cariprazine (3, 6, or 9 mg/day) during a 20-week, open-label phase, and eligible patients (eg, Positive and Negative Syndrome Scale [PANSS] total score ≤60, decrease from baseline ≥20% in PANSS total score) were randomized 1:1 to continue cariprazine or switch to PBO for up to 72 weeks of DB treatment. Relapse was defined by objective rating scale criteria, psychiatric hospitalization, and subjective clinical measures. Published studies of other oral AAPs with similar designs (e.g., stabilization phase ≥8 weeks, PBO-controlled) were used for comparison; elimination half-life of the other oral AAPs ranged from

Purpose Levomilnacipran, a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor, is approved for the treatment of major depressive disorder (MDD) in adults. The objectives of this investigation were to characterize the pharmacokinetic (PK) parameters of levomilnacipran in healthy subjects and in patients with MDD and to compare the plasma concentrations observed at clinically effective doses (40–120 mg daily) in MDD patients versus in vitro inhibitory concentration values for NE and 5-HT transporters. Methods Data from 2 trials were analyzed: a Phase I trial (healthy volunteers received a single dose of levomilnacipran extended-release capsule [ER; 25, 50, or 100 mg], escalating multiple doses of levomilnacipran ER [25–300 mg once daily], or placebo); and a Phase III trial (adults with MDD received a fixed dose of levomilnacipran ER [40, 80, or 120 mg once daily for 8 weeks]). Plasma samples of participants were assayed to determine levomilnacipran concentrations, and PK analyses were performed. Unbound plasma concentrations of levomilnacipran in MDD patients were estimated, and inhibitory concentration values were determined by curve fitting of the in vitro data. Findings C max and AUC were dose proportional after single dosing (25–100 mg) and multiple dosing (across the 25–300 mg dose range) of levomilnacipran ER in healthy subjects. Dose-proportional steady-state C max (93, 180, and 297 ng/mL) and AUC 0–τ (1520, 2935, and 4799 ng*h/mL) were also observed in patients with MDD who received levomilnacipran ER (40, 80, and 120 mg daily). T max was ~6 hours and was similar after single and multiple oral doses of levomilnacipran ER. Estimates of levomilnacipran concentration at 50%, 80%, and 90% inhibition were 19, 91, and 237 nM, respectively, for the 5-HT transporter, and 10, 41, and 92 nM for the NE transporter. Average unbound plasma concentrations for levomilnacipran in MDD patients treated with levomilnacipran ER 40, 80, or 120 mg daily exceeded the estimated concentration at 80% and 90 % inhibition for 5-HT and NE. Implications Levomilnacipran PK was dose proportional after single and multiple dosing and was similar between healthy subjects and patients with MDD. Steady-state unbound plasma concentrations of levomilnacipran across the approved dose range (40, 80, and 120 mg daily) in MDD patients were estimated to be comparable or greater than the concentrations that inhibited reuptake of NE and 5-HT by >90% and >80%, respectively, in vitro.

In contrast to that in children, pharmacokinetic, pharmacodynamic, and safety information on pegaspargase in adults is very limited. We administered a single intravenous dose of pegaspargase (2000 IU/m2) as part of a standard frontline induction regimen to 25 adults with newly diagnosed acute lymphoblastic leukemia (ALL), and obtained serum samples on several time points. The population mean peak serum concentration of asparaginase enzymatic activity was 1 IU/mL, the elimination half-life was 7 days, and the volume of distribution was 2.43 L/m2. After the single dose, asparagine deamination was complete in all patients after 2 hours, and in 100%, 81%, and 44% on days 14, 21, and 28, respectively. A pharmocodynamic correlation model showed minimal enzymatic activity of 0.2 IU/mL for optimal asparagine depletion. The kinetic posthoc analyses demonstrated enzymatic activity for 3 weeks or more. One patient developed neutralizing antiasparaginase antibodies on day 22 after administration. Pegaspargase was well tolerated, with few grade 3/4 side effects. No allergic reactions or pancreatitis were observed. In adults aged 55 years or younger, pegaspargase produces a long duration of asparagine depletion and can be given intravenously, with a safety profile that is similar to equivalent multiple doses of intramuscular Escherichia coli asparaginase.

Objective Our objective was to evaluate the pharmacokinetics of the Alzheimer's disease treatment memantine in subjects with normal and impaired renal function. Methods This was a single-center, single-dose, open-label study. Thirty-two subjects aged 18 to 80 years were assigned to 1 of 4 groups (8 subjects each) based on baseline creatinine clearan normal renal function (>80 mL/min), mild renal impairment (50–80 mL/min), moderate renal impairment (30–49 mL/min), and severe renal impairment (5–29 mL/min). A single 20-mg memantine dose was administered under fasting conditions. Assessments included pharmacokinetic and safety measures. Results Thirty-one subjects completed the study. There were no relevant differences in maximum memantine plasma concentration between subjects with normal and impaired renal function of any severity. The mean area under the plasma concentration versus time curve extrapolated to infinity was similar between subjects with normal and mildly impaired renal function but increased by 60% (95% confidence interval [CI], 24%–97%) and 115% (95% CI, 77%–152%) in subjects with moderate and severe renal impairment, respectively. Simulations predicted steady-state maximum concentration values of 82 ng/mL (95% CI, 70–95 ng/mL), 85 ng/mL (95% CI, 70–101 ng/mL), and 128 ng/mL (95% CI, 109–147 ng/mL) in healthy subjects, those with mild renal impairment, and those with moderate renal impairment, respectively, for the recommended dosing regimen of 10 mg twice daily; for subjects with severe renal impairment, a steady-state maximum concentration value of 84 ng/mL (95% CI, 68–101 ng/mL) was predicted for a dosing regimen of 5 mg twice daily. Conclusion On the basis of the predicted steady-state plasma concentrations with the use of the current dosing regimen of 10 mg twice daily, no dosage adjustments are needed for patients with mild or moderate renal impairment. A target dose of 5 mg twice daily is recommended in patients with severe renal impairment. Clinical Pharmacology & Therapeutics (2006) 79, 134–143; doi: 10.1016/j.clpt.2005.10.005

Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of major depressive disorder, is extensively hepatically metabolized. The pharmacokinetics, tolerability, and safety of vilazodone were investigated in 2 trials comparing participants with hepatic impairment with healthy controls. In these phase 1, open-label, parallel-group, single-dose pharmacokinetic studies, vilazodone (20 mg) was administered to participants with mild, moderate, or severe hepatic impairment or individually matched healthy controls. Vilazodone and M17 (the major metabolite) concentrations in plasma were analyzed using validated liquid chromatography with tandem mass spectrometry. Forty-eight participants (8 each in mild, moderate, and severe hepatic impairment groups with matched healthy controls) were evaluated for pharmacokinetic analyses. All pharmacokinetic parameters in participants with mild and moderate hepatic impairment were similar to those in healthy controls. Mean Cmax and AUC0-∞ were approximately 29% and 17% lower in participants with severe hepatic impairment compared with healthy participants; values for Tmax, and t1/2 were similar between groups. Diarrhea was experienced by more participants with hepatic impairment than controls (10 vs. 5, respectively), and vomiting (4 participants) occurred only in participants with severe hepatic impairment; other adverse events were roughly equivalent between groups. Following a single, 20-mg oral dose of vilazodone, pharmacokinetics were similar in participants with mild, moderate, or severe hepatic impairment and healthy controls. No dose adjustment is needed for patients with major depressive disorder who have mild, moderate, or severe hepatic impairment.

BACKGROUND: Memantine, a low- to moderate-affinity, uncompetitive N-methyl-d-aspartate receptor antagonist, was approved in the US for treatment of moderate to severe Alzheimer's disease in October 2003. OBJECTIVE: To determine whether an in vivo pharmacokinetic interaction exists between memantine and the acetylcholinesterase (AChE) inhibitor donepezil. METHODS: In this open-label, multiple-dose study, 24 healthy subjects (aged 18–35 y) received oral administration of memantine 10 mg on day 1. Following a 14-day washout period, subjects were orally administered donepezil 5 mg once daily for 7 days on an outpatient basis. Beginning on day 22, the donepezil dosage was doubled for 22 days to the target dose of 10 mg once daily, with the last donepezil dose concomitantly administered with memantine 10 mg on day 43. Assessments included pharmacokinetic as well as safety parameters. In addition, AChE inhibition was measured in red blood cells by radiolabeled-enzyme assay following administration of donepezil alone and after a single memantine dose. RESULTS: Data from 19 subjects who completed the study indicated no significant pharmacokinetic interactions between a single dose of memantine and multiple doses of donepezil. Percent maximum inhibition of AChE activity (mean ± SD) by donepezil was 77.8 ± 7.3% and not significantly different upon coadministration of a single dose of memantine (81.1 ± 5.7%). Two subjects withdrew due to adverse events while taking donepezil alone. Single memantine doses administered with multiple donepezil doses were well tolerated. CONCLUSIONS: The pharmacokinetic and pharmacodynamic data from this study indicated a lack of interaction between memantine and donepezil, suggesting that memantine and donepezil may be safely and effectively used in combination.

Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor with greater potency for the reuptake inhibition of norepinephrine than of serotonin, approved in the USA for the treatment of major depressive disorder (MDD) in adults. A single-dose, open-label, parallel-group study was conducted to evaluate the effects of hepatic impairment on the pharmacokinetics of levomilnacipran in adults with mild, moderate, or severe hepatic impairment and normal controls receiving a 40 mg levomilnacipran extended-release (ER) capsule. The concentrations of levomilnacipran and its inactive metabolite, N-desethyl levomilnacipran, in plasma and urine were measured using liquid chromatography–tandem mass spectrometry methods. Pharmacokinetic parameters of levomilnacipran and N-desethyl levomilnacipran were derived and assessed. Safety parameters were assessed throughout the trial. No deaths, serious adverse events, or discontinuations due to adverse events occurred. The maximum plasma drug concentration (C max) and area under the plasma concentration–time curve from time zero to infinity (AUC∞) of levomilnacipran were 28 and 32 % higher, respectively, in participants with severe hepatic impairment than in healthy participants without a notable change in the t ½, whereas the C max and AUC∞ of N-desethyl levomilnacipran were 66 and 85 % lower, respectively, suggesting liver function has minimal impact on the overall exposure of levomilnacipran but plays a significant role in the formation of the metabolite. A single dose of levomilnacipran ER 40 mg was generally well-tolerated in participants with varying degrees of hepatic impairment and healthy controls. Therefore, dose adjustment for levomilnacipran is not necessary in adult MDD patients with impaired liver function.

Objective To evaluate and compare the pharmacodynamic effects of IY-81149 and omeprazole on gastric pH in patients with gastroesophageal reflux disease. Methods Sixty male and female volunteers with gastroesophageal reflux disease were enrolled in a double-blind, two-way, crossover, dose-ranging study. Subjects were randomized into three groups, with each group comparing the effect of one of three doses of IY-81149 (5, 10, or 20 mg) with 20 mg omeprazole. IY-81149 and omeprazole were administered once daily for 5 days. Continuous 24-hour pH measurements were performed before the first dose (baseline) and after the fifth dose in both periods. Gastric acid suppression was evaluated on the basis of the following parameters: AUC(0-24), median pH in a 24-hour interval (pHmedian), and the percent time in a 24-hour interval in which the gastric pH was greater than 4 (tpH > 4). The truncated AUC parameters AUC(0-8), AUC(8-16), and AUC(16-24) were also calculated. The effects of IY-81149 and omeprazole on gastric pH were compared by use of analyses of covariance. The dose-response relationship for IY-81149 was also evaluated. Results There were no statistically significant differences between 5 mg IY-81149 and 20 mg omeprazole in terms of AUC(0-24), pHmedian, tpH > 4, AUC(0-8), and AUC(8-16). IY-81149, at 10 mg, produced a significantly greater gastric acid suppression than omeprazole on the basis of the values of AUC(0-24), pHmedian, tpH > 4, AUC(8-16), and AUC(16-24). Administration of 20 mg IY-81149 produced a significantly greater gastric acid suppression on the basis of all parameters. All doses of IY-81149 were more effective than omeprazole during 16 to 24 hours after the dose was administered. Conclusions Administration of 10 and 20 mg IY-81149 produced a statistically significantly greater and prolonged suppression of gastric pH than 20 mg omeprazole. Clinical Pharmacology & Therapeutics (2000) 68, 304–311; doi: 10.1067/mcp.2000.109155

Combinations of nucleoside analog drugs such as 6-MP. ara-C. or F-araA are synergistic against human leukemic T-cells and induce apoptotic cell death. Addition of Taxotere or PEG-ASNase to the synergistic combination of nucleoside analog drugs augments the synergism several fold by enhancing cellular apoptosis.

We examined the population pharmacokinetics (PPK) of cytosine arabinoside (ara-C) after high-dose ara-C (HDara-C) (3 g/m2 every 12 h) and after a loading bolus (LB) plus continuous infusion (C1) of ara-C for 72 h in 52 pediatric patients with leukemias, enrolled in four clinical trials. The PPK analyses of the drug were performed using the NONMEM program. The patients' ages ranged from 2 months to 19 years. The ara-C data were analyzed using a two-compartment open model. Interindividual variability was described by the constant coefficient of variation (CCV) model, while the intraindividual variability was described by a combined additive and CCV error model. The covariates age (AGE) and surface area (SA) were tested to examine their influence on the estimation of the ara-C PPK parameters. In the absence of model covariates, the data fit was characterized by considerable bias, as indicated by the plot of measured vs predicted ara-C concentrations. The fit of the data was greatly improved when the parameters total body clearance (CL), intercompartmental clearance (Q), and volumes of distribution of central (Vd1) and peripheral (Vd2) compartments were expressed as linear functions of the covariate product, AGE x SA. The final parameter estimates were: CL = 2.59 x AGE x SA 1/h, Q = 2.01 x AGE x SA 1/h, Vd1 = 0.48 x AGE x SA1, and Vd2 = 38.1 x AGE x SA1. The coefficients of variation of CL, Q, Vd1 and Vd2 were 83.79%, 12.08%, 40.0%, and 52.54%, respectively, indicating substantial interindividual variability. In separate NONMEM analyses, the PK of ara-C and its metabolite uracil arabinoside (ara-U) were modeled simultaneously in order to investigate whether the dependence of ara-C on patient age was due to increased deamination of ara-C to ara-U. The PK of ara-C were described by the two-compartment open model while the PK of ara-U were simultaneously described by the one-compartment open model. The conversion of ara-C to ara-U was modeled as a first-order kinetic process due to the relatively low concentrations of ara-C in plasma. These PPK analyses indicated that elimination of ara-C from the central compartment occurs primarily by its metabolic conversion to ara-U and that the rate of conversion of ara-C to ara-U increases with increasing patient age, which explains the higher ratios of ara-U to ara-C and, hence, the increased ara-C clearance observed in older children as compared to infants. We conclude that the NONMEM PPK methodology allowed the simultaneous analyses of data from different doses and dose regimens and explained phenomena that prior standard two-stage analyses could not.

Milnacipran, a serotonin and norepinephrine reuptake inhibitor with preferential inhibition of norepinephrine reuptake over serotonin, is approved in the United States for the management of fibromyalgia. Owing to its effects on norepinephrine and serotonin, as well as its lack of activity at other receptor systems, it was hypothesized that milnacipran would provide improvements in pain and other fibromyalgia symptoms without some of the unpleasant side effects associated with other medications historically used for treating fibromyalgia. The clinical safety and efficacy of milnacipran 100 and 200 mg/day in individuals with fibromyalgia has been investigated in four large, randomized, double-blind, placebo-controlled studies and three long-term extension studies. The clinical studies used composite responder analyses to identify the proportion of individual patients reporting simultaneous and clinically significant improvements in pain, global status, and physical function, in addition to assessing improvement in various symptom domains such as fatigue and dyscognition. In the clinical studies, patients receiving milnacipran reported significant improvements in pain and other symptoms for up to 15 months of treatment. Most adverse events were mild to moderate in severity and were related to the intrinsic pharmacologic properties of the drug. Long-term exposure to milnacipran did not result in any new safety concerns. As with other serotonin and norepinephrine reuptake inhibitors, increases in heart rate and blood pressure have been observed in some patients with milnacipran treatment.

Milnacipran is approved for management of fibromyalgia in the United States. In this double-blind, placebo- and active drug-controlled study (N = 100), effects of supratherapeutic doses of milnacipran on cardiac repolarization were evaluated in healthy volunteers. The primary outcome was the largest mean difference between milnacipran and placebo in time-matched baseline-adjusted QT interval corrected for heart rate using an individual correction formula (QTcNi). In addition, data were analyzed using the Fridericia formula (QTcF) and a post hoc piecewise QTcNi analysis based on a dichotomous cut of RR interval data at 800 ms. Moxifloxacin (400 mg single dose) was used to establish assay sensitivity. Using the QTcNi method, the largest difference in baseline-adjusted QTcNi between milnacipran 300 mg bid and placebo was -4.7 ms (90% confidence interval [CI]: -9.4 to -0.1), indicating no QT prolongation. Analysis using the Fridericia formula (QTcF) showed a maximum adjusted mean change of +7.7 ms, but QTcF versus RR interval plots indicated overcorrection with this method. The piecewise QTcNi correction method demonstrated a more accurate correction for drug-induced heart rate increase; mean baseline-adjusted between-group difference was +0.9 ms (90% CI: -6.6 to 8.3). The results suggest that milnacipran would not significantly affect cardiac repolarization at clinically relevant therapeutic and supratherapeutic concentrations.

Disturbances in N-methyl-D-aspartate (NMDA) receptor activity may play a role in attention-deficit/hyperactivity disorder (ADHD).This study is a preliminary evaluation of the safety, pharmacokinetics, and effectiveness of the NMDA receptor antagonist memantine in pediatric ADHD.An open-label, dose-finding, 8-week, trial in outpatients 6-12 years old with ADHD combined type. Memantine oral solution (2 mg/mL) was titrated to 10 mg/day (n = 8) or 20 mg/day (n = 8). Safety data and blood samples for pharmacokinetic analyses were collected. The ADHD Rating Scale-IV (ADHD-IV) and Clinical Global Impression of Severity (CGI-S) scale measured the effectiveness of memantine.There were no discontinuations due to adverse events (AEs), serious AEs, deaths, or suicides. Most AEs were mild and occurred during the first week of treatment. The 20 mg/day memantine dose was associated with a higher rate of completion and larger mean improvement on the ADHD-IV and CGI-S than 10 mg/day memantine. Pharmacokinetic analyses suggest response to memantine may be dose-dependent beyond an initial threshold concentration.This pilot study suggests that a memantine dose of 20 mg/day may be a safe and possibly effective treatment for pediatric ADHD. Further investigations of memantine in ADHD appear to be warranted.

Laishun Chen, William M Greenberg, Elimor Brand-Schieber, Julie Wangsa, Antonia Periclou, Parviz Ghahramani Forest Research Institute, a subsidiary of Actavis Inc., Jersey City, NJ, USA Purpose: Levomilnacipran extended-release (ER) is indicated for treatment of major depressive disorder in adults. We evaluated the pharmacokinetic and safety profile of levomilnacipran ER in individuals with impaired renal function. Methods: A total of 32 individuals participated in four groups (eight in each group) with normal, mild, moderately, or severely impaired renal function. Each participant received one dose of levomilnacipran ER 40mg. Blood and urine were assayed using liquid chromatography/tandem mass spectrometry. Results between normal and renally impaired groups were compared using analysis of variance. Safety measures included adverse events, laboratory evaluations, vital signs, suicidality, and electrocardiograms. Results: Following administration of levomilnacipran, mean (standard deviation) maximum plasma concentration in participants with normal renal function, and mild, moderate, or severe renal impairment was 83.9 (21.0), 81.8 (23.4), 98.7 (18.1), and 122.1 (35.1) (ng/mL), respectively; area under the curve from time zero to infinity was 2,101.0 (516.9), 2,587.8 (649.9), 4,016.4 (995.4), and 5,900.8 (1,799.3) (h·ng/mL), respectively; terminal elimination half-life was 13.5 (2.8), 17.3 (3.5), 19.1 (4.6), and 27.7 (7.4) (hours), respectively; and renal clearance was 175.9mL/min, 114.7mL/min, 69.9mL/min, and 28.6mL/min, respectively. Levomilnacipran ER was generally well tolerated with no safety issues of concern identified. Conclusion: Renal impairment was associated with increased plasma levels of levomilnacipran and prolonged half-life. No dose adjustment is required for individuals with mild renal impairment; the recommended maximum daily maintenance dose of levomilnacipran ER should not exceed 80mg for individuals with moderate renal impairment and 40mg for individuals with severe renal impairment. Keywords: antidepressant, F2695, SNRI, pharmacokinetics, renal function, major depressive disorder

Purpose Re-induction outcomes vary for children with acute lymphoblastic leukemia (ALL) and marrow relapse. We explored possible relationships among asparaginase (ASNase) activity levels, asparagine (ASN) depletion, anti-ASNase antibody titers, and response to re-induction therapy in children and adolescents with ALL and an ‘early’ first marrow relapse. Patients and methods After appropriate informed consent, we enrolled children and adolescents 1–21 years old with ALL and first marrow relapse within 12 months of completion of primary therapy. Induction therapy included intramuscular pegylated ASNase on Days 2 and 16. We assessed ASNase activity, anti-ASNase antibody titers against native and pegylated (E. coli) ASNase, and amino acid levels of asparagine (ASN) and glutamine (GLN) on Days 0, 14, and 35 of re-induction. Results Ninety-three patients were at least partially assessable. Among 21 patients with M1 marrow status at Day 35, the median Day 14 ASN level was

Purpose: To evaluate the population pharmacokinetics of pemetrexed disodium in cancer patients enrolled in four different open-label, multicenter, nonrandomized phase II studies. Methods: Pemetrexed disodium was administered as a 10-min intravenous infusion (600 mg/m2) every 21 days. A total of four blood samples were to be collected each cycle per patient (n=103 patients) during cycles 1 and 3. Plasma concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM to estimate pemetrexed disodium pharmacokinetic parameters (mean, and between- and within-patient variability) as well as relationships between the pharmacokinetic parameters and various patient-specific factors (demographic and physiologic data). Results/Conclusions: The pharmacokinetics of pemetrexed disodium were best characterized by a two-compartment model with initial distribution and terminal elimination half-lives of 0.63 h and 2.73 h, respectively. The typical value of systemic clearance (CL) in liters per hour included a relationship to creatinine clearance (CrCL) with a slope of 0.0292. Typical values of central volume (Vc), distributional CL (Q), and peripheral volume (Vp) were 11.3 l, 3.21 l/h, and 5.20 l, respectively. Between-patient variability was 19.6%, 15.6%, and 21.7% for CL, Vc, and Vp, respectively. A combined additive/proportional error model was used to describe residual variability, with a coefficient of variation of 23.7% for the proportional component and a standard deviation of 0.0410 μg/ml for the additive component. Significant patient-specific factors on CL were calculated CrCL, body weight, and to a lesser extent alanine transaminase and folate deficiency. Gender and body weight were significant factors on Vc while both body surface area and albumin were significant factors on Vp. In conclusion, population pharmacokinetic modeling revealed relationships between pharmacokinetic parameters and various patient specific factors.

The steady-state kinetics of human erythrocyte glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate: NADP+ 1-oxidoreductase, EC 1.1.1.49) dimers were studied by initial rate measurement. These experiments gave intersecting double-reciprocal plots suggesting a ternary complex mechanism with a Km for NADP and glucose 6-phosphate of 11 microM and 43 microM, respectively. These studies were combined with rate measurements in the presence of one product (NADPH), dead-end inhibitors, as well as alternative substrates. The inhibition by NADPH was found to be competitive with respect to both substrates. Alternate substrates experiments gave linear double-reciprocal plots over a wide range of substrate concentrations. The results suggest that the dimeric enzyme follows either a random or a Theorell-Chance mechanism.

Background Combining two standard-of-care medications for Alzheimer’s disease (AD) into a single once-daily dosage unit may improve treatment adherence, facilitate drug administration, and reduce caregiver burden. A new fixed-dose combination (FDC) capsule containing 28 mg memantine extended release (ER) and 10 mg donepezil was evaluated for bioequivalence with co-administered commercially available memantine ER and donepezil, and for bioavailability with regard to food intake. Methods Two phase I, single-dose, randomized, open-label, crossover studies were conducted in 18- to 45-year-old healthy individuals. In MDX-PK-104 study, fasting participants (N = 38) received co-administered memantine ER and donepezil or the FDC. In MDX-PK-105 study, participants (N = 36) received three treatments: intact FDC taken while fasting or after a high-fat meal, or FDC contents sprinkled on applesauce while fasting. Standard pharmacokinetic parameters for memantine and donepezil were calculated from the plasma concentration time-curve using non-compartmental analyses. Linear mixed-effects models were used to compare: (a) FDC versus co-administered individual drugs; (b) FDC fasted versus with food; and (c) FDC sprinkled on applesauce versus FDC intact, both fasted. Safety parameters were also evaluated. Results The FDC capsule was bioequivalent to co-administered memantine ER and donepezil. There was no significant food effect on the bioavailability of the FDC components. There were no clinically relevant differences in time to maximum plasma concentration or safety profiles across treatments. Conclusions An FDC capsule containing 28 mg memantine ER and 10 mg donepezil is bioequivalent to commercially available memantine ER and donepezil, and bioavailability is not affected by food intake or sprinkling of capsule contents on applesauce.