Antonia Periclou

Pharmacokinetic study of memantine in healthy and renally impaired subjects.

Our objective was to evaluate the pharmacokinetics of the Alzheimers disease treatment memantine in subjects with normal and impaired renal function.

Lack of Pharmacokinetic or Pharmacodynamic Interaction Between Memantine and Donepezil

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 Alzheimers 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.

A comparative pharmacodynamic study of IY‐81149 versus omeprazole in patients with gastroesophageal reflux disease

To evaluate and compare the pharmacodynamic effects of IY‐81149 and omeprazole on gastric pH in patients with gastroesophageal reflux disease.

Influence of CYP3A4 Induction/Inhibition on the Pharmacokinetics of Vilazodone in Healthy Subjects

PURPOSE Vilazodone is a serotonin reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of major depressive disorder in adults. Vilazodone seems to be metabolized primarily by the cytochrome P-450 (CYP) 3A4 isozyme and non-CYP-mediated pathways; concomitant use of drugs that affect CYP3A4 activity could potentially alter systemic exposure to vilazodone. The present studies evaluated whether CYP3A4 inhibition (study 1) or induction (study 2) affected the pharmacokinetics of vilazodone. METHODS Participants were healthy adult volunteers. Study 1 was conducted in 2 parts and evaluated the pharmacokinetics of single-dose vilazodone administered with multiple-dose (200 mg once daily) ketoconazole, a CYP3A4 inhibitor. Part 1 was an open-label pharmacokinetic assessment of a single 5-mg vilazodone dose with or without ketoconazole. Part 2 was a randomized, double-blind, placebo-controlled, crossover study comparing vilazodone pharmacokinetics after a single 10-mg dose alone or co-administered with ketoconazole or placebo. Study 2 was an open-label, multiple-dose, single-sequence study evaluating the effect of steady-state carbamazepine, a CYP3A4 substrate and inducer, on the pharmacokinetics of steady-state vilazodone (40 mg once daily). Primary pharmacokinetic parameters for both studies were AUC and Cmax for vilazodone. Lack of pharmacokinetic interaction was concluded if the 90% CIs of the ratio of vilazodone plus the CYP3A4 inhibitor/inducer relative to vilazodone alone (or plus placebo) for AUC and Cmax were within the 80% to 125% range. Subject-reported and investigator-identified adverse events (AEs), laboratory values, vital signs, and 12-lead ECG parameters were recorded. FINDINGS In study 1/parts 1 and 2 (n = 15 and 22 enrolled, respectively), mean vilazodone AUC increased 42% and 51%, respectively, in the presence of ketoconazole (expected to be at steady state) versus vilazodone alone (part 1) or with placebo (part 2). The upper limit of the 90% CIs for the vilazodone AUC and Cmax geometric mean ratios exceeded 125%. In study 2 (n = 30 enrolled), co-administration of vilazodone and the carbamazepine extended-release formulation decreased mean steady-state vilazodone exposure ~45%, and the 90% CIs for the vilazodone AUC and Cmax geometric mean ratios were not within the range of 80% to 125%. In both studies, most AEs were of mild intensity, and gastrointestinal AEs predominated. IMPLICATIONS These results suggest that up to a 50% decrease of vilazodone dosage should be considered when it is given in combination with strong CYP3A4 inhibitors; conversely, increasing the vilazodone dosage up to a maximum of 80 mg/d should be considered when it is given in combination with strong CYP3A4 inducers. (Study registration numbers: SB-659746/029; VLZ-PK-02.).

Effects of milnacipran on cardiac repolarization in healthy participants.

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.

Effect of renal impairment on the pharmacokinetics of levomilnacipran following a single oral dose of levomilnacipran extended-release capsule in humans

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 40 mg. 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 175.9 mL/min, 114.7 mL/min, 69.9 mL/min, and 28.6 mL/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 80 mg for individuals with moderate renal impairment and 40 mg for individuals with severe renal impairment.

Pharmacokinetics and Safety of Vilazodone in Hepatic Impairment.

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.

Milnacipran: a selective serotonin and norepinephrine dual reuptake inhibitor for the management of fibromyalgia

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.