Henry M. Richards

Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer’s disease

Background Currently available treatments for Alzheimer’s disease (AD) can produce mild improvements in cognitive function, behavior, and activities of daily living in patients, but their influence on long-term survival is not well established. This study was designed to assess patient survival and drug efficacy following a 2-year galantamine treatment in patients with mild to moderately severe AD. Methods In this multicenter, double-blind study, patients were randomized 1:1 to receive galantamine or placebo. One primary end point was safety; mortality was assessed. An independent Data Safety Monitoring Board monitored mortality for the total deaths reaching prespecified numbers, using a time-to-event method and a Cox-regression model. The primary efficacy end point was cognitive change from baseline to month 24, as measured by the Mini-Mental State Examination (MMSE) score, analyzed using intent-to-treat analysis with the ‘last observation carried forward’ approach, in an analysis of covariance model. Results In all, 1,024 galantamine- and 1,021 placebo-treated patients received study drug, with mean age ~73 years, and mean (standard deviation [SD]) baseline MMSE score of 19 (4.08). A total of 32% of patients (661/2,045) completed the study, 27% (554/2,045) withdrew, and 41% (830/2,045) did not complete the study and were discontinued due to a Data Safety Monitoring Board-recommended early study termination. The mortality rate was significantly lower in the galantamine group versus placebo (hazard ratio [HR] =0.58; 95% confidence interval [CI]: 0.37; 0.89) (P=0.011). Cognitive impairment, based on the mean (SD) change in MMSE scores from baseline to month 24, significantly worsened in the placebo (−2.14 [4.34]) compared with the galantamine group (−1.41 [4.05]) (P<0.001). Functional impairment, based on mean (SD) change in the Disability Assessment in Dementia score (secondary end point), at month 24 significantly worsened in the placebo (−10.81 [18.27]) versus the galantamine group (−8.16 [17.25]) (P=0.002). Incidences of treatment-emergent adverse events were 54.0% for the galantamine and 48.6% for the placebo group. Conclusion Long-term treatment with galantamine significantly reduced mortality and the decline in cognition and daily living activities, in mild to moderate AD patients. Identification This study is registered at ClinicalTrials.gov (NCT00679627).

Single- and multiple-dose pharmacokinetic studies of tramadol immediate-release tablets in children and adolescents

In these combined analyzes from 3 open‐label, phase‐1 studies, the pharmacokinetic profile of tramadol and its metabolite (M1) following administration of tramadol immediate‐release (IR) tablets in children and adolescents, 7–16 years old (studies 1 and 2: n = 38; study 3: n = 21) with painful conditions following single oral dose of tramadol IR (25–100 mg) (studies 1 and 2) or multiple oral doses of tramadol IR tablets every 6 hours for 3 days (study 3) were compared with that of healthy adults following similar treatment. Area under the curve of tramadol and its metabolite M1 in children and adolescents was lower compared with adults (Dose‐normalized [DN] AUC, h ng/mL: tramadol: 1316.87 [children]; 1418.02 [adolescents];1838.29 [adults]; M1: 342.56 [children]; 475.4 [adolescents]; 636.13 [adults]) while the Cmax remained similar (DN Cmax, ng/mL: tramadol: 203.75 [children]; 165.35 [adolescents]; 226.92 [adults]; M1: 34.93 [children]; 38.42 [adolescents]; 52.14 [adults]). The DN AUC was further lower in children and adolescents with a lower body weight (<50 kg). The weight normalized oral clearance of tramadol was higher in children and adolescents compared with adults (CL/F, mL/min/kg: 12.66 [children]; 11.75 [adolescents]; 9.06 [adults]). No new safety findings emerged. Tramadol was generally safe and well‐tolerated by children and adolescents with painful conditions.

Repeat-dose steady-state pharmacokinetic evaluation of once-daily hydromorphone extended-release (OROS(®) hydromorphone ER) in patients with chronic pain.

Objective To characterize the steady-state pharmacokinetic profile of hydromorphone extended-release (ER) in patients with chronic pain taking concomitant medications. Methods This open-label repeat-dose study enrolled 22 patients (mean age, 51.4 years; 81.8% female). All patients were receiving at least one concomitant medication; 86.4% were receiving at least two concomitant medications and 81.8% were receiving at least three. Patients receiving a stable dose of an opioid were converted to hydromorphone ER at a 5:1 ratio (morphine equivalent:hydromorphone). The dose was titrated to adequate analgesia over 3–14 days and stabilized between 8–48 mg. Oral morphine immediate-release was permitted for breakthrough pain. Area under the concentration–time curve from 0–24 hours (AUC0–24), maximum plasma concentration (Cmax), trough plasma concentration (Cmin), average plasma concentration (Cavg), and degree of fluctuation (100 × [(Cmax − Cmin) ÷ Cavg]) were calculated based on data from 14 patients. Results Dose-normalized to 16 mg, mean pharmacokinetic parameter values were: AUC0–24, 41.1 ng · h/mL; Cmax, 2.6 ng/mL; Cmin, 1.1 ng/mL; Cavg, 1.7 ng/mL; and the degree of fluctuation was 99.6%. The pharmacokinetic profile of hydromorphone ER was linear and consistent with dose proportionality. Mean pain intensity difference scores showed statistically significant improvement from 2–21 hours after dosing. Sixteen (72.7%) patients reported at least one adverse event (AE). The most common were constipation (31.8%), headache (22.7%), and vomiting (13.6%). One patient discontinued treatment due to vomiting. No deaths, serious AEs, or unexpected AEs occurred. Conclusion These findings replicate and extend the steady-state pharmacokinetic profile of hydromorphone ER, previously characterized in healthy volunteers, to a population of chronic pain patients taking numerous concomitant medications.

Medication changes after switching from CONCERTA® brand methylphenidate HCl to a generic long-acting formulation: A retrospective database study

Background Observational studies of switching from branded to generic formulations of the same drug substance often lack appropriate comparators for the subjects who switched. Three generic formulations were deemed equivalent to Concerta: an authorized generic (AG) identical except for external packaging, and two other generics (EG). Objective Compare the incidence of a combined endpoint (switching back to Concerta, changing the use of immediate release methylphenidate (MPH), stopping all long-acting methylphenidate, or starting a new medication) among people switched from Concerta to the AG versus the EG. Methods Cohort study from the Truven CCAE database of people aged 6 to 65 diagnosed with ADHD, treated with Concerta, and switched to the EG or to the AG formulation. Results In the EG arm 24.6% and in the AG arm 19.7% of subjects switched back to Concerta. The proportion of subjects meeting the combined endpoint was 39.5% in the EG arm, 32.9% in the AG arm, a crude risk ratio of 1.20 (95% CI 0.94, 1.54). After adjustment by propensity score stratification, the adjusted odds ratio (OR) was 1.23 (95% CI 0.90, 1.70). In an unplanned analysis using a different method of adjustment, the adjusted OR was 1.00 (95% CI 0.69, 1.44). Discussion This study did not detect a difference between the proportion of people who met the study endpoint in the two study arms, i.e. between those who switched to a generic formulation that was identical to Concerta except for external packaging and those who switched to the comparison generics. The high incidence of the combined endpoint in the AG arm demonstrates the need for an appropriate comparator in studies of this type. Trial registration ClinicalTrials.gov NCT02730572

The effect of UGT2B7*2 polymorphism on the pharmacokinetics of OROS® hydromorphone in Taiwanese subjects.

This open‐label, single‐center, phase I study (NCT1487564) investigated the effect of uridine diphosphate‐glucuronosyltransferase2B7 (UGT2B7 * 2) genetic polymorphism (H268Y) on the pharmacokinetics (PK) and safety of a single, oral, 16‐mg dose of OROS® hydromorphone and its metabolite in healthy Taiwanese subjects. Plasma concentrations of hydromorphone and hydromorphone‐3‐glucuronide were determined in 28 subjects. PK parameters calculated included maximum plasma concentration (Cmax); time to reach maximum plasma concentration (tmax); area under plasma concentration‐time curve from 0–48 hours (AUC0–48h) and 0‐infinite time (AUC∞); and hydromorphone‐3‐glucuronide:hydromorphone metabolic ratio (RM). Mean plasma concentrations of hydromorphone and hydromorphone‐3‐glucuronide reached a maximum between 12–18 hours and 18–21 hours, respectively. No clear trend in PK parameters and no clinically significant differences in the incidence of treatment‐emergent adverse events (TEAEs) were observed among different UGT2B7 genotypes. Our study found UGT2B7 polymorphism had no apparent effect on PK of OROS® hydromorphone; hydromorphone was well tolerated in pain‐free volunteers when coadministered with naltrexone.

Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double‐Blind, Placebo‐Controlled Multiple‐Ascending‐Dose Study

This randomized, double‐blind, parallel‐group multiple‐ascending‐dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUCtau,ss of tramadol increased approximately 2.2‐ and 3.6‐fold for the (+) enantiomer and 2.0‐ and 3.5‐fold for the (‐) enantiomer with increasing dose from 200 to 400 and 600 mg/day, whereas the Cmax,ss increased 2.1‐ and 3.3‐fold for the (+) enantiomer and 2.0‐ and 3.2‐fold for the (‐) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment‐emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study.

Single‐Dose Pharmacokinetic Study of Tramadol Extended‐Release Tablets in Children and Adolescents

Combined analyses from 2 open‐label, phase‐1 studies—the pharmacokinetic profile of tramadol and its metabolite (M1) following a single oral dose of tramadol extended release (ER) (25 to 100 mg) in children (7 to 11 years old; study 1: n = 37) and adolescents (12 to 17 years old; study 2: n = 38) with painful conditions—were historically compared with that of healthy adults following similar dosing. The dose‐normalized area under the curve (DN AUC0‐24h) and maximum concentration (DN Cmax) of tramadol and of M1 in children and in adolescents were lower than those in adults (children vs adults: tramadol, DN AUC0‐24h 82.19%; DN Cmax 80.38%, P = .0031; M1, DN AUC0‐24h 51.19%, DN Cmax 52.68%, P < .0001; adolescents vs adults: tramadol, DN AUC0‐24h 89.56%, DN Cmax 84.01%; M1, DN AUC0‐24h 85.28%, DN Cmax 83.03%, P = .0004). The arithmetic mean terminal elimination t1/2 of tramadol in children and adolescents was comparable to that in adults (children 8.4 hours; adolescents 8.5 hours; adults 7.9 hours). The most frequently reported (≥5% of participants) treatment‐emergent adverse events in children included headache, upper abdominal pain and constipation, and in adolescents were headache, nausea, dizziness, and stomach discomfort. Multiple factors may have contributed to these observations, including a higher proportion of children (56%) who may have a lower activity of CYP2D6, resulting in reduced clearance of tramadol.

Dose proportionality and pharmacokinetics of extended-release (OROS®) hydromorphone: a phase 1, open-label, randomized, crossover study in healthy Taiwanese subjects.

OBJECTIVES Osmotic-controlled release oral delivery system (OROS®) hydromorphone - an extended-release preparation - is recommended long-term therapy for chronic pain patients. Dose proportionality of OROS hydromorphone has been shown in healthy Caucasian volunteers; however, no studies have been conducted in Asian populations. To determine whether ethnic differences affect the drugs pharmacokinetic (PK) profile, we evaluated the dose proportionality of OROS hydromorphone in healthy Taiwanese adults. METHODS This 12-week, open-label, 4-way crossover, phase 1 study randomly assigned subjects to 1 of 4 treatment sequences - single oral dose OROS hydromorphone: 8 mg, 16 mg, 32 mg, or 64 mg - along with 50 mg naltrexone. Dose proportionality was assessed using a linear mixed-effects model to estimate the slope of the regression line and its 90% CI for Cmax, AUC0-48h, and AUClast. Descriptive statistics measured plasma hydromorphone concentrations, PK parameters, laboratory analytes, and vital signs. RESULTS 23 subjects completed the study; a single-dose of OROS hydromorphone increased plasma concentration steadily for 6 hours and sustained it at or near maximum levels for ~ 24 hours. After dose normalization to a 16 mg dose, all studied doses demonstrated dose proportionality for Cmax, AUClast, and AUC0-48h,as the slopes of the regression lines for Cmax, AUClast, and AUC0-48h were close to zero, and the 90% CIs within pre-specified limits. Adverse events were as expected for hydromorphone administered with concomitant naltrexone. CONCLUSIONS Single doses of 8 mg, 16 mg, 32 mg, and 64 mg of OROS hydromorphone were found to be dose proportional for Cmax, AUClast, and AUC0-48h and were generally safe and well-tolerated in healthy Taiwanese adults.

Authors' response to the letter from Dr. Srinivas.

We welcome the comments by Nuggehally R. Srinivas and appreciate his interest in our article, “Singleand multiple-dose pharmacokinetic studies of tramadol immediate-release tablets in children and adolescents.” First, we would like to clarify that the pharmacokinetic data in adults came from 1 internal published and 3 internal unpublished clinical studies with welldocumented study design details. It is unlikely that the observed lower levels of M1 in the children are due to design elements such as differences in blood sampling or differences in dosing. The last sampling time was 36 hours in the adult studies and 24 hours in the pediatric study. The lower level of quantitation of M1 in adults was between 2 and 5 ng/mL compared with 5 ng/mL observed in children. The plasma levels of M1 metabolite were undetectable 24 hours postdose in 10 of 13 children, whereas in adults, M1 levels could be detected in 63 of 67 participants at 24 hours. It is less likely that the observed lower levels of M1 in children would be due to a difference in design between studies. This is clear from Figure IB in the article, in which it can be observed that in children the plasma levels of M1 were lower from the initial sampling times onward. Nuggehally R. Srinivas commented that a systemic circulating amount of tramadol higher than 1mg/kg may cause delayed gastric emptying and decrease oral absorption in children. The tramadol dose administered in the adult studies was 75 or 112.5mg of tramadol, corresponding to a dose of 1–1.5mg/kg and hence similar to the pediatric study doses. Although, no data on absolute bioavailability are available for the pediatric population, the absolute bioavailability in adults is approximately 70%. Therefore some children could have been exposed to a circulating amount of 1mg/kg of tramadol. Nuggehally R. Srinivas also commented on possible delayed gastric emptying in children that may cause incomplete oral absorption of tramadol and the higher apparent oral clearance in children. Peripheral m-opioid effects are believed to play a predominant role in the inhibition of gastric emptying by opioids The m-opioid effect of tramadol is mainly due to its M1 metabolite. This metabolite is only formed after first pass in the liver through the CYP2D6 pathway. A comparison of the tmax values after single-dose administration demonstrates that it was 1.9 hours for tramadol and 2.7 hours for the M1 metabolite in children, whereas it was 1.9 hours for tramadol and 2.8 hours for the M1 metabolite in adults. Furthermore, as demonstrated in Figure IA in our article, a child with slower absorption does have higher plasma tramadol at later times, suggesting good absorption throughout the entire gastrointestinal tract. After multiple-dose administration in children, the tmax was 1.7 hours for tramadol and 1.8 hours for M1, which is similar to that seen in adults (tramadol, 2.1 hours; M1 metabolite, 2.9 hours). This is consistent with the absence of an impact on the pharmacokinetic profile of acetaminophen after coadministration of acetaminophen and tramadol as a fixed-dose combination versus administration as a single agent. Therefore, the data do not suggest a major difference in the rate and extent of absorption between both populations after single and multiple dosing.

Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer’s disease [Corrigendum]

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