Marci L. Chew

Anticholinergic Activity of 107 Medications Commonly Used by Older Adults

The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug‐free serum was added to medication and atropine standard‐curve samples. For medications that showed detectable AA, average steady‐state peak plasma and serum concentrations (Cmax) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L‐hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above‐average Cmax values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.

A model of anticholinergic activity of atypical antipsychotic medications

BACKGROUND Atypical antipsychotics clozapine, olanzapine, and quetiapine have significant affinity for the muscarinic receptors in vitro, while aripiprazole, risperidone, and ziprasidone do not. Dissimilarity in binding profiles may contribute to the reported differences in the anticholinergic effects of these antipsychotics. However, it is difficult with the available data to predict the likelihood of anticholinergic effects occurring with various doses of an atypical antipsychotic. METHODS We developed a model to assess the potential anticholinergic activity (AA) of atypical antipsychotics at therapeutic doses. A radioreceptor assay was used to measure in vitro AA at 6 clinically relevant concentrations of aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Using published pharmacokinetic data, in combination with the measured in vitro AA, dose-AA curves were generated. RESULTS Clozapine, and to a lesser extent olanzapine and quetiapine showed dose-dependent increases in AA. At therapeutic doses, the AA (in pmol/mL of atropine equivalents) was estimated to range from 27-250, 1-15, and 0-5.4 pmol/mL for clozapine, olanzapine, and quetiapine, respectively. Aripiprazole, risperidone, and ziprasidone did not demonstrate AA at any of the concentrations studied. CONCLUSIONS Therapeutic doses of clozapine, olanzapine, and, to a lesser extent, quetiapine are associated with clinically relevant AA.

Serum anticholinergic activity and cognition in patients with moderate-to-severe dementia.

OBJECTIVE The authors investigated the association between serum anticholinergic activity (SAA) and cognitive performance in a group of patients with moderate-to-severe dementia. METHODS SAA and cognitive performance were assessed in 26 patients admitted to a geropsychiatric unit for the treatment of behavioral disturbances associated with dementia. SAA was measured by radioreceptor competitive binding assay. Cognition was tested with the Mini-Mental State Exam and the Severe Impairment Battery. RESULTS Higher SAA was associated with lower cognitive performance. CONCLUSION This study extends to patients with moderate-to-severe dementia the finding that higher SAA is associated with lower cognitive performance.

A randomized, double-blind, placebo-controlled trial and open-label extension study to evaluate the efficacy and safety of pregabalin in the treatment of neuropathic pain associated with human immunodeficiency virus neuropathy.

&NA; This randomized, placebo‐controlled trial and open‐label extension study of pregabalin for the treatment of human immunodeficiency virus–associated distal sensory polyneuropathy did not demonstrate significant effects of pregabalin. &NA; The objective of these studies was to assess the efficacy and safety of pregabalin in the treatment of human immunodeficiency virus (HIV)–associated neuropathic pain. Patients with HIV‐associated distal sensory polyneuropathy (DSP) were randomized to treatment with flexible‐dose pregabalin (150–600 mg/day) or placebo for 17 weeks in a single‐blind, placebo lead‐in, randomized, double‐blind, parallel‐group, placebo‐controlled multinational trial. The primary efficacy outcome was the change in mean pain score on an 11‐point numeric rating scale (NRS) from baseline to study endpoint. Participants who completed this trial were invited to participate in a 6‐month open‐label extension study with pregabalin. Of the 377 patients enrolled in the randomized controlled trial (pregabalin, n = 183; placebo, n = 194), 68.4% completed treatment. In the open‐label extension, 217 patients were treated and 59.4% completed treatment. Both studies were terminated by the sponsor after a preplanned interim analysis indicated trial futility. At endpoint, the change from baseline in least‐squares mean NRS pain scores in the intent‐to‐treat population was −2.04 for pregabalin versus −2.11 for placebo (P = .709). There were no significant differences between the pregabalin and placebo groups in the secondary efficacy measures. Incidence of adverse events was lower than seen in previous pregabalin studies. Overall, this trial did not show pregabalin to be more efficacious than placebo in treating HIV‐associated DSP. Studies such as these, which fail to support their primary hypotheses, may be important in informing the methodology of future trials, especially when novel approaches to limit variability in the control group are included. ClinicalTrials.gov identifiers: NCT01049217 and NCT01145417.

Once daily controlled-release pregabalin in the treatment of patients with fibromyalgia: a phase III, double-blind, randomized withdrawal, placebo-controlled study

Abstract Objective: Safety and efficacy of a once daily controlled-released (CR) formulation of pregabalin was evaluated in patients with fibromyalgia using a placebo-controlled, randomized withdrawal design. Research design and methods: This multicenter study included 6 week single-blind pregabalin CR treatment followed by 13 week double-blind treatment with placebo or pregabalin CR. The starting dose of 165 mg/day was escalated during the first 3 weeks, up to 495 mg/day based on efficacy and tolerability. Patients with ≥50% reduction in average daily pain score at the end of the single-blind phase were randomized to continue pregabalin CR at the optimized dose (330–495 mg/day) or to placebo. The primary endpoint was time to loss of therapeutic response (LTR), defined as <30% pain reduction relative to single-blind baseline or discontinuation owing to lack of efficacy or adverse event (AE). Secondary endpoints included measures of pain severity, global assessment, functional status, tiredness/fatigue, and sleep. Clinical trial registration: ClinicalTrials.gov identifier: NCT01271933. Results: A total of 441 patients entered the single-blind phase, and 63 were randomized to pregabalin CR and 58 to placebo. The median time to LTR (Kaplan–Meier analysis) was significantly longer in the pregabalin CR group than placebo (58 vs. 22 days, p = 0.02). By trial end, 34/63 (54.0%) pregabalin CR and 41/58 (70.7%) placebo patients experienced LTR. Significantly more patients reported ‘benefit from treatment’ (Benefit, Satisfaction, and Willingness to Continue Scale) in the pregabalin CR group; no other secondary endpoints were statistically significant. Most AEs were mild to moderate in severity (most frequent: dizziness, somnolence). The percentage of pregabalin CR patients discontinuing because of AEs was 12.2% and 4.8% in the single-blind and double-blind phases, respectively (placebo, 0%). Conclusions: Time to LTR was significantly longer with pregabalin CR versus placebo in fibromyalgia patients who initially showed improvement with pregabalin CR, indicating maintenance of response. Pregabalin CR was well tolerated in most patients. Generalizability may be limited by study duration and selective population.

Adjunctive use of controlled‐release pregabalin in adults with treatment‐resistant partial seizures: A double‐blind, randomized, placebo‐controlled trial

To assess the efficacy and tolerability of add‐on pregabalin controlled‐release formulation (PGB‐CR) (doses of 165 or 330 mg/day) in patients with partial‐onset seizures (POS).

Exposure‐Response Analyses of the Effects of Pregabalin in Patients With Fibromyalgia Using Daily Pain Scores and Patient Global Impression of Change

Data from 4 phase 2/3 studies were pooled to characterize the exposure response of daily pregabalin (150–600 mg) in patients with fibromyalgia using self‐assessed daily pain scores (PAIN) and end‐of‐treatment patient global impression of change (PGIC). The exposure responses of both endpoints were characterized by an Emax model using nonlinear mixed‐effects modeling (NONMEM). Drug effect on PAIN relative to placebo was significant with additional maximum effect of 1.51 points on the logit scale and EC50 of 1.54 ng/mL (dose of 174 mg) and a rapid onset (half‐life of 11 hours), consistent with the half‐life of the drug. The decrease in PAIN with placebo occurred more slowly, reaching maximum response (1.52 points on the logit scale) after 1 month. Drug response in fibromyalgia was dependent on age and sex, with greater PAIN reduction in older patients, in addition to the effect of creatinine clearance, and in females. For PGIC, administration of pregabalin resulted in an increase in the proportion of patients reporting improvement with an ED50 of 228 mg. The analyses support the recommended dose of pregabalin in patients with fibromyalgia of 300 to 450 mg/d.

Safety, tolerability, and pharmacokinetics of pregabalin in children with refractory partial seizures: A phase 1, randomized controlled study

To evaluate the safety, tolerability, and pharmacokinetics (PK) of pregabalin as adjunctive therapy in children with refractory partial seizures.

The Pharmacokinetics of Pregabalin in Breast Milk, Plasma, and Urine of Healthy Postpartum Women.

Background: Limited data exist on the presence of pregabalin in human breast milk of nursing mothers. Objectives: This study aimed to determine pregabalin concentrations in breast milk, estimate the infant daily pregabalin dose from nursing mothers, and evaluate pregabalin pharmacokinetic data in lactating women (≥ 12 weeks postpartum). Methods: In this multiple-dose, open-label, pharmacokinetic study, 4 doses of pregabalin 150 mg were administered orally at 12-hour intervals. Urine, blood, and breast milk samples were collected up to 12, 24, and 48 hours, respectively, following the fourth dose. Pharmacokinetic parameters were estimated using noncompartmental methods. Adverse events were monitored throughout. Results: Ten healthy lactating women (age 24-37 years) received pregabalin. Geometric mean pregabalin Cmaxss and AUCτ values in breast milk were approximately 53% and 76%, respectively, of those for plasma. The mean amount of pregabalin in breast milk recovered in a 24-hour period after the last dose was 574 μg (range, 270-1720 μg), which is approximately 0.2% of the administered daily maternal dose of 300 mg. The estimated average daily infant dose of pregabalin from breast milk was 0.31 mg/kg/day, which would be approximately 7% (23% coefficient of variation) of the body weight normalized maternal dose. Approximately 89% of the dose administered was recovered in urine. Renal clearance averaged 68.2 mL/min. Adverse events were of mild or moderate severity. Conclusion: Lactation appears to have had little influence on pregabalin pharmacokinetics. Overall, the estimated dose of pregabalin in breastfed children of women receiving pregabalin is low. Pregabalin was well tolerated in lactating women. Declaration of Conflicting Interests The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Peter A. Lockwood, Lynne Pauer, Joseph M. Scavone, Maud Allard, Laure Mendes da Costa, Tanja Alebic-Kolbah, Anna Plotka, Christine W. Alvey, and Marci L. Chew were all full-time employees of Pfizer at the time the study was completed and hold stock and/or stock options in Pfizer. Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Pfizer, which was involved in the study design, the collection, analysis, and interpretation of the data, the writing of the report, and the decision to submit the paper for publication. Medical writing support was provided by Penny Gorringe, MSc, of Engage Scientific Solutions and funded by Pfizer.

Efficacy and Safety of Once-Daily Controlled-Release Pregabalin for the Treatment of Patients with Postherpetic Neuralgia: A Double-blind, Randomized Withdrawal, Placebo-Controlled Trial.

Objectives: To assess efficacy and safety of once-daily controlled-release (CR) formulation of pregabalin in patients with postherpetic neuralgia. Methods: An enriched enrollment, randomized withdrawal trial, with 6-week single-blind pregabalin treatment phase and 13-week double-blind phase, where patients with ≥50% decrease in mean pain score at single-blind end point from baseline were randomized (1:1) to pregabalin CR (82.5 to 660 mg/d) or placebo. Primary efficacy outcome was time to loss of therapeutic response (LTR) (<30% decrease in weekly mean pain score from single-blind baseline or discontinuation due to adverse event or lack of efficacy). Secondary efficacy outcomes included change in weekly mean pain score (1-wk recall period) at double-blind end point. Results: In total, 801 patients were randomized and treated in the single-blind phase, and 413 in the double-blind phase (208, pregabalin CR; 205, placebo). Pregabalin CR significantly increased time to LTR versus placebo (Kaplan-Meier analysis) with significantly fewer LTR events with pregabalin CR than with placebo (29 [13.9%] vs. 63 [30.7%]; P<0.0001). Median time to LTR was not estimable. Pregabalin CR significantly improved weekly mean pain score versus placebo: LS mean difference (95% CI) of −1.11 (−1.47, −0.75) and −1.00 (−1.34, −0.65) (P<0.0001) from single-blind baseline and double-blind baseline, respectively. Most commonly reported adverse events in the single-blind phase were dizziness, somnolence, and peripheral edema. Pregabalin CR was well tolerated. Discussion: Time to LTR was significantly longer with pregabalin CR than with placebo. Safety profile of pregabalin CR was comparable to that reported for the immediate-release formulation in patients with postherpetic neuralgia.