Establishing the content validity of the Epworth Sleepiness Scale for Children and Adolescents in Prader-Willi syndrome.

STUDY OBJECTIVES: Excessive daytime sleepiness is common in Prader-Willi syndrome (PWS), with prevalence ranging from 52% to 100%. The goal of this study was to establish the content validity (ie, evidence that an instrument measures an intended concept of interest) of the parent/caregiver version of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), a measure of daytime sleepiness, in PWS. METHODS: Qualitative, dyadic semistructured video interviews were conducted with 18 caregivers and their children with PWS from April to June 2020. Concept elicitation and cognitive interview techniques were implemented. Thematic analyses allowed for examination of themes and data patterns. RESULTS: All caregivers (mean age 49 years) were mothers of individuals with PWS who experienced troublesome daytime sleepiness (mean age 14 years). The most prevalent observable signs/symptoms of daytime sleepiness were sleepy/sleepiness (n = 17; 94.4%), tired/tiredness (n = 16; 88.9%), exhaustion/exhausted (n = 5; 27.8%), anxious/stressed (n = 5; 27.8%), irritable/frustrated (n = 5; 27.8%), having tantrums/outbursts (n = 5; 27.8%), and lethargy (n = 4; 22.2%). Daytime sleepiness impacted various aspects of health including mental, emotional, physical, and social well-being. When caregivers were asked about the activities associated with daytime sleepiness, all salient concepts elicited mapped to the ESS-CHAD; saturation was met after the first 4 interviews. Only 2 concepts, after physical exertion and while inactive/bored, did not map. Caregiver statements indicated that these concepts, although related to daytime activities, were atypical of daily routines. The ESS-CHAD was well understood and relevant to caregivers. CONCLUSIONS: This study supports the content validity of the ESS-CHAD and its appropriateness for evaluating treatment efficacy of daytime sleepiness in PWS. CITATION: Patel VP, Patroneva A, Glaze DG, Davis K, Merikle E, Revana A. Establishing the content validity of the Epworth Sleepiness Scale for Children and Adolescents in Prader-Willi syndrome. J Clin Sleep Med. 2022;18(2):485-496.

Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: a secondary analysis of 4 studies in major depressive disorder.

INTRODUCTION: Venlafaxine, a serotonin-norepinephrine reuptake inhibitor antidepressant, is metabolized primarily by the cytochrome P450 2D6 enzyme into O-desmethylvenlafaxine (ODV). The ODV/venlafaxine ratio can be used to distinguish between extensive metabolizers (EMs) and poor metabolizers (PMs). OBJECTIVES: To determine the relative efficacy and tolerability of venlafaxine in EM vs PM patients with major depressive disorder (MDD). METHOD: Data from 4 double-blind, placebo-controlled studies of patients with MDD were pooled. Blood samples were analyzed for plasma concentrations of venlafaxine, ODV, total venlafaxine + ODV, and ODV/venlafaxine ratio. Patients were classified as EMs or PMs on the basis of ODV/venlafaxine ratios. Changes from baseline in depression scale scores were compared between EMs and PMs using t tests. Rates of response, remission, discontinuation, and adverse events (AEs) were compared for EMs and PMs using Fisher exact tests. RESULTS: Compared with PMs, EMs had significantly greater mean changes from baseline on 4 of 5 depression rating scales (all 4 comparisons, P ≤ .020). A significantly greater percentage of EMs achieved response or remission by most measures compared with PMs (4 of 5 comparisons, P ≤ .015). Rates of discontinuation and AEs did not differ significantly between EMs and PMs. Since there were no substantial differences between EMs and PMs in terms of venlafaxine dose or tolerability, these factors are not likely to account for the efficacy findings. CONCLUSIONS: Venlafaxine treatment in EMs was associated with greater efficacy in MDD on virtually all measures compared with PMs, with no important tolerability differences.

Comparison of the pharmacokinetics of venlafaxine extended release and desvenlafaxine in extensive and poor cytochrome P450 2D6 metabolizers.

BACKGROUND: The goal of this study was to evaluate the impact of cytochrome P450 2D6 extensive metabolizer (EM) or poor metabolizer (PM) status on the pharmacokinetics of single doses of venlafaxine extended release (ER) and desvenlafaxine (administered as desvenlafaxine succinate) in healthy adults. METHODS: In an open-label, crossover study, 14 healthy volunteers (aged 18-55 years; 7 EMs and 7 PMs) received, in randomized sequence, single doses of venlafaxine ER 75 mg/d or desvenlafaxine 100 mg/d. Cytochrome P450 2D6 genotyping was performed, and plasma drug levels were measured. The arithmetic means and standard deviation (SD) for area under the plasma concentration-versus-time curve (AUC) and peak plasma concentration (Cmax) were calculated. Comparisons of AUC and Cmax between cytochrome P450 2D6 EMs and PMs were calculated using a Wilcoxon exact test. RESULTS: After administration of venlafaxine ER, mean Cmax and AUC of venlafaxine were significantly greater in PMs compared with EMs, whereas mean Cmax and AUC of its metabolite, desvenlafaxine, were significantly lower for PMs than for EMs (P = 0.001, all comparisons). In contrast, mean Cmax and AUC of desvenlafaxine after administration of desvenlafaxine were comparable between EMs and PMs. CONCLUSIONS: Cytochrome P450 2D6 genetic polymorphisms had no discernible impact on exposure to desvenlafaxine after desvenlafaxine administration; in contrast, compared with an EM phenotype, a PM phenotype had a significant effect on venlafaxine and desvenlafaxine plasma concentrations after venlafaxine ER administration. This reduced pharmacokinetic variability of desvenlafaxine may translate into better uniformity of response for patients receiving desvenlafaxine versus venlafaxine, but additional studies are required to test this hypothesis.

The effects of desvenlafaxine and paroxetine on the pharmacokinetics of the cytochrome P450 2D6 substrate desipramine in healthy adults.

The potential for cytochrome P450 (CYP) 2D6 substrates to interact with desvenlafaxine (administered as desvenlafaxine succinate) and paroxetine was evaluated. In an open-label, crossover study, 20 healthy volunteers (aged 21-50) were randomized to 2 series of 9 days each of desvenlafaxine (100 mg/d) or paroxetine (20 mg/d), separated by a 5-day washout. The CYP2D6 substrate desipramine (50 mg) was administered alone on day 1 and coadministered on day 6 of dosing with either desvenlafaxine or paroxetine. CYP2D6 genotype was determined at baseline. Based on least squares geometric mean ratios between reference (desipramine alone) and test treatments, desvenlafaxine produced minor increases in desipramine area under the plasma concentration versus time curve (AUC; 36%) and peak plasma concentration (C(max); 30%) (vs paroxetine: 419%, 90%, respectively; both P < .001). Desvenlafaxine produced little change in 2-hydroxydesipramine AUC (16% increase) and C(max) (0%) versus paroxetine (18% and 82% decreases, respectively; P = .008, P < .001, respectively), indicating that desvenlafaxine, especially at the recommended therapeutic dose of 50 mg/d for major depressive disorder in the United States, has little potential to interact with CYP2D6 substrates.

Effect of desvenlafaxine on the cytochrome P450 2D6 enzyme system.

BACKGROUND: The cytochrome P450 2D6 (CYP2D6) enzyme is responsible for metabolizing approximately 25% of pharmaceutical agents. Individuals with impaired CYP2D6 metabolism and those concomitantly receiving agents that inhibit CYP2D6 can have variations in concentrations of such medications and their metabolites. METHODS: Five studies assessing the interaction between desvenlafaxine and CYP2D6 are reviewed. Study 1 compared desvenlafaxine area under the plasma concentration-versus-time curve (AUC) in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) after administration of 100 mg of desvenlafaxine or 75 mg of venlafaxine extended release (ER). Studies 2 to 5 assessed the effect of concomitant administration of desvenlafaxine 100 mg (studies 2, 4, and 5) or 400 mg (study 3), paroxetine (20 mg, study 4), and duloxetine (30 mg twice daily; study 5) on the CYP2D6 probe desipramine. RESULTS: In study 1, there was no significant difference in mean desvenlafaxine AUC between the CYP2D6 EMs and PMs (-11%; P=0.641) who were administered desvenlafaxine. However, PMs receiving venlafaxine ER had significantly higher venlafaxine and lower desvenlafaxine AUCs compared with EMs (+350% and -74%, respectively; P<0.001 for each). In studies 2, 4, and 5, the mean increases in desipramine AUC with concomitant administration of desvenlafaxine 100 mg ranged from 17% to 36%; the increase with concomitant administration of desvenlafaxine 400 mg (study 3) was 90%. Paroxetine and duloxetine produced increases in mean desipramine AUC of 419% and 122%, respectively, which were significantly greater than the increases seen with desvenlafaxine 100 mg (P<0.001 for each comparison). CONCLUSIONS: Based on the findings presented here, desvenlafaxine is expected to have a low risk for variability in efficacy and safety/tolerability resulting from CYP2D6 polymorphisms or drug-drug interactions when coadministered with CYP2D6 substrates or inhibitors.

An assessment of drug-drug interactions: the effect of desvenlafaxine and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects.

A number of antidepressants inhibit the activity of the cytochrome P450 2D6 enzyme system, which can lead to drug-drug interactions. Based on its metabolic profile, desvenlafaxine, administered as desvenlafaxine succinate, a new serotonin-norepinephrine reuptake inhibitor, is not expected to have an impact on activity of CYP2D6. This single-center, randomized, open-label, four-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/day, twice the recommended therapeutic dose for major depressive disorder in the United States) and duloxetine (30 mg b.i.d.) on the pharmacokinetics (PK) of a single dose of desipramine (50 mg). A single dose of desipramine was given first to assess its PK. Desvenlafaxine or duloxetine was then administered, in a crossover design, so that steady-state levels were achieved; a single dose of desipramine was then coadministered. The geometric least-square mean ratios (coadministration versus desipramine alone) for area under the plasma concentration versus time curve (AUC) and peak plasma concentrations (C(max)) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and C(max) of desipramine associated with duloxetine administration (122 and 63%, respectively) were significantly greater than those associated with desvenlafaxine (22 and 19%, respectively; P < 0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine C(max) that was significant compared with the small increase seen with desvenlafaxine and desipramine (-24 versus 9%; P < 0.001); the difference between changes in 2-hydroxydesipramine AUC did not reach statistical significance (P = 0.054). Overall, desvenlafaxine had a minimal impact on the PK of desipramine compared with duloxetine, suggesting a lower risk for CYP2D6-mediated drug interactions.

Effect of an ATP-sensitive potassium channel opener in subjects with overactive bladder: a randomized, double-blind, placebo-controlled study (ZD0947IL/0004).

OBJECTIVES: Improvements over existing treatment standards in overactive bladder (OAB) may only be possible through the development of drugs acting via non-cholinergic pathways. This is the first clinical study to be reported in full for the use of a potassium channel opener in OAB. METHODS: This randomized, double-blind, placebo-controlled phase II study evaluated the efficacy and safety of ZD0947 (25mg/day for 12 weeks) in patients with OAB. The primary endpoint was mean volume voided per micturition per 24 hours. Key secondary endpoints were changes from baseline in mean numbers of micturition episodes (total, voluntary, and incontinent) per 24 hours. RESULTS: ZD0947 was not superior to placebo for the primary or secondary efficacy variables. The placebo-adjusted magnitude of effect for ZD0947 (approx. 4 mL) was less than the historic data for cholinergic antagonists (approx. 20 mL). Treatment was generally safe and well tolerated. CONCLUSIONS: The data for ZD0947 are disappointing. More studies are needed to advance the identification of novel, non-cholinergic therapies for OAB.