Safety,Tolerability, Pharmacokinetics,and Pharmacodynamics of Recombinant Human Parathyroid Hormone (1–34) in Healthy Chinese Subjects

Background

The recombinant human parathyroid hormone (1–34) (rhPTH[1-34]) teriparatide is the first anabolic agent approved by the US Food and Drug Administration for the treatment of osteoporosis in men and women. This study was conducted to provide support for marketing authorization of an agent biosimilar to teriparatide in China.

Objective

The main aim of the present study was to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic parameters of rhPTH(1–34) after single and multiple subcutaneous doses in healthy Chinese subjects.

Methods

Two open-label, randomized, single-center, dose-escalation studies were performed. In study 1, subjects were randomized to receive a single dose of rhPTH(1–34) (10, 20, 30, 40, 50, or 60 μg) or a multiple dose of rhPTH(1–34) (10 and 20 μg once daily for 7 consecutive days) to determine the safety profile and tolerability, as reflected by the incidence, intensity, and seriousness of the observed adverse events. In study 2, a single dose of rhPTH(1–34) (10, 20, or 40 μg) and a multiple dose of rhPTH(1–34) (20 μg) were administrated subcutaneously to investigate the pharmacokinetic and pharmacodynamic parameters.

Results

Forty-two subjects completed study 1, and 30 subjects completed study 2. rhPTH(1–34) was well tolerated during the investigated single (10–60 μg) and multiple (10–20 μg once daily for 7 consecutive days) dose ranges. The most generally reported adverse events were erythema at the injection site and gastrointestinal reactions. After single and multiple subcutaneous administration of rhPTH(1–34), the drug was rapidly absorbed, with a T_max of 20 to 30 minutes, and rapidly cleared from the plasma, with a t_½ of 47.2 to 60.6 minutes. The mean C_max, AUC_0–t, and AUC_0–∞ increased in proportion to the doses, whereas the t_½, total clearance, and T_max values were independent of the administered dose. No significant differences in pharmacokinetic parameters were noted by sex except for T_max in the 10-μg and 20-μg single-dose groups. Compared with the baseline levels, no significant changes or dose-related significant effects were observed in serum calcium and phosphate levels.

Conclusions

All rhPTH(1–34) doses appeared to be well tolerated in the population studied. Linear pharmacokinetic characteristics were displayed in the dose range studied. Chinese ClinicalTrials.gov identifier: ChiCTR-ONC-12002874.     

Etamicastat,a Novel Dopamine β-Hydroxylase Inhibitor: Tolerability,Pharmacokinetics, and Pharmacodynamics in Patients With Hypertension

Background

Etamicastat is a dopamine β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure.

Objective

This study assessed the tolerability, pharmacokinetics, and pharmacodynamics of etamicastat in patients with arterial hypertension.

Methods

This randomized, double-blind, placebo-controlled study was conducted in male patients aged between 18 and 65 years with mild to moderate hypertension. Participants received once-daily doses of etamicastat 50, 100, or 200 mg or placebo for 10 days. Antihypertensive effect was assessed by 24-hour ambulatory blood pressure monitoring (ABPM).

Results

The study enrolled 23 male volunteers, with ages between 49 and 64 years. There were no serious adverse events reported. All adverse events were mild to moderate in intensity and resolved without sequelae. Etamicastat T_max was 1 hour postdose, and mean t_½ was 19 to 28 hours following repeated administration. Etamicastat underwent N-acetylation by N-acetyltransferase 2 (NAT2), forming the metabolite BIA 5-961. Following repeated administration, mean etamicastat AUC was 2- to 3-fold greater in poor acetylators than in rapid acetylators. Approximately 50% of the etamicastat dose was recovered in urine—30% as unchanged etamicastat and 20% as BIA 5-961. Dose-dependent decreases in systolic and diastolic blood pressure were observed after 10 days of treatment. The mean (95% CI) decreases versus placebo in nighttime SBP were statistically significant with all 3 etamicastat doses (50 mg, –11.66 mm Hg [–21.57 to –1.76; P < 0.05]; 100 mg, –14.92 mm Hg [–24.98 to –4.87; P < 0.01]; and 200 mg, –13.62 mm Hg [–22.29 to –3.95; P < 0.01]).

Conclusions

Etamicastat was well tolerated and showed a pharmacokinetic profile consistent with a once-daily regimen. NAT2 phenotype markedly affected the pharmacokinetics. The antihypertensive effect of etamicastat, assessed by 24-hour ABPM, was dose dependent up to 100 mg. The assessment of etamicastat as a novel antihypertensive therapy requires further study in broader populations. EudraCT trial registration 2008-002789-09.     

A Randomized Phase I Study Comparing the Pharmacokinetics of HD201, a Trastuzumab Biosimilar,With European Union–sourced Herceptin

Purpose

This first-in-human study of HD201 was designed to evaluate the pharmacokinetic (PK) equivalence between this biosimilar candidate and trastuzumab sourced in the European Union (EU-trastuzumab)*.

The STAR Study: A Real-World,International, Observational Study of the Safety and Tolerability of,and Adherence to,Serum-Free Subcutaneous Interferon β-1a in Patients With Relapsing Multiple Sclerosis

BackgroundAdverse reactions, particularly injection site reactions (ISRs), are common reasons for nonadherence to injectable multiple sclerosis (MS) treatments. Adherence to MS treatment is important to ensure good treatment outcomes.ObjectiveThe aim of this study was to assess the local tolerability of subcutaneous (SC) serum-free interferon (IFN) β-1a in patients with relapsing MS over 1 year in a real-life, international setting. The study also assessed safety, disease activity, and adherence.MethodsThis was a prospective, international, multicenter, observational study of 251 patients with relapsing-remitting MS treated with SC serum-free IFN β-1a 44 μg or 22 μg 3 times weekly for 12 months or until early discontinuation. The primary end point was the proportion of patients with ISRs. Secondary end points included proportion of patients with adverse events (AEs); annualized relapse rate (ARR); proportion of patients remaining relapse-free; and adherence to treatment.ResultsDuring the observation period, 27.5% (69 of 251) of patients experienced nonserious ISRs, which was consistent with the incidence reported in clinical studies. Five patients discontinued treatment and 2 patients suspended treatment because of ISRs. Mean age was 35.8 years; patients were predominantly white (94.8%), and two thirds (66.1%) were female. The overall incidence of AEs was 63.7% (160 of 251), and overall safety and tolerability were assessed as excellent, very good, or good in >85% of patients. More than 70% of patients remained relapse-free, and the mean ARR was 0.4. More than 90% of patients had very good or good adherence to treatment; a significantly greater proportion of these were relapse-free at 12 months compared with those with fair or poor adherence (77.6% vs 50.0%; P = 0.0107), and their ARR was significantly lower (0.3 vs 0.9; P = 0.0055). Patients with fair or poor adherence had 4.6 times higher odds of experiencing a relapse than those with very good or good adherence.ConclusionsThe incidence of ISRs and the overall safety profile in this observational study, in an international population in a real-life setting, confirm the good local tolerability of SC serum-free IFN β-1a reported in clinical studies. The association between good adherence and a lower ARR underlines the importance of good adherence. The good local and general tolerability of SC IFN β-1a may help ensure a high level of adherence, which is associated with better clinical outcomes. ClinicalTrials.gov identifier: NCT01080027.     

Pharmacokinetics and Pharmacodynamics of (+)-Primaquine and (?)-Primaquine Enantiomers in Rhesus Macaques (Macaca mulatta)

Primaquine (PQ) remains the sole available drug to prevent relapse of Plasmodium vivax malaria more than 60 years after licensure. While this drug was administered as a racemic mixture, prior studies suggested a pharmacodynamic advantage based on differential antirelapse activity and/or toxicities of its enantiomers. Oral primaquine enantiomers prepared using a novel, easily scalable method were given for 7 days to healthy rhesus macaques in a dose-rising fashion to evaluate their effects on the blood, liver, and kidneys. The enantiomers were then administered to Plasmodium cynomolgi-infected rhesus macaques at doses of 1.3 and 0.6 mg/kg of body weight/day in combination with chloroquine. The (−)-PQ enantiomer had higher clearance and apparent volume of distribution than did (+)-PQ and was more extensively converted to the carboxy metabolite. There is evidence for differential oxidative stress with a concentration-dependent rise in methemoglobin (MetHgb) with increasing doses of (+)-PQ greater than that seen for (−)-PQ. There was a marked, reversible hepatotoxicity in 2 of 3 animals dosed with (−)-PQ at 4.5 mg/kg. (−)-PQ in combination with chloroquine was successful in preventing P. cynomolgi disease relapse at doses of 0.6 and 1.3 mg/kg/day, while 1 of 2 animals receiving (+)-PQ at 0.6 mg/kg/day relapsed. While (−)-PQ was also associated with hepatotoxicity at higher doses as seen previously, this has not been identified as a clinical concern in humans during >60 years of use. Limited evidence for increased MetHgb generation with the (+) form in the rhesus macaque model suggests that it may be possible to improve the therapeutic window for hematologic toxicity in the clinic by separating primaquine into its enantiomers.     

Population Pharmacokinetics and Exposure–Response Analyses of Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease

PurposeUstekinumab, a fully human immunoglobulin G1κ monoclonal antibody that antagonizes human interleukin-12/23p40, is an effective therapy for several immune-mediated inflammatory diseases, including Crohn's disease (CD). This work characterizes the population pharmacokinetic (PK) and exposure–response (E-R) relationships of ustekinumab in patients with CD using data from four Phase IIb/III clinical studies.MethodsSerum ustekinumab concentration–time data from 1673 patients after IV and/or SC administration of ustekinumab were fitted simultaneously using nonlinear mixed effects modeling to develop a population PK model, which was subsequently used to evaluate simulation scenarios. Logistic regression E-R models were used to assess relationships between serum ustekinumab concentrations and clinical remission after induction (n = 1910) and maintenance (n = 387) treatment.FindingsUstekinumab PK properties are well described by a two-compartment model with first-order absorption and elimination. Typical values of PK parameters for a 70-kg patient were: clearance, 0.192 L/d; volume of distribution at steady state, 4.62 L; and intercompartmental clearance, 0.287 L/d. Ustekinumab terminal elimination t_1/2 was 19 days, and bioavailability after SC administration was 78.3%. Ustekinumab clearance was not affected by coadministration of immunosuppressive agents or corticosteroids. Body weight, serum albumin, and C-reactive protein (CRP) concentrations, tumor necrosis factor (TNF) antagonist failure status, sex, race (Asian vs non-Asian), and anti-ustekinumab antibody status significantly affected ustekinumab disposition; however, the effects of these covariates on ustekinumab exposure were not clinically relevant. The population PK model predicts that a milligram/kilogram dosing approach will result in lower ustekinumab exposure in patients with lower body weight. A positive E-R relationship was established between ustekinumab concentration and efficacy outcomes. The treatment effect of ustekinumab after induction therapy was more pronounced among patients with higher baseline CRP concentrations relative to those with lower values.ImplicationsIn patients with CD, ustekinumab disposition after IV and SC administration was biexponential and consistent with those in patients with ulcerative colitis. Prior treatment with TNF antagonists or the concomitant use of immunosuppressive agents or corticosteroids had no effect on ustekinumab disposition. None of the covariates that affected ustekinumab clearance had a clinically meaningful impact on ustekinumab exposure. E-R models support recommended posology of ustekinumab in adults with CD; however, an ～6 mg/kg IV induction dose in pediatric patients with lower body weights may not provide exposure that matches that in adult patients. ClinicalTrials.gov identifiers: NCT00771667, NCT01369329, NCT01369342, and NCT01369355.     

Double-Blind,Randomized Study Evaluating the Glycemic and Anti-inflammatory Effects of Subcutaneous LY2189102, a Neutralizing IL-1β Antibody,in Patients With Type 2 Diabetes

OBJECTIVE

Inflammation is associated with pancreatic β-cell apoptosis and reduced insulin sensitivity. Literature suggests that interleukin (IL)-1β may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to determine the efficacy, safety, and tolerability of LY2189102, a neutralizing IL-1β antibody, in T2DM patients.

RESEARCH DESIGN AND METHODS

Phase II, randomized, double-blind, parallel, placebo-controlled study of subcutaneous LY2189102 (0.6, 18, and 180 mg) administered weekly for 12 weeks in T2DM patients on diet and exercise, with or without approved antidiabetic medications.

RESULTS

LY2189102 reduced HbA_1c at 12 weeks (adjusted mean differences versus placebo: −0.27, −0.38 and −0.25% for 0.6, 18 and 180 mg doses, respectively), and fasting glucose at multiple time points compared with placebo. LY2189102 also reduced postprandial glycemia, and inflammatory biomarkers, including hs-CRP and IL-6. LY2189102 was generally well tolerated.

CONCLUSIONS

Weekly subcutaneous LY2189102 for 12 weeks was well tolerated, modestly reduced HbA_1c and fasting glucose, and demonstrated significant anti-inflammatory effects in T2DM patients. Neutralizing IL-1β holds promise as a convenient adjuvant treatment for T2DM.Type 2 diabetes occurs when pancreatic β-cell function fails to compensate for insulin resistance (1,2). As the duration of diabetes increases, β-cell function progressively deteriorates, partly as a result of apoptotic cell death (3–5). Inflammation is associated with pancreatic β-cell apoptosis and reduced insulin sensitivity, supporting the notion that inflammation plays a key role in aggravating or even causing type 2 diabetes specifically or the metabolic syndrome generally (6). Interleukin (IL)-1β is an inflammatory mediator that may contribute to this pathophysiology. IL-1β expression has been observed in β-cells of patients with type 2 diabetes (7). Moreover, production and secretion of IL-1β from β-cells is induced by high glucose levels and inhibits the function and promotes the apoptosis of β-cells (7–10). The IL-1 receptor antagonist (IL-1ra) protects human β-cells from glucose-induced functional impairment (7) and apoptosis, and its expression is decreased in patients with type 2 diabetes (11).The hypothesis that blocking IL-1β activity could be therapeutic in type 2 diabetes was tested clinically with anakinra, a recombinant IL-1ra (12,13). Results from a proof-of-concept study indicated that anakinra modestly improved hemoglobin A_1c (HbA_1c) relative to placebo, reduced circulating inflammatory cytokines, and showed signs of improved β-cell secretory function after 13 weeks of daily subcutaneous dosing (13). Nine months after treatment completion, anakinra-treated patients continued to have improved proinsulin/insulin ratios and reduced inflammatory cytokines; anakinra responders required less exogenous insulin than did nonresponders (14). Clinical evaluation of a neutralizing IL-1β monoclonal antibody (XOMA 052) in type 2 diabetic patients showed similar results. XOMA 052 improved HbA_1c relative to placebo after a single intravenous infusion and after repeated subcutaneous dosing; improvements in fasting blood glucose and insulin sensitivity after subcutaneous dosing were also noted (15).Typically only a small percentage of cytokine receptors require engagement to activate downstream signaling pathways, and cytokines are typically labile proteins expressed at low concentrations. Because anakinra binds to the IL-1 receptor and has a short half-life (4–6 h) (16), it is unclear whether the modest nature of the response in type 2 diabetes was related to compound-specific properties or a reflection of the role of this cytokine pathway in the disease pathogenesis. Although XOMA 052 binds and neutralizes IL-1β directly and has a longer half-life, it was dosed in a limited number of subjects and for short duration. Further evaluation of the intervention in the IL-1β pathway in diabetes would help determine whether this approach could be a successful therapy.LY2189102 (LY) is a humanized monoclonal antibody (IgG4) that binds to IL-1β with high affinity (2.8 pmol/L) and neutralizes its activity. Previous clinical studies have evaluated its safety and pharmacokinetics, as well as its effects on signs and symptoms of rheumatoid arthritis ({"type":"clinical-trial","attrs":{"text":"NCT00380744","term_id":"NCT00380744"}}NCT00380744). This phase II study aimed to evaluate the efficacy, safety, and tolerability of LY in type 2 patients with diabetes treated with diet and exercise, with or without approved antidiabetic medications.     

Population Pharmacokinetics of Erlotinib in Patients With Non–small Cell Lung Cancer: Its Application for Individualized Dosing Regimens in Older Patients

PurposeErlotinib is an oral first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for non–small cell lung cancers (NSCLC) with EGFR-activating mutations. Older patients experience more toxicities compared with younger patients at the standard recommended dose of 150 mg once daily. The aims of this study were to describe the pharmacokinetic profile of erlotinib in unselected patients with NSCLC, to quantify and explain its variability, to challenge the standard recommended dose in older patients, and to propose clinical recommendations for the therapeutic management of patients taking erlotinib.Methods: A population pharmacokinetic model was developed using erlotinib plasma concentrations collected from patients with NSCLC participating in a routine therapeutic drug monitoring program (with the nonlinear mixed effect modeling program NONMEM). Relevant demographic characteristics, clinical factors, and co-medications were tested as potential covariates. An independent dataset was used for model validation. Simulations based on the final model allowed comparison of expected erlotinib concentrations under standard and alternative dosing regimens for smokers and for several age groups.FindingsA total of 481 erlotinib plasma concentrations from 91 patients with NSCLC were used for model building and 239 plasma drug concentrations from 107 patients for model validation. A one-compartment model with first-order absorption and elimination provided the best fit. Average erlotinib CL/F with interindividual variability (%CV) was 3.8 L/h (41.5%), and V/F was 166 L (53.8%). The absorption rate constant was 1.48 h⁻¹. The external validation showed a negligible bias of −4% (95% CI, −7 to −1) in the individual predictions, with a precision of 23%. Current smoking and use of proton pump inhibitors were associated with higher CL/F, whereas age was associated with lower CL/F. Simulations suggest that a lower dose in older patients would decrease the risk of overexposure.ImplicationsThis large cohort study confirms the substantial interindividual variability in erlotinib plasma exposure and the impact of smoking and proton pump inhibitor intake. This large variability in erlotinib pharmacokinetics indicates that the standard recommended dose of 150 mg once daily is likely not appropriate to reach the expected concentrations in each patient. Concentration monitoring should be performed to individually adjust the erlotinib dosing regimen. The observed decrease in erlotinib CL/F with age suggests that a lower starting daily dose of 100 mg with concentration-guided dose adjustment would prevent overexposure and potential toxicity in older frail patients with co-morbidities.     

Potential Drug–Drug Interactions with Combination Volasertib + Itraconazole: A Phase I,Fixed-sequence Study in Patients with Solid Tumors

PurposeThis drug–drug interaction study determined whether the metabolism and distribution of the Polo-like kinase 1 inhibitor, volasertib, is affected by co-administration of the P-glycoprotein and cytochrome P-450 3A4 inhibitor, itraconazole.MethodsThis was an uncontrolled, open-label, fixed-sequence trial of two 21-day treatment cycles in patients with various solid tumors. In cycle 1 (test), eligible patients were administered volasertib (day 1) plus itraconazole (days −3 to 15). In cycle 2 (reference), patients received volasertib monotherapy. The primary end point was the influence of co-administration of itraconazole on the pharmacokinetic profile (AUC_0–tz; C_max) of volasertib and its main metabolite, CD 10899, compared with that of volasertib monotherapy. Other end points included tolerability and preliminary therapeutic efficacy.FindingsConcurrent administration of itraconazole resulted in a slight reduction in the AUC_0–tz (geometric mean ratio, 93.6%; 90% CI, 82.1%–106.8%) and a 20% reduction in C_max (geometric mean ratio, 79.4%; 90% CI, 64.9%–97.1%) of volasertib compared with monotherapy. Of note, concurrent administration of itraconazole + volasertib had no effect on the AUC_0–∞ of volasertib. More patients reported at least one drug-related adverse event in cycle 1 than in cycle 2 (75% vs 71%). The most commonly reported drug-related adverse events (cycles 1 and 2) were thrombocytopenia (68% and 33%, respectively), leukopenia (50% and 46%), and anemia (36% and 33%). No objective responses were observed. Stable disease was observed in 25 of 28 patients (89%).ImplicationsWhile there was no clear evidence of a pharmacokinetic interaction between volasertib and itraconazole, co-administration reduced the tolerability of volasertib. Clinicaltrials.gov identifier: NCT01772563.     

Efficacy and Tolerability Exposure–Response Relationship of Retigabine (Ezogabine) Immediate-Release Tablets in Patients With Partial-Onset Seizures

Background

Retigabine (international nonproprietary name)/ezogabine (United States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (K_v7) potassium channel activity.

Objectives

The aim of this study was to explore the relationship between retigabine/ezogabine systemic exposure and efficacy and adverse events (AEs) of retigabine/ezogabine from Phase III clinical trials.

Methods

Data were combined from Studies 301 and 302, which were both randomized, double-blind, placebo-controlled, multicenter, parallel-group studies with similar inclusion and exclusion criteria. All patients had partial-onset seizures and were receiving 1 to 3 concomitant AEDs. Systemic exposure was predicted for each patient as the average steady-state AUC_0–τ during the 12-week maintenance phase, based on a population pharmacokinetic model developed for retigabine/ezogabine. Efficacy end points included reduction in total partial-seizure frequency from baseline and probability of ≥50% reduction from baseline in seizure frequency. The probabilities of occurrence of 6 AEs were also evaluated.

Results

AUC_0–τ values increased linearly over the 600- to 1200-mg/d dose range. Over the entire AUC_0–τ range, the probability of efficacy was greater than that for any AE. The slopes of the exposure–response relationship for probability of dizziness and abnormal coordination were similar to that for efficacy, whereas the slopes for dysarthria, somnolence, tremor, and blurred vision were shallower, indicating that the probability of these events occurring was less affected than the probability of efficacy by increases in retigabine/ezogabine AUC_0–τ.

Conclusions

Based on the summary statistics of pharmacokinetic parameters, systemic exposure to retigabine/ezogabine increased linearly with dose (600–1200 mg/d). Population pharmacokinetics and pharmacodynamics showed that the probability of efficacy and AEs increased with increasing systemic retigabine/ezogabine exposure, and the probability of efficacy was higher than the probability of any of the AEs. The 35%–50% between-patient variability and overlap between retigabine/ezogabine dose levels in AUC_0-τ values indicate that, as with other AEDs, doses should be individually titrated based on a balance between efficacy and tolerability.     

Real-life Performance of Edoxaban in Elderly Patients With Atrial Fibrillation: a Multicenter Propensity Score–Matched Cohort Study

PurposeThe purpose of the current study was to compare the efficacy and safety of edoxaban versus vitamin K antagonist (VKA) therapy among a cohort of elderly patients (ie, those aged ≥75 years) with atrial fibrillation (AF) in a real-life setting.MethodsA propensity score–matched cohort observational study was performed comparing the safety and efficacy of edoxaban versus VKA therapy among a cohort of elderly (aged ≥75 years) patients with AF in a real-life setting. Follow-up data were obtained through outpatient visits at 1, 3, and every 6 months. The primary safety outcome was major bleeding. The primary efficacy outcome was the composite of stroke, transient ischemic attack, and systemic embolism.FindingsA total of 130 patients receiving edoxaban 60 mg (EDO) treatment were compared with the same number of VKA recipients. The mean follow-up was 16 (2.6) months. The cumulative incidence of thromboembolic events in the EDO and VKA groups was 1.5% (2 of 130) and 2.3% (3 of 130), respectively (P < 0.6). The cumulative incidence of major bleeding events was 1.5% (2 of 130) in the EDO group and 3.1% (4 of 130) in the VKA group (P < 0.4). The total anticoagulant therapy discontinuation rate was 2.3% (3 of 130) in the EDO group and 4.6% (6 of 130) in the VKA group (P < 0.3). A nonsignificant trend in improved adherence was observed between the EDO and VKA groups (81% vs 78%; P = 0.6).ImplicationsEdoxaban therapy showed a good real-life performance among elderly patients (aged ≥75 years) with AF.     

Patient- and Physical Therapist–Level Predictors of Patient-Reported Therapeutic Alliance: An Observational,Exploratory Study of Cohorts With Knee and Low Back Pain

ObjectiveTo identify patient- and physical therapist–level predictors for therapeutic alliance at the end of an episode of physical therapy for knee or low back pain (LBP).DesignSecondary analysis of observational cohort.SettingOutpatient physical therapy clinics.ParticipantsPatients receiving physical therapy for knee (n=189) or LBP (n=252) and physical therapists (n=19). Candidate predictor variables included demographics, patient clinical characteristics, and physical therapist attitudes and beliefs (Pain Attitudes and Beliefs Scale for Physical Therapists) and confidence in providing patient-centered care (Self-Efficacy in Patient-Centeredness Questionnaire).InterventionsNot applicable.Main Outcome MeasuresPatient-reported therapeutic alliance was measured using the 12-item Work Alliance Inventory–Short Revised (WAI-SR).ResultsFinal linear mixed models indicated different patient- and physical therapist–level factor contributions in predicting final WAI-SR scores across cohorts with knee and LBP. Female sex was a consistent patient-level predictor for both knee (estimated β=1.57, P<.05) and LBP (β=1.42, P<.05), with age (β=−0.07, P<.01) and baseline function (β=0.06, P<.01) contributing to cohorts with knee and LBP, respectively. Physical therapist–level predictors included female sex (β=6.04, P<.05), Pain Attitudes and Beliefs Scale for Physiotherapists behavioral (β=0.65, P<.01), and Self-Efficacy in Patient-Centeredness Questionnaire (SEPCQ) Exploring Patient Perspective (β=−0.75, P<.01) subscale scores for LBP, with SEPCQ Sharing Information and Power subscale scores (β=0.56, P<.05) contributing to both cohorts with knee (β=0.56, P<.05) and LBP (β=0.74, P<.01). Random effects for patients nested within physical therapists were observed for both cohorts.ConclusionsThese findings provide preliminary evidence for inconsistent relationships among patient- and physical therapist–level factors and therapeutic alliance across cohorts with knee and LBP.     

Association of Metacognitive Beliefs,Obsessive Beliefs and Symptom Severity With Quality of Life in Obsessive–Compulsive Patients

The aim of this study was to evaluate the association of obsessive beliefs, obsessive–compulsive disorder severity and metacognitive beliefs to the quality of life in patients with obsessive–compulsive disorder (OCD). Sixty one adults with a principal diagnosis of OCD were recruited for the study. Participants were assessed by trained clinicians using an unstructured clinical interview, the Obsessive Beliefs Questionnaire, the Yale–Brown Obsessive–Compulsive Scale, the Metacognitive Beliefs Questionnaire and the WHO Quality of Life Questionnaire. Data were analyzed using Pearson's of correlation coefficients and multiple regression analyses. Findings indicate that obsessive beliefs, severity total OCD and metacognitive beliefs were associated with total quality of life scores. Regression analysis revealed that while OCD total severity explained 40.1% of the variance in total quality of life, obsessive beliefs (perfectionism/certainty domain) and metacognitions (cognitive self-consciousness and negative beliefs about thoughts in general) explained an additional 13.7%, 7.7% and 5.4% of the variance in QoL. Findings indicate that the metacognitive beliefs associated with OCD symptom severity are different from that associated with quality of life. The implications are that metacognitive therapy aimed at symptom reduction may not necessarily result in improved QoL in OCD patients.     

Drug–Drug Interactions of the Nonsteroidal Mineralocorticoid Receptor Antagonist Apararenone With Midazolam,Warfarin, and Digoxin: A Phase 1 Studies in Healthy Volunteers

PurposeTo characterize the clinical relevance of in vitro drug–drug interaction findings with apararenone (MT-3995), the effects of apararenone on the sensitive substrates of cytochrome P450 3A4 (midazolam) and 2C9 (warfarin), and P-glycoprotein (digoxin), were assessed through a series of studies conducted in healthy volunteers.MethodsThree studies were conducted in 56 healthy adults. Study 1 investigated the effects of the administration of apararenone with midazolam; apararenone was administered on days 2 (320 mg) and days 3–15 (20 mg/d), and midazolam 2 mg, on days 1 and 15. Study 2 investigated the effects of the administration of apararenone with warfarin; apararenone was administered on days 8–11 (40 mg/d) and days 12–27 (10 mg/d), and warfarin 25 mg, on days 1 and 21. Study 3 assessed the effects of the administration of apararenone with digoxin; apararenone was administered on days 11 (160 mg) and days 12–28 (10 mg/d), and digoxin 0.5 mg, on days 1 and 24. Pharmacokinetic parameters included C_max, AUC_0–t, and AUC_0–∞. The safety profile was evaluated based on adverse events from spontaneous reports and clinical findings.FindingsAfter the administration of midazolam together with apararenone, compared with midazolam alone, the midazolam ± apararenone treatment ratios (90% CIs) of the geometric least squares (LS) mean C_max, AUC_0–t, and AUC_0–∞ values were 1.263 (1.147–1.392), 1.342 (1.220–1.477), and 1.370 (1.225–1.534), respectively. After the administration of warfarin ± apararenone, the R-warfarin ± apararenone treatment ratios (90% CIs) of the geometric LS mean C_max, AUC_0–t, and AUC_0–∞ values were 1.008 (0.934–1.089), 1.078 (1.029–1.129), and 1.110 (1.056–1.166). Corresponding values for S-warfarin were 1.025 (0.941–1.117), 1.024 (0.979–1.071), and 1.031 (0.984–1.080). After the administration of digoxin ± apararenone, the digoxin ± apararenone treatment ratios (90% CIs) of the geometric LS mean C_max, AUC_0–t, and AUC_0–∞ values were 0.929 (0.789–1.093), 0.894 (0.797–1.033), and 0.887 (0.805–0.977), respectively. Treatment-emergent adverse events were generally of mild to moderate intensity, and no serious adverse events of any kind were reported.ImplicationsThe findings from this analysis of data from healthy volunteers suggest minimal risk for potential drug–drug interactions between apararenone and other drugs that are likely to be used concurrently in patients. ClinicalTrials.gov identifier: NCT02531568.