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BackgroundMigraine clinical profile may change with age, making it necessary to verify that migraine treatments are equally safe and effective in older patients. These analyses evaluated the effects of patient age on the pharmacokinetics (PK), efficacy, and safety of galcanezumab for prevention of migraine.MethodsAnalyses included efficacy data from three double-blind phase 3 clinical trials: two 6-month studies in episodic migraine (EVOLVE-1, EVOLVE-2: N = 1773) and one 3-month study in chronic migraine (REGAIN:N = 1113). Patients were randomized 2:1:1 to placebo, galcanezumab 120 mg, or galcanezumab 240 mg. Safety and PK data included additional phase 2 and phase 3 trials for a larger sample size of patients > 60 years (range = 18–65 for all studies). Subgroup analyses assessed efficacy measures, adverse event (AE) occurrence, and cardiovascular measurement changes by patient age group. Galcanezumab PK were evaluated using a population analysis approach, where age was examined as a potential covariate on apparent clearance (CL/F) and apparent volume of distribution (V/F) of galcanezumab.ResultsNumbers of baseline monthly migraine headache days were similar across age groups. There were no statistically significant treatment-by-age group interactions for any efficacy measures, except in episodic migraine studies where older patients appeared to have a larger reduction than younger patients in the number of monthly migraine headache days with acute medication use. Age (18–65) had a minimal effect on CL/F, and no effect on V/F. Galcanezumab-treated patients ≥60 years experienced no clinically meaningful increases in blood pressure and no increased frequency in treatment-emergent AEs, discontinuations due to AEs, serious adverse events (SAEs) overall, or cardiovascular SAEs, compared to age-matched placebo-treated patients.ConclusionsAge (up to 65 years) does not affect efficacy in migraine prevention and has no clinically meaningful influence on galcanezumab PK to warrant dose adjustment. Furthermore, older galcanezumab-treated patients experienced no increases in frequency of AEs or increases in blood pressure compared with age-matched placebo-treated patients.Trial registrationsEVOLVE-1 (NCT02614183, registered 23 November 2015), EVOLVE-2 (NCT02614196, 23 November 2015), REGAIN (NCT02614261, 23 November 2015), ART-01 (NCT01625988, 20 June 2012, ), I5Q-MC-CGAB (NCT02163993, 12 June 2014, ), I5Q-MC-CGAJ (NCT02614287, 23 November 2015, ), all retrospectively registered.

Background and Aims The pharmacokinetics (PK) and single-dose tolerability of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist being developed for once-weekly treatment of type 2 diabetes (T2D), weight management, and nonalcoholic steatohepatitis, was evaluated in subjects with renal impairment versus healthy subjects with normal renal function. Methods Forty-five subjects, categorized by baseline renal status, i.e. mild ( n  = 8, estimated glomerular filtration rate [eGFR] 60–89 mL/min/1.73m 2 ), moderate ( n  = 8, eGFR 30–59 mL/min/1.73m 2 ), severe renal impairment ( n  = 7, eGFR < 30 mL/min/1.73m 2 ), end-stage renal disease requiring dialysis ( n  = 8), and normal renal function ( n  = 14, eGFR ≥ 90 mL/min/1.73m 2 ), received a single subcutaneous dose of tirzepatide 5 mg. Tirzepatide plasma concentrations up to 648 h postdose were measured to compute PK parameters. The primary analysis evaluated the ratios of area under the plasma concentration–time curves (AUCs) and maximum plasma drug concentration ( C max ) of renal impairment versus the normal renal function group (90% confidence interval [CI]). In addition, the relationship between PK parameters and continuous variables of renal function was assessed by linear regression. Results Tirzepatide exposure was similar across renal impairment groups and healthy subjects. The 90% CI of ratios of AUCs and C max comparing each renal impairment group versus normal renal function spanned unity, except for a 25–29% increase in AUCs in the moderate renal impairment group. There was no significant relationship between tirzepatide exposure and eGFR. Few adverse events were reported across the renal impairment and normal renal function groups. The majority were mild in severity and of a gastrointestinal nature in the renal impairment groups. Conclusion There were no clinically relevant effects of renal impairment on tirzepatide PK. Dose adjustment may not be required for patients with renal impairment. Clinical Trial Registration ClinicalTrials.gov NCT03482024.

Background and Objective Tirzepatide, a novel, once-weekly, dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US as a treatment for type 2 diabetes and is under development for long-term weight management, heart failure with preserved ejection fraction, and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics and tolerability of tirzepatide in participants with hepatic impairment (with or without type 2 diabetes) versus healthy participants with normal hepatic function. Methods Participants in this parallel, single-dose, open-label study were categorized by hepatic impairment defined by the baseline Child-Pugh (CP) score A (mild impairment; n = 6), B (moderate impairment; n = 6), or C (severe impairment; n = 7) or normal hepatic function ( n = 13). All participants received a single subcutaneous 5-mg dose of tirzepatide. Blood samples were collected to determine tirzepatide plasma concentrations to estimate pharmacokinetic parameters. The primary pharmacokinetic parameters of area under the drug concentration–time curve from zero to infinity (AUC 0–∞ ) and maximum observed drug concentration ( C max ) were evaluated using an analysis of covariance. The geometric least-squares means (LSM) and mean ratios for each group, between control and hepatic impairment levels, and the corresponding 90% confidence intervals (CIs) were estimated. The analysis of the time to maximum observed drug concentration was based on a nonparametric method. The relationships between the pharmacokinetic parameters and CP classification parameters (serum albumin level, total bilirubin level, and international normalized ratio) were also assessed. Adverse events were monitored to assess safety and tolerability. Results Tirzepatide exposure, based on AUC 0–∞ and C max , was similar across the control and hepatic impairment groups. Statistical analysis showed no difference in the geometric LSM AUC 0–∞ or C max between participants in the control group and the hepatic impairment groups, with the 90% CI for the ratios of geometric LSM spanning unity (AUC 0–∞ ratio of geometric LSM vs control [90% CI 1.08 [0.879, 1.32], 0.960 [0.790, 1.17], and 0.852 [0.699, 1.04] and C max ratio of geometric LSM vs control [90% CI]: 0.916 [0.726, 1.16], 1.00 [0.802, 1.25], and 0.972 [0.784, 1.21] for mild, moderate and severe hepatic impairment groups, respectively). There was no change in median time to C max of tirzepatide across all groups (time to C max median difference vs control [90% CI]: 0 [− 4.00, 12.00], 0 [− 12.00, 12.00], and 0 [− 11.83, 4.17], respectively). There was no significant relationship between the exposure of tirzepatide and the CP score ( p > 0.1 for AUC 0–∞ , C max , and apparent total body clearance). Similarly, there was no clinically relevant relationship between the exposure of tirzepatide and serum albumin level, total bilirubin level, or international normalized ratio. The geometric LSM half-life values were also similar across the control and hepatic impairment groups. No notable differences in safety profiles were observed between participants with hepatic impairment and healthy control participants. Conclusions Tirzepatide pharmacokinetics was similar in participants with varying degrees of hepatic impairment compared with healthy participants. Thus, people with hepatic impairment treated with tirzepatide may not require dose adjustments. Clinical Trial Registration ClinicalTrials.gov identifier number NCT03940742.

SummaryBackground Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti–CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non–weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non–weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4–6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non–weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov IDNCT01346358 (Registration Date: May 3, 2011).

Background Duloxetine, a selective serotonin (5-hydroxytryptamine) and norepinephrine reuptake inhibitor, has been approved since 2004 for the treatment of adults with major depressive disorder (MDD). It is currently not approved for use in pediatric patients (aged <18 years) with MDD. The clinical development program for duloxetine in the pediatric MDD population, which consisted of three clinical studies, provided extensive data on the safety, tolerability, and pharmacokinetics of duloxetine across a wide dose range in pediatric patients of differing ages, sex, body weights, and sexual maturation. Objectives The objectives were to characterize the pharmacokinetics of duloxetine based on population modeling following daily oral administration in children and adolescents aged 7–17 years diagnosed with MDD; to estimate the magnitude of between- and within-patient variability; to identify potential patient factors affecting duloxetine pharmacokinetics, and to compare duloxetine pharmacokinetics in the pediatric population with those characterized in adults. Methods The analyses meta-dataset was created from pharmacokinetic and demographic data available from one phase II (open-label) and two phase III (randomized, double-blind) clinical trials of duloxetine in children and adolescents. Patients received 20–120 mg of oral duloxetine once daily. Duloxetine concentrations (a total of 1,581 concentrations) were obtained from 428 patients: 34 % were children (aged 7–11 years) and 66 % were adolescents (aged 12–18 years). Population modeling analyses were performed using nonlinear mixed-effects modeling and the first-order conditional estimation method with interaction. Patient factors were assessed for their potential influence on duloxetine apparent clearance (CL/ F ) and apparent volume of distribution ( V d / F ). Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the pediatric population were compared with those in adults. Results Duloxetine pharmacokinetics in pediatric patients was described by a one-compartmental model. Typical values of CL/ F , V d / F , and half-life ( t 1/2 ) at 60 mg/day of duloxetine were 79.7 L/h, 1,200 L, and 10.4 h, respectively. The between-patient variability in CL/ F and V d / F was 68 and 87 %, respectively, while within-patient variability was 57 % (proportional error) and 2.04 ng/mL (additive error). Body surface area (BSA), dose, and race had a statistically significant effect on duloxetine pharmacokinetics. With a 2.2-fold increase in BSA, the CL/ F increased about twofold. A sixfold increase in dose (20 to 120 mg) decreased CL/ F by 32 %. In American Indian patients, V d / F was 131 % higher than the other races combined. Age, sex, body mass index, serum creatinine, cytochrome P450 2D6 predicted phenotype, and menarche status did not have a statistically significant effect. Estimates of CL/ F and V d / F were higher in the pediatric population than in adults; subsequently, the average steady-state duloxetine concentration was approximately 30 % lower in the pediatric population than in adults. Conclusions Duloxetine pharmacokinetics was similar in children and adolescents with MDD. The statistically significant effects of dose, BSA, and race on duloxetine pharmacokinetics in pediatric patients did not appear to be clinically meaningful. At a given dose, the typical steady-state duloxetine concentrations in the pediatric population were lower than in adults, and the distribution of steady-state duloxetine concentrations in pediatric patients were typically in the lower range of concentrations in adults.

Objective: To determine whether duloxetine is a substrate, inhibitor or inducer of cytochrome P450 (CYP) 1A2 enzyme, using in vitro and in vivo studies in humans. Methods: Human liver microsomes or cells with expressed CYP enzymes and specific CYP inhibitors were used to identify which CYP enzymes catalyse the initial oxidation steps in the metabolism of duloxetine. The potential of duloxetine to inhibit CYP1A2 activity was determined using incubations with human liver microsomes and phenacetin, the CYP1A2 substrate. The potential for duloxetine to induce CYP1A2 activity was determined using human primary hepatocytes treated with duloxetine for 72 hours. Studies in humans were conducted using fluvoxamine, a potent CYP1A2 inhibitor, and theophylline, a CYP1A2 substrate, as probes. The subjects were healthy men and women aged 18–65 years. Single-dose duloxetine was administered either intravenously as a 10-mg infusion over 30 minutes or orally as a 60-mg dose in the presence or absence of steady-state fluvoxamine (100 mg orally once daily). Single-dose theophylline was given as 30-minute intravenous infusions of aminophylline 250 mg in the presence or absence of steady-state duloxetine (60 mg orally twice daily). Plasma concentrations of duloxetine, its metabolites and theophylline were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods and evaluated using mixed-effects ANOVA. Safety measurements included vital signs, clinical laboratory tests, a physical examination, ECG readings and adverse event reports. Results: The in vitro results indicated that duloxetine is metabolized by CYP1A2; however, duloxetine was predicted not to be an inhibitor or inducer of CYP1A2 in humans. Following oral administration in the presence of fluvoxamine, the duloxetine area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) and the maximum plasma drug concentration (C max ) significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In the presence of fluvoxamine, the oral bioavailability of duloxetine increased from 42.8% to 81.9%. In the presence of duloxetine, the theophylline AUC ∞ and C max increased by only 13% (90% CI 7, 18) and 7% (90% CI 2,14), respectively. Coadministration of duloxetine with fluvoxamine or theophylline did not result in any clinically important safety concerns, and these combinations were generally well tolerated. Conclusion: Duloxetine is metabolized primarily by CYP1A2; therefore, coadministration of duloxetine with potent CYP1A2 inhibitors should be avoided. Duloxetine does not seem to be a clinically significant inhibitor or inducer of CYP1A2; therefore, dose adjustment of CYP1A2 substrates may not be necessary when they are coadministered with duloxetine.

Objectives: The objectives of this analysis were to characterize the pharmacokinetics of duloxetine at steady state in patients, estimate the variability, identify significant covariates that may influence duloxetine pharmacokinetics and provide appropriate dosing recommendations for patients on duloxetine treatment. Methods: The pharmacokinetic meta-analysis dataset was created from one open-label clinical study and four double-blind, placebo-controlled clinical studies. Duloxetine concentrations (N = 2002) were obtained from 594 patients diagnosed with major depressive disorder (n = 223), diabetic peripheral neuropathic pain (n = 112), stress urinary incontinence (n = 128) and fibromyalgia (n = 131). Patients were given 20–60 mg/day of oral duloxetine once or twice daily (the highest dose studied was 120 mg/day). A population pharmacokinetic model was developed using a nonlinear mixed-effects modelling method. Covariates including bodyweight, age, sex, ethnicity, smoking status, disease condition, dose, dosing regimen and creatinine clearance were tested for their influence on duloxetine pharmacokinetics. The final model was used to predict steady-state duloxetine concentration-time profiles in various patient subgroups. Results: Duloxetine pharmacokinetics in patients were described by a one-compartmental pharmacokinetic model. The interpatient variability in apparent oral clearance (CL/F) was 59% and the interpatient variability in the apparent volume of distribution after oral administration (V d /F) was 97%. The residual error was 31%. Sex, smoking status, age and dose had a statistically significant effect on CL/F, whereas the V d /F was influenced by ethnicity. CL/F was 40% lower in females than in males and 30% lower in nonsmokers than in smokers. CL/F decreased with increasing dose and age. The V d /F in Hispanic patients was twice that of non-Hispanic patients. Simulations showed a considerable overlap in duloxetine exposure between the identified patient subgroups. Conclusion: Given the clinically insignificant change in the magnitude of duloxetine steady-state exposure and the considerable overlap in duloxetine exposure between the patient subgroups, specific dose recommendations based on sex, smoking status, age, dose and ethnicity are not warranted.

Combinations of olanzapine and carbamazepine are often used in clinical practice in the management of mania. To assess the efficacy and safety of olanzapine plus carbamazepine in mixed and manic bipolar episodes. Randomised, double-blind, 6-week trial of olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day; n=58) v. placebo plus carbamazepine (n=60) followed by open-label, 20-week olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day, n=86), with change in manic symptoms as main outcome measure. Safety and pharmacokinetics were also evaluated. There were no significant differences (baseline to endpoint) in efficacy measures between treatment groups, but at 6 weeks triglyceride levels were significantly higher (P=0.008) and potentially clinically significant weight gain (>or=7%) occurred more frequently (24.6% v. 3.4%, P=0.002) in the combined olanzapine and carbamazepine group. Carbamazepine reduced olanzapine concentrations but olanzapine had no effect on carbamazepine concentrations. The combination of olanzapine and carbamazepine did not have superior efficacy to carbamazepine alone. The increases in weight and triglycerides observed during combination treatment are a matter of concern.

Objective: Edivoxetine (LY2216684) is a selective and potent norepinephrine reuptake inhibitor (NERI). The pharmacokinetics (PK) and pharmacodynamics (PD) of edivoxetine were assessed in children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD) following single and once-daily oral doses of edivoxetine. Methods: During a phase 1 open-label safety, tolerability, and PK study, pediatric patients were administered edivoxetine at target doses of 0.05, 0.1, 0.2 and 0.3 mg/kg, and blood samples were collected to determine plasma concentrations of edivoxetine for PK assessments and plasma 3,4-dihydroxyphenylglycol (DHPG) concentrations for PD assessments. Edivoxetine plasma concentrations were measured using liquid chromatography with tandem mass spectrometric detection, and DHPG was measured using liquid chromatography with electrochemical detection. Results: Edivoxetine PK was comparable between children and adolescents. The time to maximum concentration (tmax) of edivoxetine was ∼2 hours, which was followed by a mono-exponential decline in plasma concentrations with a terminal elimination half-life (t1/2) of ∼6 hours. Dose-dependent increases in area under the edivoxetine plasma concentration versus time curve from zero to infinity (AUC0-∞) and maximum plasma concentration (Cmax) were observed, and there was no discernable difference in the apparent clearance (CL/F) or the apparent volume of distribution at steady state (Vss/F) across the dose range. In adolescents, edivoxetine caused a maximum decrease in plasma DHPG concentrations from baseline of ∼28%, most notably within 8 hours of edivoxetine administration. Conclusion: This initial study in pediatric patients with ADHD provides new information on the PK profile of edivoxetine, and exposures that decrease plasma DHPG consistent with the mechanism of action of a NERI. The PK and PD data inform edivoxetine pharmacology and can be used to develop comprehensive population PK and/or PK–PD models to guide dosing strategies.

Objective: The purpose of this study was to characterize duloxetine pharmacokinetics in the breast milk and plasma of lactating women and to estimate the duloxetine dose that an infant might consume if breastfed. Methods: This open-label study included six healthy women aged 22–35 years who stopped nursing during and after the study. Duloxetine 40 mg was given orally every 12 hours for 3.5 days; seven plasma and milk samples over 12 hours were obtained after the seventh dose. Plasma and milk samples were analysed using validated liquid chromatography-tandem mass spectrometry methods. Safety measures included vital signs, ECGs, laboratory tests, adverse event monitoring and depression rating scales. Results: The mean steady-state milk-to-plasma duloxetine exposure ratio was 0.25 (90% CI 0.18, 0.35). The amount of duloxetine in the breast milk was 7 μg/day (range 4–15 μg/day). The estimated infant dose was 2 μg/kg/day (range 0.6–3 μg/kg/day), which is 0.14% of the maternal dose. Dizziness, nausea and fatigue were commonly reported adverse events. No clinically important changes in safety measures occurred. Conclusion: Duloxetine is detected in breast milk, and steady-state concentrations in breast milk are about one-fourth of those in maternal plasma. As the safety of duloxetine in infants is unknown, prescribers should carefully assess, on an individual basis, the potential risks of duloxetine exposure to infants and the benefits of nursing an infant when the mother is on duloxetine therapy.