Introduction:This study explored the safety and tolerability features of donanemab (LY3002813) in patients with mild cognitive impairment due to Alzheimer's disease (AD) or mild to moderate AD dementia.Methods: Patients with AD were enrolled into the single-ascending dose phase and were administered a single, intravenous (IV) dose of donanemab (five dosing cohorts from 0.1 to 10 mg/kg) or placebo followed by a 12-week follow-up period for each dose level. After the follow-up period, the same patients proceeded into the multiple-ascending dose (MAD) phase (five cohorts) and were administered IV doses of donanemab (0.3 to 10 mg/kg) or placebo approximately once per month for up to four doses depending on the initial doses (only cohort 1 went from 0.1 mg/kg to a higher dose of 0.3 mg/kg during the MAD phase). This phase concluded with a 12-week followup period. The relative exposure assessment of an unblinded, single, subcutaneous 3-mg/kg dose of donanemab in patients with AD was also performed, followed by a 12week follow-up period. One cohort of healthy subjects received an unblinded, single, IV 1-mg/kg dose of donanemab. These two cohorts did not continue to the MAD phase.Results: Donanemab was generally well tolerated up to 10 mg/kg. After single-dose administration from 0.1 to 3.0 mg/kg, the mean terminal elimination half-life was ≈4 days, increasing to ≈10 days at 10 mg/kg. Only the 10-mg/kg dose showed changes in amyloid positron emission tomography. Amyloid reduction of 40% to 50% was achieved. Approximately 90% of subjects developed anti-drug antibodies at 3 months after a single intravenous dose.Discussion: Intravenous donanemab 10 mg/kg can reduce amyloid deposits in AD despite having a shorter than expected half-life.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTObservations from clinical studies have demonstrated that:• CYP2C19 genotype does not have a clinically relevant effect on active metabolite concentrations or platelet inhibition in prasugrel-treated subjects.• Variability of response to clopidogrel is related to the presence of reduced function CYP2C19 alleles.• Lower concentrations of clopidogrel active metabolite and reduced platelet inhibition lead to increased adverse cardiovascular events in patients with acute coronary syndromes. WHAT THIS STUDY ADDS• Observations from previous studies related to the effect of CYP2C19 genotype on plasma drug exposure and platelet response to prasugrel and clopidogrel are confirmed in this prospectively-stratified, randomized, crossover, genetic study in healthy Chinese subjects.• In this study, healthy subjects receiving prasugrel had higher exposure to its active metabolite and greater pharmacodynamic responses (inhibition of platelet aggregation) compared with clopidogrel treated subjects, regardless of CYP2C19-predicted phenotype group.• The exposure to the active metabolite of clopidogrel was lower in CYP2C19 IM compared with RM, and in CYP2C19 PM compared with IM. The inhibition of platelet aggregation was lowest in clopidogrel treated CYP2C19 PM subjects. AIMSThis open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel. METHODSNinety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)]. RESULTSPras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P < 0.001). CONCLUSIONSPrasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clop...

Aim This U.S. multicenter open-label study used a noninferiority trial design to assess the efficacy of tadalafil 20 mg to treat erectile dysfunction (ED) in the black American and Hispanic groups compared with a reference group of Caucasians. A secondary objective was to demonstrate the efficacy and safety of tadalafil 20 mg in various populations of men with ED. Methods A total of 1,911 patients with ED were enrolled into eight predefined groups: (1–3) Caucasian (Reference group), Black American, or Hispanic patients, ≤65 years of age with no diabetes mellitus or depression; (4) patients with depression, ≤65 years of age, no diabetes; (5) patients with diabetes, ≤65 years of age, no depression; (6) patients &gt;65 years of age, no diabetes or depression; (7) patients who met enrollment criteria but were not included in any other group; and (8) patients with ED due to traumatic spinal cord injury. The study had a 4-week run-in period, followed by a 12-week treatment period with tadalafil taken as needed, up to one dose/day, prior to sexual activity. Change from baseline to endpoint in the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF) was used to determine noninferiority of groups 2 and 3 from group 1. Secondary efficacy measures included other IIEF domains and Sexual Encounter Profile (SEP). Results Noninferiority analyses based on the EF domain score showed that tadalafil was as efficacious in the Hispanic and Black American groups as in the Reference group. Patients in each of the eight groups had a significant change from baseline (P &lt; 0.001) in the IIEF EF domain score and positive responses to SEP Questions 1–5. The most common treatment-emergent adverse events reported by patients in all eight groups were headache, nasal congestion, dyspepsia, flushing, and back pain. Conclusion Tadalafil 20 mg was as efficacious in the Hispanic and black American groups as in the Caucasian/Reference group. Tadalafil was efficacious and well tolerated in each of the groups studied in this trial.

No abstract

No abstract