Aims The aim of this 13 week, randomized, parallel-group study was to evaluate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of low-dose intermittent oral methotrexate (LDMTX) in patients with psoriasis. Methods Twenty-four psoriatic patients (15 male and 9 female, aged 31-73 years) were given weekly doses of MTX doses of either 7.5 mg or 15 mg with each dose divided into three aliquots given at 12 h intervals. The pharmacokinetics of MTX were evaluated at weeks 1 and 13. Skin impairment was assessed using the PASIscoring system (The Psoriasis Area and Severity Index) at baseline and at weeks 5, 9 and 13 of therapy. Haematological and biochemistry tests were also performed at these times. Results The comparison of the areas under the plasma concentration-time curve (AUC MTX ) after the first and third weekly doses showed that the extent of MTX accumulation in plasma was only about 12%. Two-way ANOVA (factors: subject and the week of therapy) on the log-transformed AUC MTX showed no effect of the week of therapy (P>0.8). Moreover, the intraindividual variability in the AUC MTX was at least 4-fold less than the interindividual variability (F-test; P<0.01). The steady-state total plasma clearance of MTX ranged from 5.0 to 18.2 l h x1 and was proportional to the renal clearance (r 2 =0.45, P<0.001) which accounted for 65t20% of the former. The renal clearance of 7-OHMTX was approximately 4-8% of that of the parent compound. PK/PD analysis revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady-state AUC MTX (r s =x0.65, P<0.001). Seventeen subjects (8 from the 7.5 mg group and 9 from the 15 mg group MTX, P=0.67) achieved a greater than 50% decrease in the initial PASI score and were classified as responders. Thirteen of 14 subjects with AUC(24,36 h)i700 nmol l x1 h responded to pharmacotherapy. Conversely, only 4 out of 10 subjects with AUC(24,36 h)<700 nmol l x1 h were responders (P<0.01, Fisher's exact test).Conclusions A strong correlation was observed between the pharmacokinetics (AUC MTX at the steady state) and antipsoriatic effect (PASI-score) of LDMTX. The considerable interindividual variability and low intraindividual variability in MTX pharmacokinetics support a role for therapeutic monitoring and dose individualization at the start of pharmacotherapy. The results of this study suggest that a steady state AUC MTX values of 700 nmol l x1 h and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values.

Alzheimer's disease (AD) is characterized by high heterogeneity in disease manifestation, progression and risk factors. High phenotypic variability is currently regarded as one of the largest hurdles in early diagnosis and in the design of clinical trials; there is therefore great interest in identifying factors driving variability that can be used for patient stratification. In addition to genetic and lifestyle factors, the individual's sex and gender are emerging as crucial drivers of phenotypic variability. Evidence exists on sex and gender differences in the rate of cognitive deterioration and brain atrophy, and in the effect of risk factors as well as in the patterns of diagnostic biomarkers. Such evidence might be of high relevance and requires attention in clinical practice and clinical trials. However, sex and gender differences are currently seldom appreciated; importantly, consideration of sex and gender differences is not currently a focus in the design and analysis of clinical trials for AD. The objective of this position paper is (i) to provide an overview of known sex and gender differences that might have implications for clinical practice, (ii) to identify the most important knowledge gaps in the field (with a special regard to clinical trials) and (iii) to provide conclusions for future studies. This scientific statement is endorsed by the European Academy of Neurology.

The relationship between MTX pharmacokinetics (AUC or erythrocytic MTX) and pharmacodynamics (PASI score) may exist. It is likely that the efficacy of psoriasis therapy with MTX could be improved by adjusting the dose according to plasma concentrations obtained after the first MTX administration.

IMPORTANCE Women represent two-thirds of patients with Alzheimer disease (AD), and sex differences might affect results of randomized clinical trials (RCTs). However, little information exists on differences in sex as reported in RCTs for AD.OBJECTIVE To assess the ratio of females to males and the reporting of sex-stratified data in large pharmaceutical RCTs for AD.DATA SOURCES A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, using ClinicalTrials.gov with the key word Alzheimer disease, and articles related to those trials were