Efficacy and Safety of Calcifediol in Young Adults with Vitamin D Deficiency: A Phase I, Multicentre, Clinical Trial-POSCAL Study.

Vitamin D deficiency is highly prevalent, and recent evidence suggests a possible association between vitamin D deficiency and various health conditions. The aim of this study was to assess monthly calcifediol treatments for vitamin D deficiency (or biweekly, if the deficiency was severe) in a young adult population with no associated comorbidities. This multicentre phase I trial started with a four month open-label treatment phase (TP) that included 101 participants (65% women with mean age 29.8 years). Eighty-two percent of the subjects (79/96) achieved 25(OH)D levels within the target range (20-60 ng/mL) by the end of the TP, and they were subsequently randomised and subjected to a double-blind, placebo-controlled, five month follow-up phase (FP). At the end of the FP, 89% of participants maintained vitamin D levels of >20 ng/mL with calcifediol, versus 49% with placebo (p < 0.001). Subjects receiving monthly calcifediol during both phases (n = 32) maintained 25(OH)D levels >20 ng/mL, whereas those on the placebo during the FP (n = 38) exhibited deficiency levels of 25(OH)D by the end of the study. No clinically relevant changes in bone metabolism parameters or toxic 25(OH)D levels were observed, and no serious adverse events were reported throughout the study. Calcifediol is a safe and effective treatment for vitamin D deficiency in the young adult population, but long-term use may be required to sustain optimal 25(OH)D levels.

Influence of sex and CYP2D6 genotype on mirtazapine disposition, evaluated in Spanish healthy volunteers.

AIMS: To evaluate the influence of sex and CYP2D6 genotype on mirtazapine disposition within two bioequivalence studies in healthy volunteers. METHODS: Seventy-two healthy volunteers were included in two standard 2 x 2 crossover bioequivalence trials. Subjects received a single 30-mg oral dose of each mirtazapine formulation in each study period. Plasma concentrations were measured from 0 to 96 or 120 h by a HPLC with coupled mass spectrometry validated method. CYP2D6 genotyping was available for 68 subjects that were classified into three phenotypic groups depending on the number of active gene copies: extensive/ultrarapid metabolizers (UM-EM), intermediate (IM) and poor metabolizers (PM). To evaluate the influence of sex and genotype on mirtazapine disposition we performed a linear mixed model for repeated measures. Pharmacokinetic data were log-transformed and AUC and C(max) adjusted to the administered dose/weight. Factors included in the model were centre, formulation, period, sequence, sex and genotype as fixed effects, and subject nested sequence x sex x genotype as random one. A second model was also performed adding the interaction sex x genotype to the previous model. RESULTS: Mirtazapine disposition evaluated as AUC(0-infinity) is influenced by sex (p=0.007) and CYP2D6 phenotype group (p=0.01). Attending to the theoretical figures provided by the model, mean (95% CI) dose/weight adjusted AUC(0-infinity) (ng h/ml)/(mg/kg) is 1516.62 (1411.27-1628.22) in EM/UM, 1613.63 (1482.14-1758.55) in IM and 2049.28 (1779.78-2357.24) in PM. In the case of C(max) these figures also show a trend to higher values in PM, but it did not reach statistical significance. Females show a lower dose/weight adjusted AUC(0-infinity): 1594.39 (1477.70-1720.28) vs. 1837.65 (1694.67-1992.70). On the contrary dose/weight adjusted C(max) is higher in females than in males: 38.33 (34.79-42.28) vs. 32.66 (29.44-36.21). CONCLUSIONS: Both CYP2D6 genotype group and sex influence the disposition of mirtazapine in healthy volunteers and confirm reported data in the literature obtained by different methods. No sex-by-genotype interaction could be detected.